Modern Rheumatology

ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20

Transverse myelitis extended to disseminated

encephalitis in systemic lupus erythematosus:
Histological evidence for vasculitis

Toshihiro Tono, Tatsuo Nagai, Takayuki Hoshiyama, Yuko Sakuma, Tatsuhiko

Wada, Sumiaki Tanaka & Shunsei Hirohata

To cite this article: Toshihiro Tono, Tatsuo Nagai, Takayuki Hoshiyama, Yuko Sakuma,
Tatsuhiko Wada, Sumiaki Tanaka & Shunsei Hirohata (2014): Transverse myelitis extended
to disseminated encephalitis in systemic lupus erythematosus: Histological evidence for
vasculitis, Modern Rheumatology

To link to this article: http://dx.doi.org/10.3109/14397595.2014.948535

Published online: 13 Aug 2014.

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ISSN 1439-7595 (print), 1439-7609 (online)

Mod Rheumatol, 2014; Early Online: 1–5

© 2014 Japan College of Rheumatology
DOI: 10.3109/14397595.2014.948535

CASE REPORT

Transverse myelitis extended to disseminated encephalitis in systemic

lupus erythematosus: Histological evidence for vasculitis
Toshihiro Tono, Tatsuo Nagai, Takayuki Hoshiyama, Yuko Sakuma, Tatsuhiko Wada, Sumiaki Tanaka,
and Shunsei Hirohata

Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
Downloaded by [Washington University in St Louis] at 22:48 05 November 2015

Abstract Keywords
A 42-year-old woman was admitted due to systemic lupus erythematosus complicated anti-NR2, Pulmonary hypertension, Vasculitis,
with glomerulonephritis and pulmonary hypertension. During the treatment for these Transverse myelitis, Acute confusional state
complications, she presented motor paresis and sensory loss caused by transverse myelitis.
In spite of methyl prednisolone pulse therapy, she further developed acute confusional state History
due to disseminated encephalitis and fell into respiratory arrest. On laboratory examination, Received 12 May 2014
elevation of anti-NR2 antibodies in serum as well as in cerebrospinal fluid was noted. Although Accepted 21 July 2014
she recovered from the disseminated encephalitis after extensive treatment with high doses Published online 14 August 2014
of corticosteroid and intravenous cyclophosphamide, she suddenly died of pulmonary
hypertension. Autopsy findings confirmed the presence of liquefaction necrosis in the entire
circumference of the whole spinal cord along with intimal hyperplasia and obliteration of the
small arteries, accompanied by mononuclear cell infiltration and disruption of internal elastic
lamina. It is therefore most likely that our patient developed longitudinal transverse myelitis
through spinal cord vasculitis, which extended to brainstem and brain parenchyma, leading to
the development of disseminated encephalitis.

Introduction
A variety of manifestations are seen in neuropsychiatric involve-
ment in systemic lupus erythematosus (NPSLE) [1]. Central
nervous system (CNS) disorders in NPSLE are classified into
neurologic syndromes (focal NPSLE) and diffuse psychiatric/
neuropsychological syndromes (diffuse NPSLE) [2]. It has been
reported that cerebrospinal fluid (CSF) IgG anti-neuronal antibody
levels were significantly elevated in patients with diffuse NPSLE
compared with those in patients without diffuse NPSLE [3,4].
Notably, DeGiorgio et al. demonstrated that a subset of
anti-DNA antibodies cross-reacted with a sequence within the
N-methyl-D-aspartate (NMDA) receptor subunit NR2 and caused
apoptosis of neuronal cells when injected into mouse brain [5].
In addition, they showed that serum titers of such cross-reactive
anti-DNA antibodies alone did not necessarily correlate with brain
damages of mice, which also required a breakdown of the blood–
brain barrier to allow such antibodies enter the CNS [6]. Indeed,
levels of anti-NR2 antibodies in CSF, but not those in sera, were
significantly elevated in patients with diffuse NPSLE compared
with those in control groups [7].
On the other hand, myelitis has been shown to occur in 1–2%
of SLE patients, much more frequently compared with the gen-
eral population [8,9]. Recent studies have shown that myelitis
in SLE consists of two distinct subsets that can be distinguished
clinically by grey matter versus white matter findings [10]. Thus,
Correspondence to: Shunsei Hirohata, MD, Department of Rheumatology
and Infectious Diseases, Kitasato University School of Medicine,
1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan.
Tel: ⫹ 81-42-778-8111. Fax: ⫹ 81-42-778-9291. E-mail: shunsei_tenpoint@
yahoo.co.jp
patients in the subset with grey matter dominant lesions show
monophasic irreversible paraplegia, corresponding to transverse
myelitis [10]. On the other hand, patients in the subset with white
matter dominant lesions show multiple attacks with remission
and relapse mimicking neuromyelitis optica, corresponding to
demyelinating syndromes in the ACR classification [2]. Notably,
patients in the former subset, transverse myelitis, show marked
elevation of CSF cell counts and total protein levels, indicating
the presence of severe inflammation, although its pathogenesis
remains unclear [10].
We report here an SLE patient who developed irreversible
transverse myelitis, followed by the development of disseminated
encephalitis mainly in the brainstem and cerebellum, manifested
by acute confusional state. The postmortem examination of the
spinal cord indicates that vasculitis played a pivotal role in the
pathogenesis of transverse myelitis, which possibly extended
to the development of the disseminated encephalitis. The role of
anti-NR2 antibodies is discussed.
Case report
A 42-year-old Japanese female was admitted to a local hospital
due to progressive dyspnea, which had begun 1 month earlier. On
admission, cardiomegaly, generalized edema, and proteinuria were
observed. Lymphopenia, positive ANA, and positive anti-Sm anti-
bodies lead to the diagnosis of SLE. Doppler echocardiography
suggested the diagnosis of pulmonary hypertension. In spite of
extensive treatment with prednisolone 30 mg/day, plasma exchange
and mechanical ventilation for 15 days, she did not improve and
was transferred to our hospital. On the transfer, physical exami-
nation revealed body length 151.7 cm, body weight 65 kg, blood
pressure 58/29 mmHg, and pulse rate 113/min with generalized
 2 T. Tono et al.
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edema but without any neurological abnormalities. Hemogram
showed hemoglobin 11.4 g/dl, white blood cell count 15,000/
mm3 with 6.6% lymphocytes and platelet count 13.7 ⫻ 104/mm3.
Urinalysis revealed protein (2⫹), glucose (⫺), and occult blood
(3⫹), with cellular casts. Serological tests disclosed C3 27 mg/
dl (normal ranges: 65–135), C4 3 mg/dl (13–35), CH50 10 U/
ml (30–40), ANA ⫻ 640 (speckled type), anti-dsDNA 10 IU/ml
(normal: ⬉ 12 IU/ml), anti-Sm 157.0 Index (normal: ⬍ 30), and
anti-RNP 97.8 Index (normal: ⬍ 22). Both serum anti-cardiolipin
β2-glycoprotein-1 complex antibodies and anti-ribosomal P pro-
tein antibodies were negative. Serum anti-aquaporin 4 antibody
and anti-neutrophil cytoplasmic antibodies were negative.
Based on these findings, her cardiac failure was judged to be
caused by active SLE, and administration of intravenous methyl
prednisolone (m-PSL) 1000 mg/day for 3 consecutive days was
started immediately, followed by prednisolone 40 mg/day along
with dobutamine, epoprostenol sodium, and sildenafil. After the
treatment, proteinuria and cardiac function gradually improved.
However, on the 30th day from the admission to our hospital, she
developed right leg paresis.
Mod Rheumatol, 2014; Early Online: 1–5
Figure 1. Spinal cord magnetic
resonance imaging (MRI) on the
occurrence of transverse myelitis. T2-
weighted MR images revealed high
intensity areas in the posterior region
of C7 and Th3–8, leading to diagnosis
of transverse myelitis due to SLE
(arrows and circles).
On the development of paresis, her consciousness was good
(Glasgow Coma Scale 15). Neurological examination revealed
moderate motor weakness of right lower limb and bilateral severe
sensory disorders in all modalities under Th6 level, with bilateral
Babinski sign. There were no abnormalities in cranial nerves and
upper extremities. Serological tests at this time showed elevation
of serum anti-NR2 antibodies 186.7 U/ml (normal: ⬍ 49.8 U/ml).
Spinal cord magnetic resonance imaging (MRI) revealed high
intensity areas in regions of C7 and Th3–8 on T2-weighted images
(Figure 1). CSF examination revealed cell count 154/mm3, protein
498 mg/dl, interleukin-6 (IL-6) 69.4 pg/ml (normal: ⬍ 4.3 pg/
ml), and anti-NR2 antibodies 14.5 U/ml (normal: ⬍ 0.249 U/ml).
These findings supported the diagnosis of transverse myelitis due
to SLE. Administration of intravenous m-PSL 1000 mg/day for 3
consecutive days and cyclophosphamide 500 mg was immediately
started, followed by increased doses of prednisolone 100 mg/day.
However, no clinical improvement was seen.
On the 7th day from the onset of transverse myelitis, she devel-
oped consciousness disturbances (Glasgow Coma Scale 8) with the
right eyelid ptosis and right upper extremity paresis and fell into
Figure 2. Brain magnetic resonance
imaging (MRI) on the development
of disseminated encephalitis. FLAIR
images revealed high intensity
areas in the ventral oblongata, pons,
midbrain, and bilateral cerebellar
hemispheres.
 DOI 10.3109/14397595.2014.948535
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Figure 3. Macroscopic findings of the spinal cord on autopsy. Myelomalacia and atrophy are seen in the thoracic spinal cord, corresponding to the high
intensity lesions on MRI (Th3–8) (arrows).
respiratory arrest on the next day. Brain MRI revealed dissemi-
nated high intensity lesions in the ventral medulla oblongata, pons,
midbrain, and bilateral cerebellar hemispheres on FLAIR images
(Figure 2). CSF examination revealed cell count 353/mm3, protein
898 mg/dl, and IL-6 1500 pg/ml. Treatment with additional intra-
venous m-PSL 1000 mg/day and cyclophosphamide 500 mg was
performed, after which she recovered from respiratory arrest and
her consciousness state gradually improved with decrease in high
intensity lesions on MRI. However, she suddenly died of cardiac
arrest, presumably due to pulmonary hypertension 4 weeks later.
Macroscopic examinations at autopsy disclosed myelomalacia
and atrophy in the thoracic spinal cord (Th3–8), corresponding
to the high intensity lesions on MRI (Figure 3). Consistently,
histopathological findings revealed the decreased staining on
Kluver–Barrera stain especially in the lower thoracic spinal cord,
indicating demyelination (Figure 4). In addition, there were scat-
tered lesions of liquefaction necrosis on the grey and white mat-
ters in the entire circumference of the spinal cord, which was not
confined to the Th3–8 regions, but observed longitudinally in the
whole spinal cord (Figure 4). Correspondingly, there were scat-
tered lesions with intimal hyperplasia and obliteration of the small
arteries, accompanied by mononuclear cell infiltration and disrup-
tion of internal elastic lamina throughout the spinal cord (Figures
4). These results indicate that longitudinal spinal cord infarction
due to vasculitis lead to the development of transverse myelitis
in our patient. Moreover, the data suggest that the disseminated
encephalitis might also be caused by the extension of the vascu-
litis, although the postmortem examination of the brain was not
permitted.
On the other hand, intimal hyperplasia, obliteration, and
plexiform lesions were observed in the periphery of the bilateral
Extensive transverse myelitis in SLE 3
pulmonary arteries (Figure 5A), confirming the presence of
pulmonary hypertension. Moreover, there were also scattered
lesions with intimal hyperplasia accompanied by mononuclear
cell infiltration and disruption of internal elastic lamina in
branches of the pulmonary arteries (Figure 5B). The data indicate
that vasculitis was not limited in the nervous system but could be
found in other organs apart from the nervous system.
Discussion
Our patient presented transverse myelitis and disseminated enceph-
alitis during extensive treatment for SLE, and finally she died of
sudden cardiac arrest, presumably due to pulmonary hypertension,
as confirmed by autopsy. It is noteworthy that our patient devel-
oped acute confusional state, leading to respiratory arrest, although
she had been intensively treated for transverse myelitis, which had
occurred 1 week earlier. Brain MRI showed scattered high intensity
areas in brainstem, cerebellum, and cerebrum on FLAIR images,
compatible with the features of disseminated encephalitis. Recent
studies have disclosed that these abnormalities are occasionally
observed in diffuse NPSLE with acute confusional state [11].
Kowal et al. showed that mice induced by antigen to express
serum anti-NR2 antibodies had no neuronal damage until break-
down of the blood–brain barrier occurred [6]. Consistently, we
have recently demonstrated that the elevation of CSF anti-NR2
antibodies through the damages of the blood–brain barrier plays a
crucial role in the development of acute confusional state in SLE
[12]. Our patient presented neuropsychiatric manifestations identi-
fied as acute confusional state 1 week after the onset of transverse
myelitis. The marked elevation of CSF protein indicates that the
transverse myelitis markedly broke down the blood–brain barrier.
 4 T. Tono et al.
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Figure 4. Histopathology of the spinal cord on autopsy. Weak staining on Kluver–Barrera staining is noted in lower cervical spinal cord and thoracic
spinal cord. Intimal thickening, mononuclear cell infiltration and disruption of internal elastic lamina are noted in arteries. Liquefaction necrosis on
the white and grey matter is seen in the circumference of the spinal cord (arrows). Left: Kluver–Barrera staining (⫻ 1), Middle: hematoxylin and eosin
staining (⫻ 50), Right: Elastica van Gieson staining (⫻ 50).
It is thus suggested that the entry of anti-NR2 antibodies from the
systemic circulation to the CNS through the damaged blood–brain
barrier might contribute to the development of acute confusional
state in our patient. Nonetheless, it is still possible that the same
mechanism might be responsible for transverse myelitis and dis-
seminated encephalitis in our patient.
Notably, autopsy findings of our patient disclosed the presence of
vasculitis of the branches of spinal arteries, which most likely caused
transverse myelitis in our patient. More importantly, the presence of
liquefaction necrosis was not confined to the high intensity lesions
on MRI but extended longitudinally throughout the whole spinal
cord. In this regard, previous studies showed that an extensive lon-
gitudinal myelitis occurred in patients with SLE [13,14]. Moreover,
one of these SLE patients developed the extending lesions to left
thalamus and right pons of the brain [14]. Therefore, it is likely
that the activity was so strong that the vasculitis extended from
the spinal cord to the brainstem and brain parenchyma despite the
intensive treatment in our patient as well, although the postmortem
examination of the brain was not permitted.
The precise mechanism of the development of transverse myeli-
tis was unclear. Very few reports on histopathology are available
due to the rarity of this disorder. Penn and Rowan noted rapid
onset of an ascending paralysis that correlated with inflamma-
tory infiltrates without vasculitis at autopsy [15]. However, there
have been other studies in the literature which demonstrated the
involvement of spinal cord arteritis in the development of myelitis
Mod Rheumatol, 2014; Early Online: 1–5
[16,17]. Consistently, the results of the postmortem examination
of our patient have clearly demonstrated that transverse myelitis
was caused by spinal cord arteritis. It should also be emphasized
that vasculitic changes were also found in branches of pulmonary
arteries in our patient. It is therefore likely that vasculitis played an
important role, at least in part, in the pathogenesis of pulmonary
hypertension in our patient.
It should be pointed out that our patient showed elevation of
anti-NR2 antibodies. In this regard, recent studies have demon-
strated that anti-NR2 antibodies activate endothelial cells, result-
ing in their production of proinflammatory cytokines through
activation of NFkB [18]. It is therefore possible that anti-NR2
antibodies might be involved in the development of transverse
myelitis through induction of spinal cord vasculitis in our patient.
Further studies are required to determine the relationship between
anti-NR2 antibodies and transverse myelitis.
Conflict of interest
None.
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