brain

sciences
Article
NMOSD—Diagnostic Dilemmas Leading towards
Final Diagnosis
Anna K. Szewczyk 1,2, * , Ewa Papuć 2 , Krystyna Mitosek-Szewczyk 3 , Michał Woś 4 and Konrad Rejdak 2, *

1 Doctoral School, Medical University of Lublin, ul. Chodźki 7, 20-093 Lublin, Poland
2 Department of Neurology, Medical University of Lublin, ul. Jaczewskiego 8, 20-954 Lublin, Poland;
oddzial.neurologii@spsk4.lublin.pl
3 Department of Child Neurology, Medical University of Lublin, ul. Profesora Antoniego Gebali 6,
20-093 Lublin, Poland; neurologia@uszd.lublin.pl
4 Department of Medical Informatics and Statistics with E-Learning Lab, ul. Jaczewskiego 4,
20-090 Lublin, Poland; ziism@umlub.pl
* Correspondence: szewczyk.anna1@gmail.com (A.K.S.); konrad.rejdak@umlub.pl (K.R.)

Abstract: (1) Background: The emergence of white matter lesions in the central nervous system
(CNS) can lead to diagnostic dilemmas. They are a common radiological symptom and their patterns
may overlap CNS or systemic diseases and provoke underdiagnosis or misdiagnosis. The aim of
the study was to assess factors influencing the underdiagnosis of neuromyelitis optica spectrum
disorder (NMOSD) as well as to estimate NMOSD epidemiology in Lubelskie voivodeship, Poland.
(2) Methods: This retrospective study included 1112 patients, who were made a tentative or an
established diagnosis of acute or subacute onset of neurological deficits. The evaluation was based
on medical history, neurological examination, laboratory and radiographic results and fulfilment of
diagnosis criteria. (3) Results: Up to 1.62 percent of patients diagnosed with white matter lesions and
up to 2.2% of the patients previously diagnosed with MS may suffer from NMOSD. The duration of
Citation: Szewczyk, A.K.; Papuć, E.; delayed diagnosis is longer for males, despite the earlier age of onset. Seropositive cases for antibodies
Mitosek-Szewczyk, K.; Woś, M.; against aquaporin-4 have worse prognosis for degree of disability. (4) Conclusions: Underdiagnosis
Rejdak, K. NMOSD—Diagnostic or misdiagnosis in NMOSD still remains a problem in clinical practice and has important implications
Dilemmas Leading towards Final for patients. The incorrect diagnosis is caused by atypical presentation or NMOSD-mimics; however,
Diagnosis. Brain Sci. 2022, 12, 885. covariates such as gender, onset and diagnosis age may also have an influence.
https://doi.org/10.3390/
brainsci12070885 Keywords: NMOSD; neuromyelitis optica; underdiagnosis; misdiagnosis; AQP4 antibody; multiple
Academic Editors: Pierre Duquette sclerosis; white matter hyperintensities; white matter lesions; epidemiology
and Chitra Mandyam

Received: 15 April 2022

Accepted: 4 July 2022
1. Introduction
Published: 6 July 2022
Immense advancements in the field of imaging enabled neuroradiology to present
Publisher’s Note: MDPI stays neutral specialists with incredible amounts of information in the case of many patients. Data and
with regard to jurisdictional claims in
the diagnostic images are incomparably more accurate with every passing year. Brain
published maps and institutional affil-
lesions are among the most frequently discovered abnormalities diagnosed. One of the
iations.
most common findings in adults are white matter lesions (WML) or white matter hyperin-
tensities (WMH). They are characterized by a hyperintense signal on T2-weighted magnetic
resonance imaging (MRI) [1]. The emergence of WML can lead to diagnostic dilemmas be-
Copyright: © 2022 by the authors.
cause they are a common radiological symptom and their pattern may overlap in particular
Licensee MDPI, Basel, Switzerland.
central nervous system (CNS), cerebrovascular or systemic diseases, which can provoke
This article is an open access article misdiagnosis or underdiagnosis [2].
distributed under the terms and One of the diseases for which changes in white matter have been identified is neu-
conditions of the Creative Commons romyelitis optica spectrum disorders (NMOSD). Symptoms of the disease are not pathog-
Attribution (CC BY) license (https:// nomonic; therefore, NMOSD should be differentiated from other entities. Besides the
creativecommons.org/licenses/by/ clinical presentation, the results of laboratory and neuroimaging are taken into account.
4.0/). The diagnostic criteria currently distinguish two types of NMOSD: with a positive or

Brain Sci. 2022, 12, 885. https://doi.org/10.3390/brainsci12070885 https://www.mdpi.com/journal/brainsci

Brain Sci. 2022, 12, 885 2 of 14

negative/unknown test for antibodies against aquaporin 4 in the immunoglobulin G class

(AQP4-Ab). According to the “Core clinical characteristic” criteria, 1 of 6 CNS regions may
be involved: optic nerve(s), spinal cord, area postrema of the dorsal medulla, brainstem,
cerebellum or diencephalon [3].
The basic role in the appearance of NMOSD is attributed to antibodies against bilateral
astrocytic water channels—aquaporin 4. They are a good marker of the disease activity,
because they can be detected both before and after the onset of the disease [4]. The
binding of AQP4 immunoglobulin G to astrocytic water channels activates inflammatory
events. Activation of the complement system results in lymphocytic infiltration, necrosis
and extensive destruction of further CNS cells, i.e., neuronal cells and oligodendrocytes.
Immunoglobulins specifically binding to astrocytes show the highest affinity for binding
to spinal cord and optic nerve astrocytes, whereas binding to astrocytes in the brain
is weaker [5,6]. As a result of this reaction, neurological defects occur. Non-specific
distribution of aquaporin 4 channels leads to the occasional appearance of symptoms from
other parts of the body. Outside the nervous system, the presence of these channels has
been described in peripheral AQP4-expressing cells [7] of various organs such as kidneys,
lungs or skeletal muscle [8].
Immunotherapy, clinically homogeneous phenotypes with heterogeneous pathogen-
esis, and insufficient sensitivity of the diagnostic test may affect false serostatus results
of the AQP4-Ab marker. In use, it is recommended to utilize the cell-based assays (CBA)
method, whose mean sensitivity is 76% and false-positive rate is 0.1% [9–11]. In the case
of AQP4-Ab negative patients, additional tests can be considered, e.g., anti-myelin oligo-
dendrocyte glycoproteins (anti-MOG antibodies) and probably antibodies for aquaporin 1
(AQP1-Ab) [9,12–14].
The aim of this study was to find a correlation between gender, serological status,
number of relapses, disability status or duration of delayed diagnosis. We also tried to
estimate NMOSD epidemiology in Lubelskie voivodeship, Poland. To select the proper
literature, a systematic search in the PubMed/MEDLINE database was prepared, based
on the preferred reporting items for systematic reviews and meta-analysis (PRISMA)
guidelines. The studies were published in Polish, English and French languages. Titles and
abstracts of publications were searched for the following key words: NMOSD, MS, ADEM,
white matter lesions, white matter hyperintensities, epidemiology, prognosis, quality of
life, laboratory markers, and AQP4-IgG.

2. Materials and Methods

This retrospective study included 1112 patients, who were hospitalized or transferred
to our department between the end of 2014 and mid-2018 to make a tentative possible or
an established diagnosis of acute or subacute onset of neurological deficits, which may
indicate damage to the CNS. These abnormalities in the neurological examination occurred
in conjunction with uncharacteristic and/or unclear morphology, hyperintense lesions
within the white matter in MRI of the head, which could correspond, among others, to
demyelinating or vascular lesions and required further differential diagnosis. Patient eval-
uation was made according to current diagnosis criteria for MS (2010 or 2017 McDonald
criteria for diagnosis of multiple sclerosis [15,16]), NMOSD (the International Panel for
NMO Diagnostic for NMOSD diagnosis [3]) and acute disseminated encephalomyelitis
(ADEM) (2012 revised IPMSSG criteria) [17,18]. The final diagnosis was based on previous
medical history, physical examination (including neurological examination) as well as
laboratory results. During the hospitalization, all patients underwent lumbar puncture
with the assessment of the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid
(CSF) as well as laboratory tests for tick-borne meningitis and viral diseases (cytomegaly
virus CMV, human immunodeficiency viruses HIV, Epstein–Barr virus, herpes simplex
virus). Furthermore, to rule out some systemic diseases, patients were tested for vascular or
coagulation disorders (e.g., Protein C and S, Homocysteine and antibodies of autoimmune
diseases (including p-ANCA, c-ANCA, anti-cardiolipin antibodies, thyroid peroxidase
Brain Sci. 2022, 12, 885 3 of 14

(TPO) antibody, thyroglobulin antibody (TGAB) and Lupus anticoagulant (LA)). If neces-
sary, procedures were extended to spinal cord MRI. Neoplastic screening was performed in
all patients up to 40 years old.
The aquaporin-4 antibody test was performed on patients who had not fulfilled the
diagnostic criteria for MS or have had a very severe relapse, responding poorly to treatment
with intravenous methylprednisolone (patients with an already stated diagnosis were also
taken into account). The anti-aquaporin 4 antibody was detected in the serum through a
CBA (outsourcing). The criterion excluding from this analysis was the patient’s lack of
consent to perform a lumbar puncture and prior diagnosis of clinically isolated syndrome
(CIS). CIS is defined as an episode lasting at least 24 h with or without recovery, when
patient reported and presented symptoms reflecting acute or subacute multifocal or focal
inflammatory demyelinating event in the CNS. This episode was not associated with
infection or fever and was similar to typical MS relapse with the proviso that patient was
never diagnosed with MS [16].
Furthermore, the group categorized as NMOSD was subjected to statistical analysis.
Statistical analysis was performed using Statistica software (version 13, StatSoft, Lublin,
Poland) using Mann–Whitney U test. Data expressed on a quantitative scale are pre-
sented as mean with standard deviation (SD). The level of statistical significance was set at
p < 0.05.

3. Results
The whole group comprised 796 women and 316 men, all Caucasian type and orig-
inating from Lubelskie voivodeship, wherein the ratio of women to men was 2.52:1. Of
1112 patients, 18 people, or 1.62%, suffered from NMOSD. Others were diagnosed with MS
801 (72.03%), ADEM 16 (1.44%) and yet other 277 (24.91%) with non-specific white matter
lesions (NSWML). The estimated average prevalence rate of NMOSD in the Lubelskie
voivodeship (a region located in southeastern Poland) was 0.86:100,000. When assessing
the annual rate, the yearly index is assumed as 4.5 cases per year (estimated incidence rate
was 0.21:100,000). The annualized relapse rate (ARR) ratio was 1.13 ± 0.67.
A detailed description of 18 Caucasian patients eventually diagnosed with NMOSD is
provided in Table 1. The ratio between women and men was 3.5:1. All patients were tested
for the presence of OCBs in the CSF and had MRI of the head and spinal cord per-formed,
which excluded the possibility of MS diagnosis.
A statistical evaluation of collected data divided into gender and serostatus is given
in Table 2. The average age of NMOSD onset was 44.67 ± 24.53 years. For women, it was
higher than for men: 45.14 ± 16.94 and 43.00 ± 16.39, retrospectively. Considering only the
group of women, the first symptoms of the disease appeared later in the seronegative than
in the seropositive group (48.00 ± 11.46 vs. 44.00 ± 19.13). For both genders, the average
duration of delayed diagnosis was 5.28 ± 6.90 years; for female patients it was shorter than
for male (p = 0.056), as illustrated in Figure 1.
The average expanded disability status scale (EDSS) at the last visit (based on the
information card of hospital treatment) was 5.00 ± 3.21. The average EDSS in women was
5.46 ± 1.95 and was higher in AQP4−Ab-positive than AQP4−Ab-negative females (6.15
± 1.84 vs. 3.75 ± 0.87). These results may be related to the average number of relapses 4.70
± 2.58 and 3.00 ± 1.16, respectively, for seropositive and seronegative women. EDSS in
men had a lower value of 3.38 ± 2.25, while the average number of relapses 3.00 ± 1.15
was similar to seropositive women. Figure 2 shows that average number of relapses for
women was higher than for men (p = 0.034).
Brain Sci. 2022, 12, 885 4 of 14

Table 1. Description of the disease course for every patient (end 2014–mid 2018). ON—optic neuritis,
AM—acute myelitis, AQP4-Ab—aquaporin-4 antibody, EDSS—expanded disability status scale,
NMOSD—neuromyelitis optica spectrum disorder.

Clinical
Patient Duration of
Onset Age AQP4-Ab First Attack Total Number Presentation
Ordinal Sex Delayed Diagnosis First Diagnosis
(Years) Status Area of Relapses at the Last
Number (Years)
Visit (EDSS)
1 Woman 36 12 + Pituitary adenoma ON + AM 8 6.5
Symptomatic
2 Woman 76 2 + Ischemic stroke cerebral 5 7.5
syndrome
Suspicion of
3 Woman 15 3 + ON + AM 2 4.0
NMOSD
Symptomatic
Vascular brain
4 Woman 53 8 + cerebral 5 8.5
damage
syndrome
5 Woman 64 4 + Genetic disease AM 3 7.0
Suspicion of
6 Woman 32 1 + AM 1 4.5
NMOSD
7 Woman 33 15 + Multiple sclerosis ON 8 7.5
8 Woman 42 3 + ON ON 6 3.5
9 Woman 27 10 + Multiple sclerosis ON 7 8.0
Suspicion of
10 Woman 62 1 + AM 2 4.5
NMOSD
Unspecific
11 Woman 65 1 − demyelinating AM 2 3.5
syndrome
12 Woman 43 3 − Spinal cord tumor AM 4 3.5
13 Woman 44 6 − ON ON 4 3.0
Myelitis and/or
14 Woman 40 1 − AM 2 5.0
encephalitis
Unspecific
15 Man 43 5 − demyelinating AM 4 3.5
syndrome
16 Man 20 14 − ON ON 2 1.5
Unspecific
17 Man 57 4 − demyelinating AM 4 6.5
syndrome
Unspecific
18 Man 52 2 − demyelinating AM 2 2.0
syndrome

Table 2. Statistical evaluation of data broken down by gender and serostatus. W—women, M—
men, B—both women and men, AQP4+—present antibodies against aquaporin 4, AQP4−—absent
antibodies against aquaporin 4.

Gender and Standard

Average Median Minimum Maximum
Serostatus Deviation
B 44.67 43 15 76 24.53
W 45.14 42.5 15 76 16.94
Onset age (years) W AQP4+ 44 39 15 76 19.13
W AQP4− 48 43.5 40 65 11.46
M 43 47.5 20 57 16.39
B 5.28 3.5 1 15 6.90
Duration of W 5 3 1 15 4.56
delayed diagnosis W AQP4+ 5.90 3.50 1 15 5.00
(years) W AQP4− 2.75 2 1 6 2.36
M 6.25 4.50 2 14 5.32
B 3.94 4 1 8 3.27
W 4.21 4 1 8 2.36
Total number of
W AQP4+ 4.70 5 1 8 2.58
relapses
W AQP4− 3 3 2 4 1.16
M 3 3 2 4 1.15
B 5 4.5 1.5 8.5 3.21
Clinical
W 5.46 4.75 3 8.50 1.95
presentation at
W AQP4+ 6.15 6.75 3.50 8.50 1.84
the last visit
W AQP4− 3.75 3.50 3 5 0.87
(EDSS)
M 3.38 2.75 1.50 6.50 2.25
 tation at the W AQP4+ 6.15 6.75 3.50 8.50 1.84
ast visit (EDSS) W AQP4− 3.75 3.50 3 5 0.87
M 3.38 2.75 1.50 6.50 2.25

Brain Sci. 2022, 12, 885 5 of 14

Brain Sci. 2022, 12, x FOR PEER REVIEW 6 of 15

Figure 1. Duration of delayed diagnosis in women and men (average value in years).

Figure 1. Duration of delayed diagnosis in women and men (average value in years).

The average expanded disability status scale (EDSS) at the last visit (based on the
information card of hospital treatment) was 5.00 ± 3.21. The average EDSS in women was
5.46 ± 1.95 and was higher in AQP4−Ab-positive than AQP4−Ab-negative females (6.15 ±
1.84 vs. 3.75 ± 0.87). These results may be related to the average number of relapses 4.70 ±
2.58 and 3.00 ± 1.16, respectively, for seropositive and seronegative women. EDSS in men
had a lower value of 3.38 ± 2.25, while the average number of relapses 3.00 ± 1.15 was
similar to seropositive women. Figure 2 shows that average number of relapses for women
was higher than for men (p = 0.034).

Figure 2. Total number of relapses in women and men (average value).

Figure 2. Total number of relapses in women and men (average value).
Evaluating concomitant diseases or infections, there was no autoimmune disease in
any of the subjects in the study group. Almost half of the patients (eight people) had disease
Evaluating concomitant diseases or infections, there was no autoimmune disease in
relapses after inflammation of the bladder or the urinary tract. Micturition disorders that
any of the subjects in the study group. Almost half of the patients (eight people) had dis-
appear and strengthen with the duration of the disease may secondarily result in more
ease relapses after inflammation of the bladder or the urinary tract. Micturition disorders
frequent infections. Additionally, 40% of patients reported psychiatric problems such as
that appear and strengthen with the duration of the disease may secondarily result in
depression, suicidal thoughts, and alcoholism.
more frequent infections. Additionally, 40% of patients reported psychiatric problems
All patients admitted to the hospital during the relapse received intravenous methyl-
such as depression, suicidal thoughts, and alcoholism.
prednisolone. The duration of treatment depended on the drug tolerance; however, most of
All patients admitted to the hospital during the relapse received intravenous
the patients received the full treatment, 5 g in total (1 g daily for 5 days, intravenously). In
methylprednisolone.
order The duration
to prolong the therapeutic of treatment
effect, some patients depended on the drug tolerance;
received methylprednisolone how-
or pred-
ever, most of the patients received the full treatment, 5 g in total (1 g daily
nisone orally, with dose maintenance or gradual reduction in the dose, for home use. In the for 5 days,
caseintravenously).
of an incomplete Inresponse
order to prolong the
to treatment therapeutic
or no therapeuticeffect, some
effect of patientsmethyl-
intravenous received
prednisolone (which was especially noticeable during severe relapses), several patients in
methylprednisolone or prednisone orally, with dose maintenance or gradual reduction
the dose,either
underwent for home use. In the case(three
a plasmapheresis of an to
incomplete responsecases,
five cycles)—five to treatment or no therapeu-
or immunoglobulin
tic(dose
cycle effectaccording
of intravenous
to bodymethylprednisolone
weight)—two patients. (which was especially noticeable during se-
vere
At the time of making the diagnosis of NMOSD,asome
relapses), several patients underwent either plasmapheresis (three to
patients switched tofive cycles)—
treatment
five cases, or immunoglobulin cycle (dose according to body weight)—two
with azathioprine (four people) or rituximab (one person); however, due to poor tolerance of patients.
At the time of making the diagnosis of NMOSD, some patients switched to treatment
with azathioprine (four people) or rituximab (one person); however, due to poor tolerance
of the drug, three patients withdrew from azathioprine treatment. Prior to the final diag-
nosis of NMOSD, patients diagnosed with MS received as treatment: cladribine, metho-
Brain Sci. 2022, 12, 885 6 of 14

the drug, three patients withdrew from azathioprine treatment. Prior to the final diagnosis
of NMOSD, patients diagnosed with MS received as treatment: cladribine, methotrexate,
interferon beta-1b or glatiramer acetate, with a weak therapeutic effect.
In accordance with diagnostic criteria, all AQP4-Ab-seropositive patients had at least
one core clinical characteristic (in this group we observed optic neuritis, acute myelitis or
area postrema syndrome); alternative diagnosis was excluded. In a seronegative group,
to allow for the diagnosis, at least one core clinical characteristic (optic neuritis, acute
myelitis or acute brainstem syndrome), dissemination in space and fulfilment of additional
MRI was required. Each AQP4-Ab-negative patient had longitudinal extensive myelitis
(LETM), involving at least three contiguous segments of the spinal cord, observed in
neuroradiological studies.

4. Discussion
4.1. Misdiagnosis and Underdiagnosis
Practitioners must be very sensitive and aware of the pitfalls not only in the diagnosis
of MS [19], but also in other disease entities with WML. The nature and type of neurologi-
cal symptoms presented by the patient should, together with neurological examination,
laboratory and imaging results, influence the diagnosis. Sometimes, in the unclear cases, an
interdisciplinary assessment would be invaluable. A misleading radiological result can be
observed in diseases such as primary systemic diseases and vasculopathies but also infec-
tious and genetic pathologies; therefore, the need to use specific serological markers (such
as antibodies) that could direct us to the correct diagnosis seems to be enormous [2,19].
This study found that underdiagnosis of NMOSD is still a common problem which
may be associated with many factors. The literature describes cases of imitation of NMOSD
by other diseases [20,21], also in children [22]. Perhaps, the complexity of the diagnostic
process may be a problem as well as the long time period from the appearance of the
first symptom to diagnosis of NMOSD, as has already been described for MS [23,24].
Unfortunately, making an incorrect diagnosis can be associated with significant patient’s
risk, morbidity and large financial outlays. Our analysis showed that the duration of
delayed diagnosis may reach even 5.28 ± 6.89 years and is longer for men compared
to women (p = 0.056), while time without treatment or with improper treatment is of
paramount importance. The shortest duration of misdiagnosis was obtained for women
and was less than 3 years.
At the moment, there is little literature regarding the subject of incorrect diagnosis
in NMOSD but there is some about misdiagnosis in MS. Kaisey et al. (2019) [25] eval-
uated a cohort of patients with a new diagnosis of MS and estimated the incidence of
MS misdiagnosis. Of 241 patients referred to academic MS referral centers, 43 patients
had incorrect diagnoses. The most common correct diagnosis was migraine, autoimmune
disease (including two cases with NMOSD), miscellaneous, e.g., peripheral neuropathy,
and optic neuropathy. Probably, misdiagnosis arose because of incorrect application of
diagnostic criteria or misinterpretation. It seems that the above problems should also be
taken into account when making the diagnosis of NMOSD. In case of an atypical disease
course, observation or further evaluation is recommended, instead of making an immediate
diagnosis of MS [26]. In our study group, only 3 patients out of 18 (16.67%) obtained a sus-
picion of NMOSD from the very beginning of the disease. Among the remaining patients,
the most common first diagnoses were either unspecified demyelinating syndrome, optic
neuritis or MS.
It has not been suggested that in case of typical clinical or radiological manifestation of
multiple sclerosis, clinicians need to perform testing for AQP4−Ab or MOG-Ab. Moreover,
the use of cerebrospinal fluid instead of blood serum can lead to a delay and missed
diagnosis of NMOSD—detection of the antibody can be missed. It was previously informed
that about 7% of patients initially diagnosed as having MS may have a diagnosis of
NMOSD [27]; our results amounted to 2.2% (18 from 819).
Brain Sci. 2022, 12, 885 7 of 14

It is surprising that among the first diagnoses, units such as tumors (pituitary adenoma,
spinal cord tumor), myelitis and/or encephalomyelitis, and cerebrovascular disorders
(ischemic stroke and vascular brain diseases) appeared. Analyzing the symptoms presented
by patients during the initial diagnosis, visual disturbances and sphincter disorders caused
the greatest diagnostic dilemmas. Additionally, the age at which first symptoms appeared
and family history had an important influence on misdiagnosis.
The family history of adrenoleukodystrophy in a nephew and slowly long-term pro-
gressive spastic paresis may have influenced the diagnosis of adrenomyeloneuropathy
(AMN), the adult form of X-linked adrenoleukodystrophy (X-ALD). However, it is not
exceptional that X-ALD is misdiagnosed with MS [28,29].
Visual disturbances were seen in the patient diagnosed with pituitary adenoma and
vascular brain damage. One of the patients presented progressive visual impairment in
one, then in both eyes, and was assessed in the department of ophthalmology. An MRI of
the head and eye sockets, made at a later date, excluded the above diagnosis. A second
patient with visual impairment presented also headaches and dizziness. Disseminated
vascular lesions localized subcortically were described in the MRI of the head; however,
post-inflammatory thinning of the optic junction was noted. In this case, an unequivocal
diagnosis of vascular diseases can be surprising. A 76-year-old patient fell down and pre-
sented poorly reversible hemiparesis. Presented symptoms, patient’s age and head-imaging
examination suggested vascular disease influenced ischemic stroke diagnosis; however,
in time, this patient presented more symptoms, which required extended diagnostics and
correction of the first diagnosis.
Sphincter disorders have been observed in patients diagnosed with spinal cord tumors
and myelitis and/or encephalomyelitis. The first patient showed spastic paresis with im-
paired sensation. The second one presented sudden flaccid paresis of the lower limbs, with
exclusion of polyneuropathy and spinal cord hernia in a lumbosacral MRI. Several similar
cases in the literature can be found [30–32]. Additionally, it has been suggested that correct
diagnosis in elderly patients may be hampered by vascular changes (T2/FLAIR-weighted
imaging in MRI) visible in head-imaging studies arising with age and the overlapping of
inflammatory changes resulting from the ongoing disease [33]. Age-related and vascular
changes are the most common causes of WML in the elderly, but MS lesions can have
similar symptoms [34].
Perhaps, the extended time to diagnosis may be due to hospitalizing and diagnosing
patients in various hospitals (e.g., with smaller diagnostic capabilities). It follows from
our observation that patients diagnosed with optic neuritis are often not referred or do
not report themselves for further diagnosis to neurological departments, and until next
relapse they disappear from the care system. It also appears that making a diagnosis of MS
with the onset of ON slows down further differential diagnosis, especially with regard to
the appearance of subsequent relapses (e.g., patient number 7, 9, as well as 1). Interesting
results were observed by Khalilidehkordi et al. (2020) [35], suggesting that ON, especially
as the first relapse, is more common in NMOSD than MS. The frequency of ON is higher
at a younger age and with aging, relapses turn into transverse myelitis. We can observe a
very similar tendency in our group of respondents.
An additional problem in the diagnosis of patients with suspicion of NMOSD is
the presence of oligoclonal bands in CSF. In our group, all patients tested for OCB were
negative; however, Jarius S. et al. reported their presence in approx. 18% of seropositive
cases and they disappear during disease remission. Similarly, 8% of CSF samples during
relapses demonstrated intrathecal IgG synthesis [36,37].

4.2. Demography
According to demographic characteristics, NMOSD is more common in women, but
demography is also dependent on the disease phase. The average female to male ratio of
2.5:1 or even 9:1 [38] is decomposed into patients with single-phase disease—1:1 and the
group of patients with relapsing NMOSD—5:1 [39]. Many centers received other statistical
Brain Sci. 2022, 12, 885 8 of 14

data; therefore, the changes in the incidence of the disease taken into account depend on the
racial and geographical origin of the subject [40,41]. Our study confirmed the predominance
of women with NMOSD over men. The average female to male ratio is 3.5:1, while for
relapsing NMOSD ratio is estimated at 3.25:1. We observed single-phase disease only in
one case of a seropositive woman.
In this study, the median age of illness was 43 years, while statistical data report 39
years. With age, the number of seropositive women increases, and is the highest at the
age of 65 [39,41]. In our sample, we observed a lower age of onset of symptoms in men
compared to women (43.00 ± 16.39 vs. 45.14 ± 16.94); additionally, seropositive women
were older in comparison to seronegative.
Population-based studies show a worldwide incidence of about 0.05–0.4 per 100,000
and a prevalence of 0.52–4.4 per 100,000 people [41,42]. In the Caucasian population, the
prevalence (according to the criteria from 2006) was 1.007 and the incidence was 0.0286 per
100,000 person-years. The prevalence increased 1.9-fold by applying criteria from 2015. For
countries closest to Poland, the prevalence was: Austria, 0.7 per 100,000; Catalonia, 0.89 per
100,000; Northwest England, 0.72 per 100,000; and Southeast Wales, 1.96 per 100,000 [43].
For countries bordering Poland, the most recent epidemiological study performed in
Slovakia estimate the crude incidence rate was 0.88 per 1,000,000 person-years and the
age-adjusted point prevalence rate was 1.42 per 100,000 persons [44]. For the central-
east Europe country of Hungary, the numbers published in 2020, the authors reported
the crude prevalence was 1.91 per 100,000 persons and the age-standardized prevalence
was 1.87 per 100,000 persons [45]. We estimate that the prevalence in Poland should be
similar but there are no proven data. For our region of Poland, the estimated average
prevalence rate was 0.86:100,000 and incidence rate was 0.21:100,000. The authors decided
to deal with this topic due to the lack of epidemiological data regarding NMOSD on the
Polish population as well as smaller, local data. Among the available epidemiological
data concerning demyelinating disorders in the Polish population, data collected from
administrative health claims concerning MS incidence and prevalence in adults [46] and
children [47] can be found and agree with numbers shown for central European countries.

4.3. The Annualized Relapse Rate

Due to the fact that clinical prognosis in NMOSD is directly related to relapse, we tried
to estimate the mean annualized relapse rate (ARR) ratio. For our group of responders,
the mean ARR was 1.13 ± 0.67. Pittock et al. (2019), in the randomized, double-blind,
time-to-time trial of a total 143 patients, report the mean annualized relapse rate (ARR ±
SD) before obtaining the treatment with eculizumab at 1.99 ± 0.9 [48].
When comparing NMOSD and MS, relapses are almost two times more frequent in
the first one and give higher disability. Data from the USA and Germany point out that
the economic and health resource burden are the highest when the patient is in the active
disease period (with physical impairment and/or permanent disability). The disproportion
of healthcare resources and costs between active and inactive months of observation were
EUR 7159.08 and EUR 714.17, respectively. These results may be related to the frequency of
hospital admissions, extended duration of hospitalization as well as expenses associated
with outpatient prescriptions [35,49]. Using effective therapies would be beneficial for the
diminution of healthcare and clinical burden (e.g., relapse risk reduction) [50] as well as
the burden of concomitant comorbidities [51].

4.4. Impact on Quality of Life

The high rate of EDSS is reported as one of the main factors predicting quality of life
(QoL) [52]. Rehabilitation of a patient is important because it allows for at least partial
return to the activity of everyday life [53]. The disease is progressive and with each relapse
it leads to increased disability in the form of paralysis and/or blindness as well as to a
decrease in the QoL of patients [54]. Mealy et al. (2019) conducted a study on a group
of AQP4-positive patients, noting, as in our studies, higher disability in elderly patients.
Brain Sci. 2022, 12, 885 9 of 14

Possibly, this is due to decreased neuroplasticity or increased severity of attacks and poorer
healing. The factors presented above seem to indicate a need for increased aggressiveness
of treatment in the elderly.
Our research shows that seropositive cases (EDSS 6.15 ± 1.84) have a worse prognosis
for the future degree of disability than seronegative cases (EDSS 3.75 ± 0.87 seronegative
women and 3.75 ± 0.87 group of men). Additionally, statistical significance was obtained
between the average EDSS range for women and men (p = 0.034). These results may be
related to the average number of relapses, which for seropositive women is higher than
for seronegative cases. A positive correlation between the duration of the diseases (here,
older age) and the number of relapses can be seen, while older women achieve higher
EDSS scores in a shorter time than younger cases. Additionally, quite a high percentage of
disability at the end of assessment was seen in the study group, with EDSS 5.0 and higher
obtained by eight patients, which means mobility impairment.
Our sample showed a psychiatric problem in up to 40% of patients. Quality of
life, disability, chronic fatigue and pain can strongly affect this result. NMOSD patients
with concurrent pain are more likely to experience depression compared to non-painful
patients. [55,56]. Chronic fatigue affects up to 71% of patients with NMOSD and may be
associated with treatment, mood or sleep disorders [52,57].

4.5. Treatment
The majority of patients with acute exacerbation of the disease were treated with glu-
cocorticoid infusions, plasmapheresis or administration of intravenous immunoglobulins
(IVIg). As recommended, treatment with corticosteroids should be carried out for 3–5 days
at a dose of 1 g per day [58]. Methylprednisolone is often a well-tolerated intravenous drug.
After intravenous pulses, it is advisable to initiate oral corticotherapy with prednisone for a
period of up to 2–6 months. The length of treatment depends on the severity of the relapse
and the improvement after treatment. It is an anti-inflammatory and immunosuppressive
therapy that aims to reduce the oedema and inflammatory response in the spinal cord.
Plasmapheresis/plasma exchange (PLEX) is included in the treatment if there is no response
to corticosteroids or the response is very poor. In total, five to seven cycles of plasmaphere-
sis are recommended (over a 2-week period). Studies show that plasma exchange has
a greater impact on reducing the degree of disability after acute myelitis. Intravenous
administration of immunoglobulins is not typically used, although it may be an alternative
to plasmapheresis. Azathioprine, rituximab, mycophenolate mofetil, methotrexate and
mitoxantrone are mentioned as preventive treatments [59,60]; however, as our research
shows, they are not always well tolerated by patients. For currently available drugs such as
rituximab, mycophenolate mofetil and azathioprine, the American Academy of Neurology
give class IV (Level U of recommendation for clinical practice) [61]. It is well known that
certain MS treatments can increase the severity or frequency of NMOSD relapses [62,63].
Studies indicated that some patients underwent superfluous MS disease-modifying therapy
(DMT), which is a direct result of an incorrect diagnosis (which was also observed in our
group of respondents). It can lead to unnecessary morbidity, inadequate treatment, mental
suffering and economic consequences [26,64].
Since 2019, three new drugs were approved by the FDA to use in NMOSD patients.
Each monoclonal body has its own unique mode of action. Satralizumab inhibits inter-
leukin 6 (IL-6) signaling by binding to soluble or membrane-bound IL6-Receptor (IL-6R).
Eculizumab specifically binds to the terminal complement component 5 (C5), thereby
inhibiting final downstream effector mechanisms of the complement system (preventing
the cleavage of C5 to C5a and C5b). Before entering the clinical trials, all patients received
vaccination against Neisseria meningitides. The last drug, inebilizumab, targets the CD19
surface antigen on B-Lymphocytes, including plasmablasts and some plasma cells. The use
of tocilizumab, which was the first humanized monoclonal antibody against IL-6R, should
also be considered. Its positive effects have been reported in relapses, disability, fatigue
and pain. There are also a few drugs under development: aquaporumab, bortezomib,
Brain Sci. 2022, 12, 885 10 of 14

revulizumab, sivelestat and ublituximab. Appropriate treatment should be provided for

each patient individually, but further recommendations for the use of new drugs are still
under development [65,66].

4.6. Paraneoplastic NMOSD

Cancer screening is not routinely performed in patients suspected of heaving or
diagnosed with NMOSD. However, it seems that the association between NMOSD and
cancer is more frequent in elderly patients. The available data indicate up to 15% of
NMOSD-seropositive patients suffering from cancer [67], which may suggest, in some
cases, a tumor-initiated immune response [68]. Shahmohammadi et al. (2021) [37], in
their systematic review, showed female predominance over male with a mean age of
52.21 ± 17.14 and 52.16 ± 17.21 years old. Interestingly, the authors assumed that prior to
the detection of NMOSD biomarkers, many patients could be diagnosed with suspected
underlying cancer such as paraneoplastic myelitis or optic neuritis. It must be taken into
account that the appearance of neoplasms is also influenced by the age of the patient or
the drugs used (drug-inducedmalignancies); however, cancer resection may positively
influence the course of the disease (e.g., number of relapses). Coexisting neoplasms such as
breast, lung and genitourinary (especially ovary) were the most repeated ones in NMOSD,
which should be considered in cancer screening around 50 years of age [37,67,69,70]. On
the other hand, onconeural screening does not appear to be routinely recommended, but
only in exceptional cases [71].

5. Limitations
The analysis of patients was conducted retrospectively, therefore, it was not possible to
directly assess the physician’s decision making and the application of the diagnostic criteria
(anti-MOG antibodies tests were not performed in this cohort; nevertheless, seronegative
patients did not present symptoms indicative of anti-MOG disease). It must be remembered
that NMOSD is a very rare disease and at the moment only a retrospective analysis allows
for a broader assessment of this phenomenon (such as epidemiologic and clinical features).
The prevalence of NMOSD in Lublin province corresponds to the other regions worldwide
with a predominantly Caucasian population. Unfortunately, our data did not allow for an
accurate estimation of population-based incidence and prevalence rates, because of the
small sample size and limited samples from a single academic medical center. The next
step would be to validate the results in a broader clinical setting.

6. Conclusions
Underdiagnosis still remains a problem in contemporary clinical practice and has
important implications for patients with acute or subacute onset of neurological deficits,
causing a delay in starting proper treatment. It appears that underdiagnosis in some
neurological patients is associated with atypical presentation, long time to symptoms’ de-
velopment, mimicking or misdiagnosis of different diseases, and inappropriate application
or misinterpretation of diagnostic criteria. Perhaps, covariates such as gender, onset age,
and diagnosis age also take part.
Our studies showed that up to 1.62 percent of patients diagnosed with hyperintense
lesions within the white matter may suffer from NMOSD, and up to 2.2% of those who were
previously diagnosed with MS. To establish the correct diagnosis is still challenging, which
is shown by the difference in the first and final diagnosis. NMOSD diagnostic criteria from
2015 help to make the correct diagnosis; however, overlapping clinical and radiological
findings often make discrimination difficult. In atypical cases, watchful waiting might be
the best approach instead of making a hasty diagnosis, which may have important conse-
quences. On the other hand, quick diagnosis, appropriate patient follow-up and proper
treatment may reduce long-term disability in NMOSD patients. Our study confirmed a
female predominance in NMOSD. In our cohort, AQP4-Ab was more frequent in female
patients. The age of onset is lower in men and seropositive women; however, a longer
Brain Sci. 2022, 12, 885 11 of 14

duration of delayed diagnosis was observed in both groups. Additionally, seropositive

cases have a worse prognosis for the future degree of disability than seronegative cases,
which may be associated with a higher number of relapses. The estimated prevalence and
incidence of NMOSD in Lubelskie voivodeship (Poland) is similar to numbers in the other
areas with a majority Caucasian population. Nevertheless, such data did not allow for an
accurate estimate of population-based incidence and prevalence rates. An increased size of
the control group seems to be the next logical step towards the validation of the results in a
broader clinical setting.

Author Contributions: Conceptualization, A.K.S. and K.R.; methodology, A.K.S. and K.M.-S.; soft-
ware, M.W.; validation, M.W., A.K.S. and E.P.; formal analysis, A.K.S.; investigation, E.P.; resources,
A.K.S. and E.P.; data curation, A.K.S. and K.M.-S.; writing—original draft preparation, A.K.S.;
writing—review and editing, A.K.S. and K.M.-S.; visualization, M.W.; supervision, K.R.; project
administration, A.K.S. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki, and approved by the Ethics Committee of Medical University of Lublin, Poland.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Habes, M.; Sotiras, A.; Erus, G.; Toledo, J.B.; Janowitz, D.; Wolk, D.A.; Shou, H.; Bryan, N.R.; Doshi, J.; Völzke, H.; et al.
White matter lesions spatial heterogeneity, links to risk factors, cognition, genetics, and atrophy. Neurology 2018, 91, E964–E975.
[CrossRef] [PubMed]
2. Wildner, P.; Stasiołek, M.; Matysiak, M. Differential diagnosis of multiple sclerosis and other inflammatory CNS diseases. Mult.
Scler. Relat. Disord. 2020, 37, 101452. [CrossRef] [PubMed]
3. Wingerchuk, D.M.; Banwell, B.; Bennett, J.L.; Cabre, P.; Carroll, W.; Chitnis, T.; De Seze, J.; Fujihara, K.; Greenberg, B.; Jacob,
A.; et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015, 85, 177–189.
[CrossRef] [PubMed]
4. Sellner, J.; Boggild, M.; Clanet, M.; Hintzen, R.Q.; Illes, Z.; Montalban, X.; Du Pasquier, R.A.; Polman, C.H.; Sorensen, P.S.; Hemmer,
B. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur. J. Neurol. 2010, 17, 1019–1032. [CrossRef]
5. Drori, T.; Chapman, J. Diagnosis and classification of neuromyelitis optica (Devic’s Syndrome). Autoimmun. Rev. 2014, 13, 531–533.
[CrossRef]
6. Rejdak, K.; Papuć, E. Cladribine suppresses disease activity in neuromyelitis optica spectrum disorder: A 2-year follow-up study.
Eur. J. Neurol. 2021, 28, 3167–3172. [CrossRef]
7. Papadopoulos, M.C.; Verkman, A.S. Aquaporin 4 and neuromyelitis optica. Lancet Neurol. 2012, 11, 535–544. [CrossRef]
8. Rosales, D.; Kister, I. Common and Rare Manifestations of Neuromyelitis Optica Spectrum Disorder. Curr. Allergy Asthma Rep.
2016, 16, 1–8. [CrossRef]
9. Tzartos, J.S.; Stergiou, C.; Kilidireas, K.; Zisimopoulou, P.; Thomaidis, T.; Tzartos, S.J. Anti-Aquaporin-1 Autoantibodies in
Patients with Neuromyelitis Optica Spectrum Disorders. PLoS ONE 2013, 8, e74773. [CrossRef]
10. Pittock, S.J.; Lennon, V.A.; Bakshi, N.; Shen, L.; McKeon, A.; Quach, H.; Briggs, F.B.S.; Bernstein, A.L.; Schaefer, C.A.; Barcellos,
L.F. Seroprevalence of aquaporin-4-IgG in a Northern California population representative cohort of multiple sclerosis. JAMA
Neurol. 2014, 71, 1433–1436. [CrossRef]
11. Gahlen, A.; Trampe, A.K.; Haupeltshofer, S.; Ringelstein, M.; Aktas, O.; Berthele, A.; Wildemann, B.; Gold, R.; Jarius, S.; Kleiter, I.
Aquaporin-4 antibodies in patients treated with natalizumab for suspected MS. Neurol. Neuroimmunol. NeuroInflamm. 2017, 4,
1–10. [CrossRef] [PubMed]
12. Jasiak-Zatonska, M.; Kalinowska-Lyszczarz, A.; Michalak, S.; Kozubski, W. The Immunology of Neuromyelitis Optica—Current
Knowledge, Clinical Implications, Controversies and Future Perspectives. Int. J. Mol. Sci. 2016, 17, 273. [CrossRef] [PubMed]
13. Hyun, J.W.; Jeong, I.H.; Joung, A.; Kim, S.H.; Kim, H.J. Evaluation of the 2015 diagnostic criteria for neuromyelitis optica spectrum
disorder. Neurology 2016, 86, 1772–1779. [CrossRef] [PubMed]
14. García-Miranda, P.; Morón-Civanto, F.J.; Martínez-Olivo, M.D.M.; Suárez-Luna, N.; Ramírez-Lorca, R.; Lebrato-Hernández, L.;
Lamas-Pérez, R.; Navarro, G.; Abril-Jaramillo, J.; García-Sánchez, M.I.; et al. Predictive value of serum antibodies and point
mutations of AQP4, AQP1 and MOG in a cohort of spanish patients with neuromyelitis optica spectrum disorders. Int. J. Mol. Sci.
2019, 20, 5810. [CrossRef] [PubMed]
Brain Sci. 2022, 12, 885 12 of 14

15. Polman, C.H.; Reingold, S.C.; Banwell, B.; Clanet, M.; Cohen, J.A.; Filippi, M.; Fujihara, K.; Havrdova, E.; Hutchinson, M.; Kappos,
L.; et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann. Neurol. 2011, 69, 292–302.
[CrossRef]
16. Thompson, A.J.; Banwell, B.L.; Barkhof, F.; Carroll, W.M.; Coetzee, T.; Comi, G.; Correale, J.; Fazekas, F.; Filippi, M.; Freedman,
M.S.; et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018, 17, 162–173. [CrossRef]
17. Cole, J.; Evans, E.; Mwangi, M.; Mar, S. Acute Disseminated Encephalomyelitis in Children: An Updated Review Based on
Current Diagnostic Criteria. Pediatr. Neurol. 2019, 100, 26–34. [CrossRef]
18. Krupp, L.B.; Tardieu, M.; Amato, M.P.; Banwell, B.; Chitnis, T.; Dale, R.C.; Ghezzi, A.; Hintzen, R.; Kornberg, A.; Pohl, D.; et al.
International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central
nervous system demyelinating disorders: Revisions to the 2007 definitions. Mult. Scler. J. 2013, 19, 1261–1267. [CrossRef]
19. Siva, A. Common Clinical and Imaging Conditions Misdiagnosed as Multiple Sclerosis: A Current Approach to the Differential
Diagnosis of Multiple Sclerosis. Neurol. Clin. 2018, 36, 69–117. [CrossRef]
20. van Rooij, L.C.; Wattjes, M.P.; de Jong, B.A.; van Oosten, B.W. Neuromyelitis optica spectrum disorder mimicking multiple
sclerosis. Mult. Scler. Relat. Disord. 2017, 17, 54–56. [CrossRef]
21. Suchdev, K.; Razmjou, S.; Venkatachalam, P.; Khan, O.A.; Mohamed, W.; Ibrahim, M.S. Late onset neuromyelitis optica mimicking
an acute stroke in an elderly patient. J. Neuroimmunol. 2017, 309, 1–3. [CrossRef] [PubMed]
22. Chhabda, S.; Malik, P.; Reddy, N.; Muthusamy, K.; Mirsky, D.; Sudhakar, S.; Mankad, K. Relapsing Demyelinating Syndromes in
Children: A Practical Review of Neuroradiological Mimics. Front. Neurol. 2020, 11, 1–17. [CrossRef] [PubMed]
23. Steenhof, M.; Stenager, E.; Nielsen, N.M.; Kyvik, K.; Möller, S.; Hertz, J.M. Familial multiple sclerosis patients have a shorter
delay in diagnosis than sporadic cases. Mult. Scler. Relat. Disord. 2019, 32, 97–102. [CrossRef] [PubMed]
24. Adamec, I.; Barun, B.; Gabelić, T.; Zadro, I.; Habek, M. Delay in the diagnosis of multiple sclerosis in Croatia. Clin. Neurol.
Neurosurg. 2013, 115, 70–72. [CrossRef] [PubMed]
25. Kaisey, M.; Solomon, A.J.; Luu, M.; Giesser, B.S.; Sicotte, N.L. Incidence of multiple sclerosis misdiagnosis in referrals to two
academic centers. Mult. Scler. Relat. Disord. 2019, 30, 51–56. [CrossRef] [PubMed]
26. Solomon, A.J.; Naismith, R.T.; Cross, A.H. Misdiagnosis of multiple sclerosis: Impact of the 2017 McDonald criteria on clinical
practice. Neurology 2019, 92, 26–33. [CrossRef] [PubMed]
27. Avasarala, J.; Pettigrew, C.; Sutton, P.; Guduru, Z.; Gurwell, J.; Sokola, B.S.; Mullins, S. Can a diagnosis of multiple sclerosis be
made without ruling out neuromyelitis optica spectrum disorder? Mult. Scler. Relat. Disord. 2020, 40, 101949. [CrossRef]
28. Brandão de Paiva, A.R.; Filho, C.R.P.; Porto, A.M.; Feltrin, F.S.; Kok, F.; Camargo, C.H.F. When multiple sclerosis and X-linked
adrenoleukodystrophy are tangled: A challenging case. Neurol. Clin. Pract. 2018, 8, 156–158. [CrossRef]
29. Di Filippo, M.; Luchetti, E.; Prontera, P.; Donti, E.; Floridi, P.; Di Gregorio, M.; Tambasco, N.; Sarchielli, P.; Calabresi, P.
Heterozygous X-linked adrenoleukodystrophy-associated myelopathy mimicking primary progressive multiple sclerosis. J.
Neurol. 2011, 258, 323–324. [CrossRef]
30. Kageyama, H.; Suzuki, T.; Ohara, Y. Intramedullary spinal cord germinoma clinically mimicking multiple sclerosis: A case report.
Surg. Neurol. Int. 2019, 10, 201. [CrossRef]
31. Yamaguchi, R.; Kohga, H.; Tosaka, M.; Sekine, A.; Mizushima, K.; Harigaya, Y.; Yoshimoto, Y. A Case of Optic Neuritis
Concomitant with Pituitary Tumor During Pregnancy. World Neurosurg. 2016, 93, 488.e1–488.e4. [CrossRef] [PubMed]
32. Blaverman, D.; Lachmann, E.; Tunkel, R.; Nagler, W. Multiple sclerosis Presenting as a Spinal Cord Tumor. Arch. Phys. Med.
Regabilit. 1997, 78, 1274–1276. [CrossRef]
33. Ayrignac, X.; Carra-Dallière, C.; Labauge, P. Diagnostic and therapeutic issues of inflammatory diseases of the elderly. Rev. Neurol.
(Paris) 2020, 176, 739–749. [CrossRef] [PubMed]
34. Geraldes, R.; Ciccarelli, O.; Barkhof, F.; Fazekas, F.; DeLuca, G.C.; Gasperini, C.; Filippi, M.; Rovira, A.; Enzinger, C.; Sastre-Garriga,
J.; et al. The current role of MRI in differentiating multiple sclerosis from its imaging mimics. Nat. Rev. Neurol. 2018, 14, 199–213.
[CrossRef]
35. Khalilidehkordi, E.; Clarke, L.; Arnett, S.; Bukhari, W.; Jimenez Sanchez, S.; O’Gorman, C.; Sun, J.; Prain, K.M.; Woodhall, M.;
Silvestrini, R.; et al. Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal
Variation. Front. Neurol. 2020, 11, 1–8. [CrossRef]
36. Jarius, S.; Wildemann, B.; Paul, F. Neuromyelitis optica: Clinical features, immunopathogenesis and treatment. Clin. Exp. Immunol.
2014, 176, 149–164. [CrossRef]
37. Shahmohammadi, S.; Doosti, R.; Shahmohammadi, A.; Azimi, A.; Sahraian, M.A.; Fattahi, M.R.; Moghadasi, A.N. Neuromyelitis
optica spectrum disorder (NMOSD) associated with cancer: A systematic review. Mult. Scler. Relat. Disord. 2021, 56, 103227.
[CrossRef]
38. Wingerchuk, D.M.; Lennon, V.A.; Lucchinetti, C.F.; Pittock, S.J.; Weinshenker, B.G. The spectrum of neuromyelitis optica. Lancet
Neurol. 2007, 6, 805–815. [CrossRef]
39. Wingerchuk, D.M.; Weinshenker, B.G. Neuromyelitis optica (Devic’s syndrome). Handb. Clin. Neurol. 2014, 122, 581–599.
[CrossRef]
40. Pittock, S.J.; Lucchinetti, C.F. Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies: A
decade later. Ann. N. Y. Acad. Sci. 2016, 1366, 20–39. [CrossRef]
Brain Sci. 2022, 12, 885 13 of 14

41. Pandit, L.; Asgari, N.; Apiwattanakul, M.; Palace, J.; Paul, F.; Leite, M.I.; Kleiter, I.; Chitnis, T.; Iorio, R.; Würfel, J.; et al.
Demographic and clinical features of neuromyelitis optica: A review. Mult. Scler. J. 2015, 21, 845–853. [CrossRef] [PubMed]
42. Bui, M.-L.; Gould, J.K.; Mentreddy, A.; Sigsbee, E.; Lalama, H. Neuromyelitis Optica Spectrum Disorder: A Rare Case of Isolated
Brainstem Syndrome. Cureus 2019, 11, e5644. [CrossRef]
43. Papp, V.; Illes, Z.; Magyari, M.; Koch-Henriksen, N.; Kant, M.; Pfleger, C.C.; Roemer, S.F.; Jensen, M.B.; Petersen, A.E.; Nielsen,
H.H.; et al. Nationwide prevalence and incidence study of neuromyelitis optica spectrum disorder in Denmark. Neurology 2018,
91, E2265–E2275. [CrossRef] [PubMed]
44. Szilasiová, J.; Gazda, J.; Cimprichová, A.; Cvengrošová, A.; Donáth, V.; Fedičová, M.; Gurčík, L.; Hančinová, V.; Jurčaga, F.;
Kahancová, E.; et al. Incidence and prevalence of neuromyelitis optica spectrum disorders in Slovakia. Neurol. Res. 2022, 44,
38–46. [CrossRef] [PubMed]
45. Papp, V.; Iljicsov, A.; Rajda, C.; Magyari, M.; Koch-Henriksen, N.; Petersen, T.; Jakab, G.; Deme, I.; Nagy, F.; Imre, P.; et al. A
population-based epidemiological study of neuromyelitis optica spectrum disorder in Hungary. Eur. J. Neurol. 2020, 27, 308–317.
[CrossRef]
46. Wnuk, M.; Maluchnik, M.; Perwieniec, J.; Podwojcic, K.; Szelag, M.; Walkiewicz, D.; Zakrzewski, M.; Kulakowska, A.; Brola, W.;
Rejdak, K.; et al. Multiple sclerosis incidence and prevalence in Poland: Data from administrative health claims. Mult. Scler. Relat.
Disord. 2021, 55, 103162. [CrossRef]
47. Brola, W.; Steinborn, B.; Niewada, M.; Mazurkiewicz-Bełdzińska, M.; Jóźwiak, S.; Sobolewski, P.; Żak, M.; Wilski, M.; Bilska, M.;
Siedlarska, M.; et al. Pediatric-onset multiple sclerosis in Poland: A registry-based retrospective cohort study. Mult. Scler. Relat.
Disord. 2022, 57, 103344. [CrossRef]
48. Pittock, S.J.; Berthele, A.; Fujihara, K.; Kim, H.J.; Levy, M.; Palace, J.; Nakashima, I.; Terzi, M.; Totolyan, N.; Viswanathan, S.; et al.
Eculizumab in Aquaporin-4–Positive Neuromyelitis Optica Spectrum Disorder. N. Engl. J. Med. 2019, 381, 614–625. [CrossRef]
49. Knapp, R.K.; Hardtstock, F.; Wilke, T.; Maywald, U.; Deiters, B.; Schneider, S.; Mouchet, J. Evaluating the Economic Burden of
Relapses in Neuromyelitis Optica Spectrum Disorder: A Real-World Analysis Using German Claims Data. Neurol. Ther. 2022, 11,
247–263. [CrossRef]
50. Royston, M.; Kielhorn, A.; Weycker, D.; Shaff, M.; Houde, L.; Tanvir, I.; Bhattacharyya, S.; Levy, M. Neuromyelitis Optica
Spectrum Disorder: Clinical Burden and Cost of Relapses and Disease-Related Care in US Clinical Practice. Neurol. Ther. 2021, 10,
767–783. [CrossRef]
51. Exuzides, A.; Sheinson, D.; Sidiropoulos, P.; Magrini, F.; Gholizadeh, S.; Surinach, A.; Cook, L.; Meyer, C.S.; Yeaman, M. Burden
and cost of comorbidities in patients with neuromyelitis optica spectrum disorder. J. Neurol. Sci. 2021, 427, 117530. [CrossRef]
[PubMed]
52. Seok, J.M.; Choi, M.; Cho, E.B.; Lee, H.L.; Kim, B.J.; Lee, K.H.; Song, P.; Joo, E.Y.; Min, J.H. Fatigue in patients with neuromyelitis
optica spectrum disorder and its impact on quality of life. PLoS ONE 2017, 12, 1–11. [CrossRef] [PubMed]
53. De Seze, J.; Kremer, L.; Collongues, N. Neuromyelitis optica spectrum disorder (NMOSD): A new concept. Rev. Neurol. (Paris)
2016, 172, 256–262. [CrossRef] [PubMed]
54. Mealy, M.A.; Mossburg, S.E.; Kim, S.H.; Messina, S.; Borisow, N.; Lopez-Gonzalez, R.; Ospina, J.P.; Scheel, M.; Yeshokumar, A.K.;
Awad, A.; et al. Long-term disability in neuromyelitis optica spectrum disorder with a history of myelitis is associated with age at
onset, delay in diagnosis/preventive treatment, MRI lesion length and presence of symptomatic brain lesions. Mult. Scler. Relat.
Disord. 2019, 28, 64–68. [CrossRef]
55. Asseyer, S.; Schmidt, F.; Chien, C.; Scheel, M.; Ruprecht, K.; Bellmann-Strobl, J.; Brandt, A.U.; Paul, F. Pain in AQP4-IgG-positive
and MOG-IgG-positive neuromyelitis optica spectrum disorders. Mult. Scler. J. Exp. Transl. Clin. 2018, 4, 205521731879668.
[CrossRef]
56. Bradl, M.; Kanamori, Y.; Nakashima, I.; Misu, T.; Fujihara, K.; Lassmann, H.; Sandkühler, J. Pain in neuromyelitis optica-prevalence,
pathogenesis and therapy. Nat. Rev. Neurol. 2014, 10, 529–536. [CrossRef]
57. Eizaguirre, M.B.; Alonso, R.; Vanotti, S.; Garcea, O. Cognitive impairment in neuromyelitis optica spectrum disorders: What do
we know? Mult. Scler. Relat. Disord. 2017, 18, 225–229. [CrossRef]
58. Sherman, E.; Han, M.H. Acute and Chronic Management of Neuromyelitis Optica Spectrum Disorder. Curr. Treat. Options Neurol.
2015, 17, 1–4. [CrossRef]
59. Kleiter, I.; Gold, R. Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders. Neurotherapeutics 2016, 13, 70–83.
[CrossRef]
60. Kessler, R.A.; Mealy, M.A.; Levy, M. Treatment of Neuromyelitis Optica Spectrum Disorder: Acute, Preventive, and Symptomatic.
Curr. Treat. Options Neurol. 2016, 18, 1–15. [CrossRef]
61. Marignier, R.; Calvo, A.C.; Vukusic, S. Neuromyelitis optica and neuromyelitis optica spectrum disorders. Curr. Opin. Neurol.
2017, 30, 208–215. [CrossRef] [PubMed]
62. Kleiter, I.; Hellwig, K.; Berthele, A.; Kümpfel, T.; Linker, R.A.; Hartung, H.P.; Paul, F.; Aktas, O. Failure of natalizumab to prevent
relapses in neuromyelitis optica. Arch. Neurol. 2012, 69, 239–245. [CrossRef] [PubMed]
63. Zabad, R.K.; Stewart, R.; Healey, K.M. Pattern Recognition of the Multiple Sclerosis Syndrome. Brain Sci. 2017, 7, 138. [CrossRef]
[PubMed]
64. Solomon, A.J.; Weinshenker, B.G. Misdiagnosis of multiple sclerosis: Frequency, causes, effects, and prevention. Curr. Neurol.
Neurosci. Rep. 2013, 13, 1–7. [CrossRef]
Brain Sci. 2022, 12, 885 14 of 14

65. Held, F.; Klein, A.-K.; Berthele, A. Drug Treatment of Neuromyelitis Optica Spectrum Disorders: Out with the Old, in with the
New? ImmunoTargets Ther. 2021, 10, 87–101. [CrossRef]
66. Holmøy, T.; Høglund, R.A.; Illes, Z.; Myhr, K.M.; Torkildsen, Ø. Recent progress in maintenance treatment of neuromyelitis optica
spectrum disorder. J. Neurol. 2021, 268, 4522–4536. [CrossRef]
67. Ontaneda, D.; Fox, R.J. Is neuromyelitis optica with advanced age of onset a paraneoplastic disorder? Int. J. Neurosci. 2014, 124,
509–511. [CrossRef]
68. Pittock, S.J.; Lennon, V.A. Aquaporin-4 autoantibodies in a paraneoplastic context. Arch. Neurol. 2008, 65, 629–632. [CrossRef]
69. Yuan, J.; Jia, Z.; Qin, W.; Hu, W. Paraneoplastic neuromyelitis optica spectrum disorder associated with breast cancer. Clin. Interv.
Aging 2019, 14, 1039–1044. [CrossRef]
70. Maiorca, C.; Moret, F.; Martines, V.; Tramontano, D.; Papassifachis, M.A.; Bini, S.; Caramazza, C.; Fontana, M.; Lucia, P.; Inghilleri,
M. Paraneoplastic Neuromyelitis Optica Spectrum Disorder Associated With Lung Adenocarcinoma: A Case Report. Front. Med.
2022, 8, 1–7. [CrossRef]
71. Berger, B.; Hottenrott, T.; Rauer, S.; Stich, O. Screening for onconeural antibodies in neuromyelitis optica spectrum disorders.
BMC Neurol. 2017, 17, 9–12. [CrossRef] [PubMed]