BRIEF RESEARCH REPORT
published: 30 June 2020
doi: 10.3389/fneur.2020.00536
Recurrent Fulminant Tumefactive
Demyelination With Marburg-Like
Features and Atypical Presentation:
Therapeutic Dilemmas and Review of
Literature
Aigli G. Vakrakou 1*, Dimitrios Tzanetakos 1 , Theodore Argyrakos 2 , Georgios Koutsis 1 ,
Maria-Eleptheria Evangelopoulos 1 , Elisabeth Andreadou 1 , Maria Anagnostouli 1 ,
Marianthi Breza 1 , John S. Tzartos 1 , Elias Gialafos 1 , Antonios N. Dimitrakopoulos 1 ,
Georgios Velonakis 3 , Panagiotis Toulas 3 , Leonidas Stefanis 1 and Constantinos Kilidireas 1
1
Edited by:
Maria Pia Amato,
University of Florence, Italy
Reviewed by:
Rocco Totaro,
San Salvatore Hospital, Italy
Mattia Fonderico,
University of Florence, Italy
*Correspondence:
Aigli G. Vakrakou
avakrakou@med.uoa.gr
Specialty section:
This article was submitted to
Multiple Sclerosis and
Neuroimmunology,
a section of the journal
Frontiers in Neurology
Received: 02 March 2020
Accepted: 14 May 2020
Published: 30 June 2020
Citation:
Vakrakou AG, Tzanetakos D,
Argyrakos T, Koutsis G,
Evangelopoulos M-E, Andreadou E,
Anagnostouli M, Breza M, Tzartos JS,
Gialafos E, Dimitrakopoulos AN,
Velonakis G, Toulas P, Stefanis L and
Kilidireas C (2020) Recurrent
Fulminant Tumefactive Demyelination
With Marburg-Like Features and
Atypical Presentation: Therapeutic
Dilemmas and Review of Literature.
Front. Neurol. 11:536.
doi: 10.3389/fneur.2020.00536
Frontiers in Neurology | www.frontiersin.org
Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Aeginition Hospital, National and
Kapodistrian University of Athens, Athens, Greece, 2 Department of Pathology, Evaggelismos Hospital, Athens, Greece,
3
Research Unit of Radiology, 2nd Department of Radiology, National and Kapodistrian University of Athens, Athens, Greece
Atypical forms of demyelinating diseases with tumor-like lesions and aggressive course
represent a diagnostic and therapeutic challenge for neurologists. Herein, we describe
a 50-year-old woman presenting with subacute onset of left hemiparesis, memory
difficulties and headache. Brain MRI revealed a tumefactive right frontal-parietal lesion
with perilesional edema, mass effect and homogenous post-contrast enhancement,
along with other small atypical lesions in the white-matter. Brain biopsy of cerebral
lesion ruled out lymphoma or any other neoplastic process and patient placed on
corticosteroids with complete clinical/radiological remission. Two years after disease
initiation, there was disease exacerbation with reappearance of the tumor-like mass.
The patient initially responded to high doses of corticosteroids but soon became
resistant. Plasma-exchange sessions were not able to limit disease burden. Resistance
to therapeutic efforts led to a second biopsy that showed perivascular demyelination,
predominantly consisting of macrophages, with a small number of T and B lymphocytes,
and the presence of reactive astrocytes, typical of Creutzfeldt-Peters cells. The patient
received high doses of cyclophosphamide with substantial clinical/radiological response
but relapsed after 7-intensive cycles. She received 4-weekly doses of rituximab with
disease exacerbation and brainstem involvement. She eventually died with complicated
pneumonia. We present a very rare case of recurrent tumefactive demyelinating lesions,
with atypical tumor-like characteristics, with initial response to corticosteroids and
cyclophosphamide, but subsequent development of drug-resistance and unexpected
exacerbation upon rituximab administration. Our clinical case raises therapeutic
dilemmas and points to the need for immediate and appropriate immunosuppression
in difficult to treat tumefactive CNS lesions with Marburg-like features.
Keywords: tumefactive multiple sclerosis, brain biopsy, rituximab, cyclophosphamide, marburg-variant
1
June 2020 | Volume 11 | Article 536
Vakrakou et al.
Tumefactive Demyelination With Marburg-Like Features
INTRODUCTION
autoimmune factors resulted negative. CSF analysis showed only
increased IgG index (0.617), the absence of oligoclonal bands,
and was negative for the detection of various common pathogens
among which JC virus (PCR). Brain biopsy of cerebral lesion
was performed and indicated the presence of foamy CD68positive macrophages (macrophage rich lesion, with absence
of expression of CD1a, Langerin, CD143, BRAFV600E, and S100 markers by the macrophage histiocytes), along with dense
perivascular presence of a variable numbers of T lymphocytes
and a small number of B cells (images not available). No reaction
with the antibody SV-40 that detects polyoma virus such as SV40, JK, BK etc. was observed. There was no histological evidence
of lymphoma or any other neoplastic process. The patient was
treated with high doses of dexamethasone and levetiracetam
(1,000 mg per day, initiated after brain biopsy by neurosurgeons),
with gradual substantial clinical (EDSS = 0), and radiological
remission (TDL lesion was not evident and only some T2hyperintense areas persisted). A follow up brain MRI, 1 year after,
also revealed resolution of the intraparenchymal mass lesion.
Two years after disease initiation, the patient experienced
memory deficits, mild disorientation in time and space, gait
instability and left upper extremity weakness, 15 days before her
admission to our hospital. Neurological examination showed
left hemiparesis. Brain MRI imaging revealed reappearance of a
tumor-like mass, in the same site as the initial presentation, with
a greater mass effect and strong contrast enhancement (almost
homogeneous) (Figure 1). Spine MRI was normal. Evaluation
of serological parameters, including AQ4 (Euroimmun,
Lübeck, Germany) and MOG abs (live cell-based assay), was
negative, except for the presence of serum monoclonal IgA
(k) type paraprotein (11). Bone marrow examination revealed
findings compatible with MGUS (less that ∼5% were CD138+
plasma cells).
The patient was placed initially on dexamethasone (12
mg/days) treatment due to the mass effect of lesion and
then was initiated on intravenously administered pulses of
Methylprednisolone (total 10.5 gr), followed by tapering with
oral methylprednisolone. The patient exhibited significant
clinical improvement along with partial radiological remission
of the tumefactive lesion, that showed significant reduction
in contrast enhancement. We considered that our patient
suffered an aggressive form of tumefactive demyelination,
with Marburg -like characteristics and decided to start her
on a cyclophosphamide protocol. Nevertheless, during routine
laboratory evaluation, we observed an asymptomatic elevation
of liver enzymes (AST, ALT). The patient was evaluated by a
gastroenterologist, underwent ultrasound imaging and placed
on ursodeoxycholic acid, considering that liver dysfunction was
associated with high doses of corticosteroids. Due to recurrence
of left hemiparesis, 3 months after the second clinical attack,
our patent received 750 mg Methylprednisolone and a low dose
of cyclophosphamide (500 mg), that led to further deterioration
of liver enzymes and no clinical response. At that time point a
magnetic resonance spectroscopy (MRS) study of the frontal lobe
lesion was performed, and was consistent with a demyelinating
central nervous disease {high choline (Cho)/creatine (Cr) = 6.4,
high Cho / N-acetylaspartate (NAA) = 2.57, high NAA/Cr =
Tumefactive demyelinating lesions (TDL), characterized by the
presence of large (>2 cm), tumor-like lesions in CNS with
perilesional edema, mass effect and/or broken ring-enhancement
on MRI imaging, require a careful differential diagnosis, mainly
ruling out an underlying tumor-mimicker (1, 2). The prevalence
of TDLs has been reported to be 1–2 per 1000 cases of
Multiple Sclerosis (3). Nevertheless, this prevalence has not
been replicated in all studies due to disease heterogenicity
and to the lack of appropriate registries in all countries,
with studies showing a range of prevalence between 1.4–
8.2% of Multiple Sclerosis patients (4). The demographics of
patients with tumefactive demyelinating lesions show a slight
preference of the disease to women than in men, and seems
to mostly affect patients in the third and fourth decade (4).
TDL may emerge during the disease course of Multiple Sclerosis
(MS) or even be its first clinical presentation (Tumefactive
MS) (2, 5). Interestingly, specific disease modifying drugs
(e.g., fingolimod) used in MS have been associated with the
appearance of TDL lesions, especially after drug-initiation or
cessation (6–8). Nevertheless, TDL could represent a unique
form of isolated atypical demyelinating disease, without classical
radiological MS features, presenting either as monophasic
disease (Monophasic TDL) or as recurrent TDL (Recurrent
TDL). Studies examining the pathology of TDL lesions have
shown tissue similarities with prototypical MS lesions, albeit
with the unique appearance of Creutzfeldt– Peters cells and
dystrophic astrocytes (9). A rare atypical demyelinating disease,
that shares radiological and pathological similarities with TDL
and MS, is the Marburg variant of MS (10). Marburg’s disease
course is considered to be monophasic, with poor response
to conventional acute treatments, leading soon to death. The
hallmark of Marburg’s pathology are highly destructive lesions
with extensive macrophage infiltration, massive demyelination,
and axonal injury with overt necrosis and cavitation (9).
CASE PRESENTATION
We describe a 50-year-old woman, with an unremarkable
past medical history, who presented with irritability, memory
difficulties, severe headache and mild difficulty in gait, 1-month
prior to her admission to hospital (hospitalization in another
Neurology Department). Her physical examination showed left
pyramidal tract signs, with a Babinski reflex on the left and
motor deficit of the left upper (4+/5 MRC) and lower limb
(5-/5 MRC). Magnetic resonance imaging (MRI) of the brain
revealed a tumefactive right frontal-parietal lesion (T2/FLAIR
hyperintense lesion), with perilesional edema, mass effect and
with homogenous post-contrast enhancement, along with other
small atypical lesions in the white matter (Figure 1). One of the
white matter lesions in the left fronto-parietal junction displayed
a ring-like appearance after gadolinium administration, whereas
multiple other lesions exhibited a patchy enhancement pattern
(Figure 1). Search for a primary neoplasm was negative (chest
and abdominal CT scan). An extensive serological workup
performed to exclude common infectious (including HIV) and
Frontiers in Neurology | www.frontiersin.org
2
June 2020 | Volume 11 | Article 536
Vakrakou et al.
Tumefactive Demyelination With Marburg-Like Features
FIGURE 1 | Brain MRI’s in chronological order showing the effect of various treatment modalities.
with mannitol and 6 gr of Methylprednisolone with modest
clinical improvement.
The extremely aggressive nature of the disease and the
resistance to intense therapeutic options prompted us to
reconsider the diagnosis and perform a second brain biopsy
(1 month after the 4th dose of Rituximab). Histopathologic
analysis revealed inflammatory demyelination particularly in
areas of perivascular cuffing, predominantly consisting of
CD68 macrophages (Figure 2). Parenchymal and to lesser
extent perivascular infiltrates composed of small number of T
lymphocytes, with relatively fewer B cells (Figure 2). Moreover,
we observed the presence of reactive astrocytes with concomitant
presence of nuclei with ’granular mitosis’, typical of CreutzfeldtPeters cells, frequently seen in tumefactive demyelinating
lesions. Again, both lymphoma and Progressive multifocal
leukoencephalopathy (PML) were excluded (Figure 2). The
possibility of “ghost lymphoma” (i.e., vanishing of primary
central nervous system diffuse large B cell lymphoma after steroid
1.4 ratio within the center of the lesion, presence of glutamic
acid, lactate, and lipids}. We decided to switch to less hepatotoxic
treatments, and therefore placed our patient on PLEX (plasma
exchange) sessions (n = 6). PLEX was unable to control the
disease burden and a new brain imaging showed an expansion
of the tumefactive lesion that involved more white matter
areas, with more pronounced insult of the centrum semiovale,
expansion to the left hemisphere, extensive invasion of the cortex
and more Gd (gadolinium)-enhancing areas (Figure 1). Taking
into consideration the published therapeutic effect of Rituximab
on TDL, we decided to continue our therapeutic efforts with
cycles of Rituximab (12–14). Our patient received 4 cycles of
Rituximab (600 mg every week for 1 month) and remained
clinically stable up till the third cycle. Disease exacerbation was
observed following the 4th dose of Rituximab with worsening
of hemiparesis and signs of intracranial hypertension (Figure 1).
Interestingly, our patient relapsed while the total number of
peripheral CD20 cells were 0. She received rescue therapy
Frontiers in Neurology | www.frontiersin.org
3
June 2020 | Volume 11 | Article 536
Vakrakou et al.
Tumefactive Demyelination With Marburg-Like Features
we placed our patient on high doses of cyclophosphamide (1
gr/m2, every 21 days), for the ensuing consecutive 7 months,
along with prophylactic antibiotics. Our patient responded in
a dramatic fashion to cyclophosphamide infusions, with initial
improvement of her clinical condition, and without manifesting
treatment) could not be excluded totally, but did not seem
plausible, especially since it was not observed in two different
biopsies of the patient (Figure 2).
Given that the patient’s liver enzymes returned to normal
values and the scenario of a CNS lymphoma seemed remote,
FIGURE 2 | Histopathological study of the tumefactive lesion showing active demyelination (second biopsy). Immunohistochemical (IHC) findings of parenchymal
inflammatory infiltrates were invariably present and mainly consisted of macrophage rich lesions (A), accompanied by foamy macrophages with perivascular cuffing (B,
black arrow) and astrocytes with granular mitosis, also known as Creutzfeldt-Peters cells (C, black arrow: Creutzfeldt cell with fragmented micronuclei) (hematoxylin
and eosin stain). Tissue section with extensive macrophage infiltration (D, IHC for CD68/clone PGM1), with mainly perivascular location (E, black arrow). Relative
axonal preservation (IHC stain for neurofilaments) (F). Demyelination was observed as a loss of Luxol fast blue staining (Kluver-Barrera stain), and was most obvious in
perivascular areas (G, black arrow, region of pallor, indicating myelin loss). Presence of granules of myelin inside the cytoplasm of macrophages, in contrast to
elongated structures forming the classical myelin sheaths (H, black arrows, granules of myelin). Perivascular demyelination was also evident by loss of Myelin Basic
Protein (MBP), in perivascular spaces (I, black arrow, IHC stain for MBP). Only few B cells were observed in tissue sections (J: IHC for CD20). Progressive multifocal
leukoencephalopathy was excluded by the absence of staining with antibodies against Simian Virus-40 and p53 (K,L, respectively).
Frontiers in Neurology | www.frontiersin.org
4
June 2020 | Volume 11 | Article 536
Vakrakou et al.
Tumefactive Demyelination With Marburg-Like Features
progression of the disease. Her residual deficits included mild
left sided disability with an EDSS of 2. Brain MRI showed a
reduction in the mass effect, as well as a reduction of contrast
enhancement of prior lesions (Figure 1). Nevertheless, a new
relapse (3 years after the first clinical attack) occurred after the
seventh dose of cyclophosphamide, with expansion of lesions
to the brainstem. She was placed on Rituximab with no clinical
response. She deteriorated clinically, and finally died from
complicated pneumonia after a long hospitalization period (5months) (Figure 1). Post-mortem brain tissue examination was
indicative of demyelinating lesions of the CNS without evidence
of a neoplastic process.
entities. An extended assessment for underlying infection, autoimmune and oncological disorders was performed in our case
to rule out the various differential diagnosis, which is presented
in Table 1 (15, 17, 22–26). The main differential diagnosis that
remained was among tumefactive MS and the Marburg variant
of MS.
An atypical and fulminant form of MS is the Marburg variant
of disease. It was firstly described in 1906, and the classical form
of the disease is characterized by a monophasic, highly aggressive
course with rapid disease progression leading to death within
weeks to months (27). The major histomorphological features of
the disease involve intense macrophage infiltration, widespread
demyelination (not only restricted to the perivascular areas),
with further evidence of necrosis and cavitation, hypertrophic
astrocytes and severe axonal injury (28). The fatal outcome
of Marburg is mainly attributed to brainstem involvement
and to the highly intense inflammatory process that involves
tumefactive lesions with mass effect, usually not responding
to acute treatments (high doses of corticosteroids). The role
of plasma exchange is controversial, with past reports showing
improvement in some patients; however, recent data support the
inefficiency or even worsening of the disease (29, 30). Regarding
the highly inflammatory nature of the disease, more aggressive
immunosuppression is warranted, and treatment decisions are
based on prior case reports. There are some reports showing
encouraging results with the use of high dose cyclophosphamide,
others with mitoxantrone and a more recently published case
with alemtuzumab (31–33). Nevertheless, previously reported
cases were unsuccessfully treated with cyclophosphamide with
death within weeks to months after treatment (34, 35). A possible
explanation for the heterogeneity in cyclophosphamide response
could be the different treatment protocols (dose, frequency, time
to treatment) applied to patients.
Tumefactive MS is one of the rare variants of MS. There
are no therapeutic guidelines, but acute treatment involves
high doses of corticosteroids and if needed plasma exchange
therapy (25). Long term therapy, based on case reports, involves
disease-modifying treatments classically used in typical MS (36,
37). Recent evidence supports that fingolimod and natalizumab
should be avoided in MS patient with tumefactive lesions due to
TDL exacerbation (25). Aggressive cases have been treated with
Rituximab and/or cyclophosphamide (14). Pathological features
are somewhat similar to those seen in prototypical MS, but with
prominent Creutzfeldt– Peters cells and dystrophic astrocytes (9).
Our patient presented both features of Marburg variant of MS
(aggressive and finally fatal disease outcome, diffuse infiltrative
lesions on MRI unlike typical MS lesions) and tumefactive
MS (typical histopathology, recurrent TDL appearance).
Nevertheless, there are atypical features for both diagnoses. In
particular, regarding the diagnosis of Marburg, atypical features
include the recurrent nature of disease, and the absence of
overt necrosis, as well as of axonal degeneration on biopsy.
Regarding tumefactive MS, an atypical feature is the eventual
resistance to all conventional therapies (corticosteroids, plex
cyclophosphamide, rituximab). We consider our case unique,
due to its distinct neuropathological findings and the ultimately
poor response to high dose immunosuppressive treatment. The
DISCUSSION
Fulminant demyelinating diseases represent a diagnostic
challenge for clinicians and include acute disseminated
encephalomyelitis, multiple sclerosis variants (Marburg variant,
Tumefactive MS, Balo’s concentric sclerosis) and neuromyelitis
optica spectrum disorders (15). Herein we presented an
extremely rare case with recurrent TDL appearance on
brain imaging, with atypical tumor-like features (mass effect,
homogenous enhancement, recurrence in the same anatomical
site and expansion), with initial response to high doses of
steroids and cyclophosmamide but subsequent resistance, with
exacerbation after rituximab administration, and finally with
fatal outcome. Tumefactive demyelination is considered to be not
a distinct disease entity but rather a type of lesions encountered
in different disease settings with Multiple Sclerosis and its
variants to be the most prevalent (5). Nevertheless, TDL might
occur in patients with other atypical demyelinating syndromes
such as Acute Disseminated Encephalomyelitis (ADEM),
AQ4 IgG seropositive or MOG-seropositive Neuromyelitis
Optica Spectrum Disorders (NMOSD), as well as other
neuroinflammatory disorders, such as Neurosarcoidosis or
Behçet’s disease (4). Of note, the spectrum of MOG antibodyassociated encephalomyelitis the last years has expanded to
involve cases with TDL and ADEM-like presentation, clinical
presentations that could fit to our patient history (11, 16).
Nevertheless, our patient was negative for both MOG and AQ4
autoantibodies. Another question regarding the differential
diagnosis of our case is whether the observed demyelinating
lesions could be encountered as part of a paraneoplastic
syndrome or as part of an autoimmune encephalitis (17, 18).
Screening for an underlying malignancy with whole body
computed tomography and onconeural antibodies was
negative. Particularly anti-NMDAR encephalitis has been
recently associated with demyelinating events as concurrent or
independent episodes (19–21). Whether the radiological and
pathological differences between above disorders are sufficient
to define them as separate diseases remain unclear. Till today
a limited number of specific biomarkers exist to distinguish
between the various demyelinating syndrome subtypes. The
emergence of NMDAR, AQ4, and MOG IgG autoantibodies
changed our diagnostic and treatment strategies, but more
research is needed to expand our knowledge about these disease
Frontiers in Neurology | www.frontiersin.org
5
June 2020 | Volume 11 | Article 536
Vakrakou et al.
Tumefactive Demyelination With Marburg-Like Features
main histopathological finding (from two tissue biopsies during
disease evolution and postmortem biopsy) was the perivascular
demyelination and the accumulation of macrophage-rich
lesions in inflamed tissue specimens. B and T cells were present
to a lesser extent. Interestingly, our patient suffered disease
exacerbation twice after 4 cycles of rituximab without the
presence of B cells in the periphery.
Various hypothesis can be made to delineate the postrituximab relapses. Studies in mice in models of experimental
autoimmune encephalomyelitis (EAE) and in human diseases
such as Sjögren’s syndrome or rheumatoid arthritis have shown
that anti-CD20 treatment may not eliminate a fraction of
memory antigen-experienced B cells, presumably in organs other
than the blood (lymphoid tissues). In individuals with increased
constitutive levels of the cytokine BAFF (tumor necrosis
factor ligand superfamily member 13B), BAFF, a potent B cell
stimulator, may promote a fast-clonal expansion of insufficiently
depleted remaining B-cells. Nevertheless, peripheral blood
immunophenotyping in our case, after rituximab treatment, did
not reveal reemergence of B cells upon clinical relapse, indicating
that other possible mechanisms independent of memory B cells
may account for disease exarbetation. An alternative explanation
could be the reactivation of autoreactive long-lived plasma
cells, which are not targeted by rituximab. This observation is
consistent with other reports of an increase in disease activity
shortly after rituximab treatment in MS and NMO (38, 39).
Finally, there is a cross-talk among specific subsets of regulatory
B cells and cells of the myeloid lineage, resulting in a suppressive
effect of B cells (IL-10 producing B cells) over the activation
status and proinflammatory differentiation of monocytes (40,
41). This is highlighted in a recently published case report
showing vast CNS infiltration of monocytes after administration
of alemtuzumab in an NMO patient (42). Overall, these findings
suggest that the therapeutic use of rituximab or other B-cell
depleting therapies in various demyelinating diseases, including
our case, requires high clinical vigilance, since post-rituximab
effects could be variable, depending on the inflammatory milieu
and the interaction with cells of myeloid lineages.
The largest case series of biopsy-proven tumefactive
demyelination with 168 cases by Luchinetti et al., has shown
that 14% of patients exhibited a monophasic course, and 70%
of patients eventually developed definite multiple sclerosis, with
the median time to relapse to be 4.8 years (43). Regarding the
severity of the overall clinical course of TDLs, Staley A Brod et
al., showed that patients with Tumefactive MS exhibit a benign
disease course and are successfully treated with classical MS
disease-modifying therapy (44). Till today there are no clear
clinical/serological and/or radiographical biomarkers assessing
the risk for disease evolution and conversion to clinically definite
MS. This information is critically important because determines
our further therapeutic strategies after the first TDL appearance.
There is no consensus regarding the use of disease modifying
therapies (DMT) to decrease the risk of a second clinical attack.
Many clinicians suggest using DMTs only in patients with a
higher risk of conversion or in patients fulfilling MS diagnostic
criteria. Potential suggested risk factors described the literature,
include age at disease onset, a particularly disabling first attack,
the type of enhancement pattern, and the concomitant with
TABLE 1 | Differential diagnosis of pseudotumoral lesions in brain MRI (tumors
excluded).
Differential diagnosis
of pseudotumoral
lesions in brain MRI
(tumors excluded)
Disease entities
CATEGORY
Multiple sclerosis
During disease course
Upon drug initiation (fingolimod)
Upon drug cessation (fingolimod, tysabri)
Atypical MS
Balo’s concentric sclerosis
Schilder’s sclerosis (myelinoclastic diffuse sclerosis)
Marburg varinat
Acute hemorrhagic leukoencephalitis (AHL)
Idiopathic demyalinting
syndromes
ADEM
NMO spectrum disorders
MOG-encephalomyelitis
Monophasic TDL
Recurrent TDL
Neuroinflammatory
disorders
Sarcoidosis
Behcet’s disease
IgG4 disease
Systemic Lupus Erythematosus
Sjogren’s Syndrome
Cerebral vasculitis (primary or secondary)
Paraneoplastic
Germ cell tumor
Renal cell carcinoma
Lymphoma
Infectious
HIV
Abscess—bacterial, fungal
Tuberculoma
Toxoplasmosis
Cryptococcoma
Progressive multifocal leukoencephalopathy (PML)
Lyme disease
Syphilis
Genetic disorders/
leuko-vasculopathies
Genetic—retinal vasculopathy with cerebral
leukoencephalopathy and systemic manifestations
(RVCL-S)
CADASIL
Cerebral amyloid angiopathy
Inherited leukodystrophy/ Adult-onset leukoencephalopathy with axonal spheroids
leukoencephalopathy
and pigmented glia (ALSP) related to CSF1R gene
mutations
X-linked adrenoleukodystrophy (ALD)
Others
Osmotic myelinolysis
Radiation Leukoencephalopathy
Posterior reversible encephalopathy syndrome (PRES)
Tacrolimus
Bevacizumab
AHL,
acute
hemorrhagic
leucoencephalitis;
ADEM,
acute
disseminated
encephalomyelitis; NMO, neuromyelitis optica; MOG, myelin oligodendrocyte
glycoprotein; TDL, tumefactive demyelinating lesion; PML, progressive multifocal
leukoencephalopathy; RVCL-S, retinal vasculopathy with cerebral leukoencephalopathy
and systemic manifestations; CADASIL, cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy; ALSP, adult-onset leukoencephalopathy
with axonal spheroids and pigmented glia; CSF1R, colony stimulating factor 1 receptor;
ALD, adrenoleukodystrophy; PRES, posterior reversible encephalopathy syndrome.
Frontiers in Neurology | www.frontiersin.org
6
June 2020 | Volume 11 | Article 536
Vakrakou et al.
Tumefactive Demyelination With Marburg-Like Features
response despite a strenuous immunosuppressive attempt points
out the need for future research in this area. Our clinical case is
of great importance, as it raises therapeutic dilemmas, and points
to the need for immediate and appropriate immunosuppression
in difficult to treat tumefactive CNS lesions. It also highlights
the need for better assessment of risk factors favoring disease
relapse after the first TDL attack, in order to better determine
optimal therapeutic strategies. Moreover, it underlines the value
of neuropathological analysis of tumefactive lesions, not only for
exclusion of other alternative diagnosis, but also for revealing
the type of tissue inflammation in a attempt to better define the
appropriate treatment options.
TDL presence of other typical MS lesions (1). Regarding our
case, during the initial clinical attack of TDL (hospitalization
in another hospital), we postulate that there was insufficient
evidence that time point for starting MS disease modifying
therapy (DMT). OCBs were tested negative, brain MRI revealed
white matter lesions not typical for classical MS lesions and
there was almost complete clinical and radiological response to
corticosteroids. Nevertheless, the natural history of the disease
stresses the need for future studies assessing better the risk for
disease recurrence (new serum or CSF biomarkers, IgG index).
Diagnosis of TDL does not usually involve brain tissue
biopsy, since emerging neuroimaging data contribute to
proper diagnosis. The employment of various techniques,
such as magnetic resonance spectroscopy (MRS), Positron
emission tomography–computed tomography (PET-CT) and
8F-fluoroethyl-L-tyrosine (FET) PET can differentiate between
tumor or tumefactive demyelinating (45–48). Nevertheless, the
accuracy of this discrimination is not always optimal and there
are limitations and gray zones. In one of the largest cohorts
of biopsy-proven TDLs, about 30% of biopsies were initially
misdiagnosed (43). Close monitoring of disease evolution with
neurologic examination, repeated MRI scans and exclusion
of other etiologies with appropriate work-up, aid the proper
diagnosis. Atypical MRI characteristics (pattern of contrast
enhancement, mass effect, oedema), inconclusive results of
MRS, inappropriate response to immunotherapy render brain
biopsy necessary.
DATA AVAILABILITY STATEMENT
The datasets generated for this study are available on request to
the corresponding author.
ETHICS STATEMENT
Written informed consent was obtained from the next of kin
of the patient for the publication of any potentially identifiable
images or data included in this article.
AUTHOR’S NOTE
This case submission met all of the requirements for publication
under the approval of the ethics committee of Eginition
Hospital (12360/2.12.2019).
CONCLUSIONS
AUTHOR CONTRIBUTIONS
Herein, we report a case of late-onset recurrent Tumefactive
Demyelinating lesion (TDL) mimicking a brain tumor. The
demyelinating nature of the lesion was confirmed by brain biopsy
and post-portem tissue examination as well. In our extremely
rare case of fulminant tumefactive demyelination, only high
doses of cyclophosphamide were able to control disease for
a limited time period (7-months), indicating that alternative
high-dose immunosuppressive therapies (e.g., hematopoietic
stem cell transplantation) could possibly exhibit a therapeutic
benefit. Of note, plasmapheresis did not control the highly
aggressive tumefactive demyelination. The lack of therapeutic
AV wrote, edited manuscript, and designed figure. DT, GK,
M-EE, EA, MA, MB, JT, EG, and AD collected clinical data
and treated patients in the hospital. GV and PT analyzed MRI
data. TA analyzed tissue biopsies by immunochemistry and
critically revised manuscript. LS and CK contributed to drafting
of the work and revising it critically for important intellectual
content. All authors provided approval for publication of the
content of the paper and agreed to be accountable for all aspects
of the work.
REFERENCES
5. Hardy TA, Chataway J. Tumefactive demyelination: an approach to
diagnosis and management. J Neurol Neurosurg Psychiatr. (2013) 84:1047–53.
doi: 10.1136/jnnp-2012-304498
6. Giordana MT, Cavalla P, Uccelli A, Laroni A, Bandini F, Vercellino
M, et al. Overexpression of sphingosine-1-phosphate receptors on
reactive astrocytes drives neuropathology of multiple sclerosis rebound
after fingolimod discontinuation. Mult Scler. (2018) 24:1133–7.
doi: 10.1177/1352458518763095
7. Sanchez P, Meca-Lallana V, Vivancos J. Tumefactive multiple sclerosis lesions
associated with fingolimod treatment: report of 5 cases. Mult Scler Relat
Disord. (2018) 25:95–8. doi: 10.1016/j.msard.2018.07.001
8. Sato K, Niino M, Kawashima A, Yamada M, Miyazaki Y, Fukazawa
T. Disease exacerbation after the cessation of fingolimod treatment in
japanese patients with multiple sclerosis. Intern Med. (2018) 57:2647–55.
doi: 10.2169/internalmedicine.0793-18
1. Abdoli M, Freedman MS. Neuro-oncology dilemma: tumour or
tumefactive demyelinating lesion. Mult Scler Relat Disord. (2015) 4:555–66.
doi: 10.1016/j.msard.2015.07.013
2. Frederick MC, Cameron MH. Tumefactive demyelinating lesions in multiple
sclerosis and associated disorders. Curr Neurol Neurosci Rep. (2016) 16:26.
doi: 10.1007/s11910-016-0626-9
3. Poser S, Luer W, Bruhn H, Frahm J, Bruck Y, Felgenhauer K.
Acute demyelinating disease. Classification and non-invasive diagnosis
Acta Neurol Scand. (1992) 86:579–85. doi: 10.1111/j.1600-0404.1992.
tb05490.x
4. Hardy TA. Pseudotumoral demyelinating lesions: diagnostic approach
and long-term outcome. Curr Opin Neurol. (2019) 32:467–74.
doi: 10.1097/wco.0000000000000683
Frontiers in Neurology | www.frontiersin.org
7
June 2020 | Volume 11 | Article 536
Vakrakou et al.
Tumefactive Demyelination With Marburg-Like Features
27. Turatti M, Gajofatto A, Rossi F, Vedovello M, Benedetti MD. Long survival
and clinical stability in Marburg’s variant multiple sclerosis. Neurol Sci. (2010)
31:807–11. doi: 10.1007/s10072-010-0287-4
28. Nunes JC, Radbruch H, Walz R, Lin K, Stenzel W, Prokop S, et al.
The most fulminant course of the Marburg variant of multiple sclerosisautopsy findings. Mult Scler. (2015) 21:485–7. doi: 10.1177/1352458514
537366
29. Rodriguez M, Karnes WE, Bartleson JD, Pineda AA. Plasmapheresis in acute
episodes of fulminant CNS inflammatory demyelination. Neurology. (1993)
43:1100–4. doi: 10.1212/wnl.43.6.1100
30. Weinshenker BG, O’Brien PC, Petterson TM, Noseworthy JH, Lucchinetti CF,
Dodick DW, et al. A randomized trial of plasma exchange in acute central
nervous system inflammatory demyelinating disease. Ann Neurol. (1999)
46:878–86. doi: 10.1002/1531-8249(199912)46:6<878::aid-ana10>3.0.co;2-q
31. Jeffery DR, Lefkowitz DS, Crittenden JP. Treatment of Marburg variant
multiple sclerosis with mitoxantrone. J Neuroimaging. (2004) 14, 58–62.
doi: 10.1177/1051228403259393
32. Gobbin F, Marangi A, Orlandi R, Richelli S, Turatti M, Calabrese M, et al.
A case of acute fulminant multiple sclerosis treated with alemtuzumab. Mult
Scler Relat Disord. (2017) 17:9–11. doi: 10.1016/j.msard.2017.06.007
33. Avila-Ornelas J, Labat E, Alfonso G, Serrano C, Fiorito F. An
extremely aggressive case of Marburg’s disease treated with high dose
cyclophosphamide. A case report Mult Scler Relat Disord. (2019) 31:51–3.
doi: 10.1016/j.msard.2019.03.014
34. Johnson MD, Lavin P, Whetsell WOJr. Fulminant monophasic multiple
sclerosis, Marburg’s type. J Neurol Neurosurg Psychiatr. (1990) 53:918–21.
doi: 10.1136/jnnp.53.10.918
35. Wood DD, Bilbao JM, O’Connors P, Moscarello MA. Acute multiple sclerosis.
(Marburg type) is associated with developmentally immature myelin basic
protein. Ann Neurol. (1996) 40:18–24. doi: 10.1002/ana.410400106
36. Haupts MR, Schimrigk SK, Brune N, Chan A, Ahle G, Hellwig K,
et al. Fulminant tumefactive multiple sclerosis: therapeutic implications of
histopathology. J Neurol. (2008) 255:1272–3. doi: 10.1007/s00415-008-0883-x
37. Siffrin V, Muller-Forell W, von Pein H, Zipp F. How to treat
tumefactive demyelinating disease? Mult Scler. (2014) 20:631–3.
doi: 10.1177/1352458513516891
38. Nakashima I, Takahashi T, Cree BA, Kim HJ, Suzuki C, Genain CP,
et al. Transient increases in anti-aquaporin-4 antibody titers following
rituximab treatment in neuromyelitis optica, in association with elevated
serum BAFF levels. J Clin Neurosci. (2011) 18:997–8. doi: 10.1016/j.jocn.2010.
12.011
39. Perumal JS, Kister I, Howard J, Herbert J. Disease exacerbation after rituximab
induction in neuromyelitis optica. Neurol Neuroimmunol Neuroinflamm.
(2015) 2:e61. doi: 10.1212/nxi.0000000000000061
40. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells
regulate autoimmunity by provision of IL-10. Nat Immunol. (2002) 3:944–50.
doi: 10.1038/ni833
41. Lehmann-Horn K, Schleich E, Hertzenberg D, Hapfelmeier A, Kumpfel
T, von Bubnoff N, et al. Anti-CD20 B-cell depletion enhances monocyte
reactivity in neuroimmunological disorders. J Neuroinflammation. (2011)
8:146. doi: 10.1186/1742-2094-8-146
42. Gelfand JM, Cotter J, Klingman J, Huang EJ, Cree BA. Massive CNS
monocytic infiltration at autopsy in an alemtuzumab-treated patient
with NMO. Neurol Neuroimmunol Neuroinflamm. (2014) 1:e34.
doi: 10.1212/nxi.0000000000000034
43. Lucchinetti, C. F., Gavrilova, R. H., Metz, I., Parisi, J. E., Scheithauer,
B. W., Weigand, S., et al.. (2008). Clinical and radiographic spectrum of
pathologically confirmed tumefactive multiple sclerosis. Brain 131(Pt 7),
1759–1775. doi: 10.1093/brain/awn098
44. Brod SA, Lindsey JW, Nelson F. Tumefactive demyelination:
Clinical outcomes, lesion evolution and treatments. Mult Scler J Exp
Transl Clin. (2019) 5:2055217319855755. doi: 10.1177/2055217319
855755
45. Saindane AM, Cha S, Law M, Xue X, Knopp EA, Zagzag D. Proton MR
spectroscopy of tumefactive demyelinating lesions. AJNR Am J Neuroradiol.
(2002) 23:1378–86.
46. Cianfoni A, Niku S, Imbesi SG. Metabolite findings in tumefactive
demyelinating lesions utilizing short echo time proton magnetic
9. Hu W, Lucchinetti CF. The pathological spectrum of CNS inflammatory
demyelinating diseases. Semin Immunopathol. (2009) 31:439–53.
doi: 10.1007/s00281-009-0178-z
10. Hardy TA, Tobin WO, Lucchinetti CF. Exploring the overlap between
multiple sclerosis, tumefactive demyelination and Balo’s concentric
sclerosis. Mult Scler. (2016) 22:986–92. doi: 10.1177/135245851
6641776
11. Tzartos JS, Karagiorgou K, Tzanetakos D, Breza M, Evangelopoulos
ME, Pelidou SH, et al. Deciphering anti-MOG IgG antibodies: clinical
and radiological spectrum, and comparison of antibody detection
assays. J Neurol Sci. (2020) 410:116673. doi: 10.1016/j.jns.2020.
116673
12. Fan X, Mahta A, De Jager PL, Kesari S. Rituximab for tumefactive
inflammatory demyelination: a case report. Clin Neurol Neurosurg. (2012)
114:1326–8. doi: 10.1016/j.clineuro.2012.03.010
13. Sempere AP, Feliu-Rey E, Sanchez-Perez R, Nieto-Navarro J. Neurological
picture. Rituximab for tumefactive demyelination refractory to corticosteroids
and plasma exchange. J Neurol Neurosurg Psychiatry. (2013) 84:1338–9.
doi: 10.1136/jnnp-2013-305456
14. Sanchez P, Meca-Lallana V, Barbosa A, Manzanares R, Palmi I, Vivancos
J. Tumefactive demyelinating lesions of 15 patients: clinico-radiological
features, management and review of the literature. J Neurol Sci. (2017)
381:32–8. doi: 10.1016/j.jns.2017.08.005
15. Ayrignac X, Carra-Dalliere C, Labauge P. Atypical inflammatory
demyelinating lesions and atypical multiple sclerosis. Rev Neurol. (Paris).
(2018) 174:408–18. doi: 10.1016/j.neurol.2018.03.007
16. Miyaue N, Yamanishi Y, Tada S, Ando R, Yabe H, Nagai M, et al.
A case of ADEM-like presentation with anti-MOG antibody following
tumefactive demyelinating lesion. Mult Scler Relat Disord. (2019) 31:62–4.
doi: 10.1016/j.msard.2019.03.018
17. Broadfoot JR, Archer HA, Coulthard E, Appelman AP, Sutak J,
Braybrooke JP, et al. Paraneoplastic tumefactive demyelination with
underlying combined germ cell cancer. Pract Neurol. (2015) 15:451–5.
doi: 10.1136/practneurol-2015-001146
18. Spadaro M, Gerdes LA, Mayer MC, Ertl-Wagner B, Laurent S, Krumbholz
M, et al. Histopathology and clinical course of MOG-antibodyassociated encephalomyelitis. Ann Clin Transl Neurol. (2015) 2:295–301.
doi: 10.1002/acn3.164
19. Titulaer MJ, Hoftberger R, Iizuka T, Leypoldt F, McCracken L, Cellucci T,
et al. Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate
receptor encephalitis. Ann Neurol. (2014) 75:411–28. doi: 10.1002/ana.
24117
20. Jarius S, Metz I, Konig FB, Ruprecht K, Reindl M, Paul F, et al. Screening
for MOG-IgG and 27 other anti-glial and anti-neuronal autoantibodies
in ’pattern II multiple sclerosis’ and brain biopsy findings in a MOGIgG-positive case. Mult Scler. (2016) 22:1541–9. doi: 10.1177/1352458515
622986
21. Thebault S, Hanes I, Woulfe J, Bourque PR. Paraneoplastic recurrent
tumefactive demyelination in a 62-year-old man with metastatic
seminoma. Neurol Neuroimmunol Neuroinflamm. (2019) 6:e527.
doi: 10.1212/nxi.0000000000000527
22. Xia L, Lin S, Wang ZC, Li SW, Xu L, Wu J, et al. Tumefactive demyelinating
lesions: nine cases and a review of the literature. Neurosurg Rev. (2009)
32:171–9; discussion 179. doi: 10.1007/s10143-009-0185-5
23. Eckstein C, Saidha S, Levy M. A differential diagnosis of central nervous
system demyelination: beyond multiple sclerosis. J Neurol. (2012) 259:801–16.
doi: 10.1007/s00415-011-6240-5
24. Hardy TA, Reddel SW, Barnett MH, Palace J, Lucchinetti CF,
Weinshenker BG. Atypical inflammatory demyelinating syndromes of
the CNS. Lancet Neurol. (2016) 15:967–81. doi: 10.1016/s1474-4422(16)
30043-6
25. Algahtani H, Shirah B, Alassiri A. Tumefactive demyelinating lesions:
A comprehensive review. Mult Scler Relat Disord. (2017) 14:72–9.
doi: 10.1016/j.msard.2017.04.003
26. Van Haver AS, Debruyne F, Sanders K, Verstappen A. Paraneoplastic
tumefactive demyelination in a 47-year-old man with underlying seminoma.
Mult Scler Relat Disord. (2020) 42:102060. doi: 10.1016/j.msard.2020.
102060
Frontiers in Neurology | www.frontiersin.org
8
June 2020 | Volume 11 | Article 536
Vakrakou et al.
Tumefactive Demyelination With Marburg-Like Features
Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
resonance
spectroscopy.
AJNR
Am
J
Neuroradiol.
(2007)
28:272–7.
47. Takenaka S, Shinoda J, Asano Y, Aki T, Miwa K, Ito T, et al. Metabolic
assessment of monofocal acute inflammatory demyelination using
MR spectroscopy and (11)C-methionine-, (11)C-choline-, and (18)Ffluorodeoxyglucose-PET. Brain Tumor Pathol. (2011) 28:229–38.
doi: 10.1007/s10014-011-0027-3
48. Barbagallo M, Albatly AA, Schreiner S, Hayward-Konnecke HK, Buck A,
Kollias SS, et al. Value of 18F-FET PET in patients with suspected tumefactive
demyelinating disease-preliminary experience from a retrospective
analysis. Clin Nucl Med. (2018) 43:e385–e391. doi: 10.1097/rlu.000000000
0002244
Frontiers in Neurology | www.frontiersin.org
Copyright © 2020 Vakrakou, Tzanetakos, Argyrakos, Koutsis, Evangelopoulos,
Andreadou, Anagnostouli, Breza, Tzartos, Gialafos, Dimitrakopoulos, Velonakis,
Toulas, Stefanis and Kilidireas. This is an open-access article distributed under the
terms of the Creative Commons Attribution License (CC BY). The use, distribution
or reproduction in other forums is permitted, provided the original author(s) and
the copyright owner(s) are credited and that the original publication in this journal
is cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
9
June 2020 | Volume 11 | Article 536