RESEARCH ARTICLE Open Access
Modifications of longitudinally extensive
transverse myelitis and brainstem lesions in the
course of neuromyelitis optica (NMO): a
population-based, descriptive study
Nasrin Asgari1,5,6*, Hanne Pernille Bro Skejoe2, Soeren Thue Lillevang3, Troels Steenstrup4, Egon Stenager1,5
and Kirsten Ohm Kyvik5
Background: Neuromyelitis optica (NMO) includes transverse myelitis, optic neuritis and brain lesions.
Recent studies have indicated that the brainstem is an important site of attack in NMO. Longitudinally extensive
transverse myelitis (LETM) is an important component of the clinical diagnosis of NMO. The frequency of brainstem
and LETM lesions, changes over time of LETM and the clinical consequences in the course of NMO have only been
Methods: The study was a population-based retrospective case series with clinical and magnetic resonance
imaging (MRI) follow-up of 35 patients with definite NMO and a relapsing-remitting course.
Results: Brainstem lesions were observed in 25 patients, 18 in medulla oblongata (11 in area postrema). Lesions in
the pons, mesencephalon and diencephalon occurred in 10, 7 and 7 patients, respectively. Lesions were
symptomatic in medulla oblongata and pons, asymptomatic in mesencephalon and diencephalon. Brainstem
lesions were observed significantly more often in anti-aquaporin-4 (AQP-4) antibody positive than in seronegative
patients (p< 0.002).
LETM was demonstrated by MRI of the spinal cord in 30/36 patients, 23/30 of whom had follow-up MRI of the
spinal cord. Recurrent LETM was observed in five patients. In nine patients the LETM changed into multiple lesions
during remission or treatment. Spinal cord atrophy was observed in 12/23 (52%) patients, correlating to Expanded
Disability Status Scale (r= 0.88, p< 0.001).
Conclusions: NMO patients had frequent occurrence of brainstem lesions and LETM. Brainstem lesions were
associated with anti-AQP4 antibody positivity. LETM lesions differentiated over time and the outcome included
relapses, fragmentation and atrophy. Correlation was observed between spinal cord atrophy and neurological
Keywords: Neuromyelitis optica, Brainstem lesions, Area postrema, Longitudinally extensive transverse myelitis,
Anti-aquaporin-4 antibody, Magnetic resonance imaging
* Correspondence: email@example.com
1The Multiple Sclerosis Clinic of Southern Jutland (Vejle, Sonderborg, Esbjerg),
Jutland Vejle Hospital, Vejle DK-7100, Denmark
5Institute of Regional Research, University of Southern Denmark, Odense,
Full list of author information is available at the end of the article
© 2013 Asgari et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Asgari et al. BMC Neurology 2013, 13:33
Neuromyelitis optica (NMO) is characterized by inflam-
mation of the optic nerve and the spinal cord . Disco-
very of serum immunoglobulin G autoantibody towards
the water channel aquaporin 4 (AQP4) led to the re-
cognition of NMO patients with clinical signs and/or
lesions in the CNS outside of the optic nerve and
spinal cord [2-4].
NMO is diagnosed by the demonstration of a combi-
nation of clinical manifestations, radiological abnor-
malities and serological demonstration of anti-AQP4
antibodies . The diagnosis of definite NMO may be
made solely on clinical and magnetic resonance imaging
(MRI)-based analysis in a high proportion of cases
[2,4,5]. However, the demonstration of anti-AQP4 anti-
bodies/NMO-IgG is obligatory in the diagnosis of the
NMO spectrum disease, which includes patients with
clinical signs and/or MRI lesions in the CNS outside of
the optic nerve and spinal cord . Thus, NMO may
include more complex and heterogeneous clinical pre-
sentations with brain syndromes occasionally leading to
considerable diagnostic difficulty. A number of studies
have shown brain abnormalities as detected by MRI in
60-71% of NMO patients [3,6-9]. The brain lesions are
often localized at sites of high AQP4 expression .
The heterogeneous clinical presentations in such NMO
patients include brain syndromes such as endocrino-
pathies , posterior reversible encephalopathy syn-
drome  and brainstem syndrome. The brainstem
syndrome may lead to respiratory failure  or persis-
tent intractable hiccups and nausea [13,14].
Peripheral blood is a likely source for antibody in the
CNS , but it is not known how anti-AQP4 antibodies
reach the CNS . The clinical occurrence of brain-
stem lesions including area postrema may be related to
the areas with high density of AQP4 expression and lack
of blood brain barrier [17,18] and it has been sug-
gested that area postrema is a portal of entry to the
CNS for anti-AQP4 antibodies [13,18]. However, more
detailed studies are required to obtain evidence for
the frequency and clinical consequences of brainstem
In the spinal cord the longitudinally extensive transverse
myelitis (LETM) lesion, regarded as typical for NMO, is
characterized by involvement of three or more vertebral
segments . The changes over time of LETMs and their
long term clinical consequences have only been sparsely
The aims of the present study were to estimate the
frequency of abnormalities of the brainstem and the spinal
cord lesions during the course of NMO and to obtain
information about dynamic changes of spinal cord lesions
during long-term follow-up. Symptoms and clinical fin-
dings were reported.
A clinical database for NMO patients diagnosed in the
time period 1998-2008 in the Region of Southern
Denmark was established as part of a population-based
study reported in detail elsewhere . The study was a
population-based retrospective case series with longitu-
dinal prospective follow-up as described in detail previ-
ously . NMO patients were diagnosed according to
the Wingerchuk 2006 criteria . Information was
obtained by means of review of medical records, a ques-
tionnaire, a clinical examination, re-evaluation of previ-
ous MRIs of CNS, study examination of supplementary
MRIs and serum anti-AQP4-antibody determinations.
A total of 36 patients with definite NMO were identified in
the database and included in the present study. All patients
were Caucasians except one. All had a relapsing-remitting
course except one, who had a monophasic course. The
female: male ratio was 2.8: 1 and mean age at onset was
35.6 years (15–64 years). Disability was retrieved from the
medical records where it had been measured by Expanded
Disability Status Scale (EDSS) .
Since the study was retrospective, several types of MRI
scanners were used with a variety of imaging techniques.
T2-weighted (T2W), T1-weighted (T1W) images with
or without gadolinium (Gd), diffusion-weighted imaging
(DWI) and fluid-attenuated inversion recovery (FLAIR)
sequences were analysed in MRIs of brain. T2W, T1W
with or without gadolinium and short tau inversion
recovery (STIR) sequences were analysed in spinal cord
imaging. Supplementary MRIs of CNS were performed on
a 1.5 Tesla scanner (GE, Paris, France). The typology and
characteristics of brainstem lesions were described in de-
tail based on a combination of information from the axial
and/or sagittal T2-weighted, the T1-weighted + gadoli-
nium and FLAIR MRIs. The lesions (≥ 3 mm) were de-
scribed by location (infratentorial, medulla oblongata, area
postrema, pons, mesencephalon, diencephalon). Spinal
cord MRI was either reported as normal, as abnormal with
a shorter lesion not suggestive of NMO, or as LETM (cord
lesion extending 3 or more vertebral segments). LETMs
had a high signal on T2-weighted images and if obtained
during acute episodes of myelitis showed hypointensity on
T1-weighted images. Spinal cord atrophy was defined as a
sagittal diameter of≤4 mm on T1 weighted sequences
 and was classified with regard to extent of atrophy, 0
denotes no atrophy, focal denotes atrophy of limited ex-
tent, and general atrophy denotes changes involving both
cervical and thoracic spinal cord. The neuroradiologist
Asgari et al. BMC Neurology 2013, 13:33
Page 2 of 8
was blinded to clinical history and results of other investi-
gations. MRI data were reported in a written.
IgG AQP4 antibodies were measured with a recombi-
nant immuno-fluorescence assay using HEK293 cells
transfected with recombinant human full-length AQP4
gene [21,22]. Materials were obtained from Euroimmun
(Lubeck, Germany). Patient sera were screened at a 1:10
dilution. Analyses were done in an accredited labora-
tory at the Department of Clinical Immunology, Odense
Spinal cord atrophy was classified as no atrophy, focal
atrophy or general atrophy and EDSS was divided in
three groups (categorical variables with 3 categories).
Intergroup differences were analyzed using polychoric
correlation and Fisher’s exact test on the corresponding
3x3 tables. Statistical analyses were performed using
Stata 11 (StataCorp LP, College Station, Texas, USA).
The limit of significance was chosen as p<0.05.
Protocol approvals, registrations, and patient consent
The study which formed the basis for the database was ap-
proved by The Committee on Biomedical Research Ethics
for the Region of Southern Denmark (Ref. no. S-20080142)
and The Danish Data Protection Agency (Ref. no. 2008-
41-2826). All patients provided written informed consent.
Radiological and clinical characteristics of brainstem lesions
The frequency of brainstem abnormalities was estimated
for 31/35 NMO patients who had available follow-up
MRI analysis. Lesions were observed in the brainstem at
least once in 25/31 (81%) patients, 18 (72%) of whom
were seropositive (Table 1). MRI-lesions in the medulla
oblongata were detected in 18 (58%) patients. Of those
patients 11 had lesions in the area postrema (Figure 1).
Lesions in the pons occurred in 10/25 (40%) and in the
mesencephalon in 7/25 (28%) patients. Lastly, hypothal-
amic and thalamic lesions were observed in 7/25 (28%).
A significantly higher frequency of brainstem lesions
were observed in anti-AQP-4 antibody positive (18/18)
than in seronegative (7/13) patients (p<0.002).
Based on information from questionnaires and patient
files, lesions were uniformly symptomatic in medulla
oblongata and pons. Patients with lesions in mesence-
phalon and diencephalon did not show apparent symp-
toms. The symptoms were typically polysymptomatic
and reversible. The clinical presentation mainly reflected
dysfunction of the medulla oblongata and included
symptoms such as respiratory failure in 6/31 (19%), 5
seropositive, intractable hiccups and nausea in 9/31
(29%), 8 seropositive, vomiting and nausea in 13/31
(42%), 9 seropositive and bradycardia, blood pressure
fluctuations in 5/31 (16%), 4 seropositive. Other clinical
signs in the patients with brainstem lesions were: vertigo
23 (74%), 13 seropositive, diplopia 6 (19%), 3 seroposi-
tive, facial weakness 2 (6%), 2 seropositive, nystagmus 2
(6%), 1 seropositive and ataxia 4(13%), 3 seropositive.
Overall, anti-AQP4-antibody determinations were posi-
tive in 72% of the patients.
Radiological and clinical characteristics of spinal cord lesions
Spinal cord MRI demonstrated LETM in 30/36 patients.
Cervical LETM occurred in 21/30 (70%), 8 (27%)
reaching into the brainstem. Thoracic TM occurred in
9/30 (30%) cases. Cord lesions involving both cervical
and thoracic cord was observed in 13/30 (43%).
Table 1 Characteristics of brainstems lesions in NMO patients (31)
Clinical manifestations Anti-AQP4 antibodies positiveAnti-AQP4 antibodies negative
Number of patients= 18Number of patients=13
MRI of brain
At disease onsetAt follow-up At disease onsetAt follow-up
Topological distribution of Brainstem lesions**
F/m SymAsym EDDSF/mSym Asym EDDS
2-4 5-78-92-4 5-78-9
Medulla oblongata10/2120444 4/260240
Area postrema6/280332 1/230012
Hypothalamic and thalamic5/005122 1/100110
* = meeting the Barkhof criteria for dissemination in space used in the McDonald criteria as described previously . ** = Lesions were observed in the brainstem
a total of 25/31 NMO patients.
Asgari et al. BMC Neurology 2013, 13:33
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The patients with LETM had symptoms including
tetraplegia or paraplegia, a well-defined symmetric sen-
sory affection and different degrees of pain and paroxys-
mal tonic spasms of the trunk and the extremities. The
cervical lesions tended to be accompanied by sphincter
dysfunction to a higher degree than the thoracic lesions.
Out of 30 patients 23 had follow-up MRIs of spinal
cord, 17/23 (74%) were anti-AQP4 seropositive (Table 2).
Recurrent LETM was observed in 5/23 patients (22%),
all female. Following treatment with high-dose steroids,
LETMs changed into multiple shorter plaques in 9/23
(39%) patients. Primary MRI was performed within two
days of symptoms followed by treatment with high-dose
steroids. The time interval from steroid treatment to the
control MRI was three to six months (Figures 2 and 3).
Evaluation of spinal cord atrophy was determined in
23/30 NMO patients who had follow-up MRIs over a
period of time. Focal spinal cord atrophy at the site of
Figure 1 Typical brain MRI lesions in neuromyelitis optica. Representative MRI of six NMO patients; Upper row: FLAIR; lower row: T2W, A.
Lesions in hypothalamic region, B. Lesions in periaqueductal matter in mesencephalon, C and D. Lesions in medulla oblongata, E and F. Lesions
in area postrema of the medulla oblongata.
Table 2 Clinical characterisation and MRI follow-up of NMO patients with longitudinally extensive transverse myelitis
(LETM) (n= 23)
Number of patients=17
F/M Anti-AQP4 antibodies positive F/M Anti-AQP4 antibodies negative
Number of patients= 6
Duration of diseaseEDSS Score Duration of diseaseEDSS Score
2-4 y5-10 y2-4 5-78-9 2-4 y5-10 y2-45-78-9
MRI of the spinal cord
Single LETM14/317107557 3/3633141
Brainstem involvement 7/0752016 1/0101001
Relapsing LETM4/0431013 1/0110010
Multiple shorter TM5/1642015 1/2321021
Focal atrophy of SC0000000 3/2550050
General atrophy of SC4/1541005 1/1211002
F/M = Female/male, EDSS = Expanded Disability Status Scale, LETM = longitudinally extensive transverse myelitis, SC = Spinal cord, TM = Transverse myelitis.
Asgari et al. BMC Neurology 2013, 13:33
Page 4 of 8
previous LETM was seen in 5/23 (22%) patients, after
2-4 year duration of disease and with an EDSS score of 5-7.
General spinal cord atrophy was observed in 7/23 (30%)
patients after 2-4 years duration of disease in two and after
5-10 years in five with an EDDS score of 7-9. A strong
correlation was observed (r=0.88) between the occurrence
of spinal cord atrophy and disability as analyzed by
the polychoric correlation and the Fisher’s exact test
(p<0.001). Normal appearance of the spinal cord was only
observed in 3/23 (13%) patients and myelitis lesions shorter
than LETM were found in 7/23 (30%) patients, after
2-4 year duration of disease with an EDSS score of 2-4
(Figures 2 and 4).
In the present study of 35 cases from a population-based
NMO cohort a high frequency of brainstem lesions and
corresponding clinical signs was observed. Brainstem
abnormalities were detected by MRI in 81%, the majority
observed in the medulla oblongata (58%) including 35%
with lesions in the area postrema. Brainstem lesions
were observed more often in AQP4 antibody positive
than in seronegative patients (p<0.002). There was a
high degree of agreement between MRI and clinical
presentation of brainstem lesions. The study supports
the notion that the brainstem, in particular medulla
oblongata and area postrema, are important points of
attack in NMO [13,18]. These data are in accordance
with a multicenter study in Caucasians that found that
seropositive patients were predominantly female and
had a more severe clinical course . Furthermore, a
study from China observed that lesions in the brainstem
occurred in a significant proportion of patients .
A relative lack of intrathecal synthesis of anti-AQP4
antibodies/NMO-IgG [24,25] and perivascular pathology
in NMO suggests entry of antibody from blood vessels
to CNS . The BBB restricts entry of serum proteins
into the CNS . However, the BBB is not absolute,
notably in circumventricular areas including the area
Figure 2 Characteristics of follow-up MRI of longitudinally
extensive transverse myelitis (LETM) in 23 NMO patients.
Figure 3 Modifications of longitudinally extensive transverse myelitis (LETM). Spinal cord MRI: sagittal T2WI of spinal cord from an
anti-AQP4 antibody positive patient with NMO A: primary LETM in the upper thoracic cord (arrow) extending from Th1 – 6 (lower limit not
shown) B: Fragmentation (small arrows) of the earlier LETM following treatment with high-dose steroids and a new LETM (circle) in the lower
cervical cord 3 months later.
Asgari et al. BMC Neurology 2013, 13:33
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