Keywords: Neuromyelitis Optica - Prevalence - Epidemiology
Palavras-chave: Neuromielite Óptica - Prevalência - Epidemiologia
INTRODUCTION
Neuromyelitis optica spectrum disorder (NMOSD) is the second most frequent demyelinating
disease of the Central Nervous System (CNS), after multiple sclerosis (MS)[1 ]. It has been known since 1894 when Devic published the first description of NMOSD,
characterized by myelitis and optic neuritis[1 ],[2 ]. Until 1999 NMOSD was misdiagnosed as MS, only this year when the first review of
the clinical course of neuromyelitis optica disease was published it changed. In that
review, it was recognized that NMOSD most frequently manifests with a relapsing course
and that its clinical, laboratory, and imaging features allow it to be distinguished
from MS[3 ]. A specific biomarker was discovered in 2004: a serum autoantibody immunoglobulin
(IgG) against the aquaporin-4 (AQP4) water channel in the CNS, which was named AQP4-IgG
or NMO-IgG[1 ],[4 ]. The current international consensus on the diagnostic criteria for NMO was published
in 2015 and unified the nomenclature to “neuromyelitis optica spectrum disorders”
(NMOSDs) to encompass all the patients regardless of serological features[5 ]. The core clinical events refer to six neuroanatomically defined sites in the CNS:
optic nerve, spinal cord, area postrema, brain stem, diencephalon, or cerebrum[1 ]–[5 ]. The most frequent clinical features of NMOSD are the following: strength failure
(paraparesis or tetraparesis), sensitivity failure, loss of sphincter control, blindness,
and intractable vomiting or hiccups[1 ]–[4 ].
The prevalence of NMOSD has been reported to vary widely in different studies worldwide.
It occurs most frequently among Asians and Afro-descendants[1 ]–[8 ]; women (70–90%) and non-whites, and the average age of onset is 40 years old[1 ],[5 ]. The proportion of patients with NMOSD among all demyelinating disorders ranges
from 1.2 to 39.3%, according to the geographical region[1 ]–[10 ]. NMOSD prevalence rates have been reported as 0.72-4.4/100,000 in Europe and 0.9
to 2.6/100,000 in Asia[1 ],[2 ],[6 ]–[8 ]. Across the Americas, extreme values have been described. The lowest was in Cuba:
0.52/100,000[9 ]; and the highest was in Martinique: 10/100.000[10 ]. In South America, the frequency of NMOSD is 11.8% among all demyelinating disorders,
but the prevalence is unknown[11 ]. In a Brazilian series of patients, it was estimated that NMOSD represented 6-15%
of all demyelinating diseases[12 ]. Because of the rarity of NMOSD and the lack of preclinical models, there are not
enough cohort studies. Historically, NMOSD has been a difficult disease to study epidemiologically,
and its prevalence has been estimated from reference center results[13 ].
According to the national census of 2010, 46.7% of Brazilians identify themselves
as being of mixed ancestry[14 ]. The state of Goiás, located in the Midwestern region, is in the “heart of Brazil”
and surrounds the Brasília Federal District. It is the seventh-largest state in Brazil,
with an area of approximately 340,126 km[2 ]
[14 ]. The prevalence of multiple sclerosis in the state of Goiás has been reported as
22.4/100,000[15 ], but the prevalence of NMOSD in the state of Goiás remains unknown. According to
an autosomal genetic study, the population of Goiás is derived from the miscegenation
of three main ancestral groups: 3% native Amerindians, 83.7% Europeans (mainly Portuguese)
and 13.3% Afro-descendants, typically from sub-Saharan Africa[16 ],[17 ].
This study aimed to evaluate the prevalence of NMOSD in the Goiás state, focusing
on demographic characteristics in terms of ethnicity and ancestry, clinical manifestations,
radiological and laboratory features, treatments, and outcomes.
METHODS
This study was approved by the Research Ethics Committee of the Medical School of
the Universidade Federal de Goiás, under CAAE number 8380.9317.9.0000.5078. Written
and verbal consent was obtained from all subjects before the study procedures were
started. This was a population-based descriptive cross-sectional study conducted at
Centro de Referência e Investigação em Esclerose Múltipla (CRIEM), a demyelinating diseases reference center in Goiás state, located in Midwestern
Brazil. Data were collected/patients were interviewed from 2017 to 2020.
Were included a total of 48 patients who fulfilled the International Panel for NMOSD
Diagnosis 2015 criteria, and after they were classified according to their AQP4-IgG
serostatus. Individuals fulfilling the inclusion criteria and without the exclusion
criteria were eligible for enrollment. To accept the diagnosis of NMOSD, at least
one specific core clinical criterion was needed among AQP4-IgG seropositive patients;
or at least two specific core clinical criteria were needed when individuals were
seronegative. Each patient's diagnosis required confirmation from and follow-up by
at least two neurologists.
The main source of our information was a specific questionnaire which was filled out
by one neurologist and reviewed by another neurologist, to determine participant eligibility.
Our data were based on the hospital records and all the patients were interviewed
and examined by the researcher group, to complete missing information. The first part
of this questionnaire asked for general demographic information regarding the NMOSD
patients, focusing on personal data: current age, gender, and ethnic categories, such
as skin color and ancestry as far back as the third degree. The second part of this
questionnaire was oriented toward personal medical history: age at disease onset,
initial clinical event, number of relapses, and autoimmune comorbidities. We also
requested information about other clinical comorbidities such as hypertension, diabetes,
and thyroid dysfunction. Autoantibody seropositivity was defined as the detection
of AQP4-IgG at any point during the participant's history and using any laboratory
method. The presence of oligoclonal bands and antinuclear antibodies was also evaluated.
All the radiological features, seen both on old and on current scans, were reevaluated
by a group of neurologists, during the 24 months of this study.
We evaluated all the treatment strategies that were used to improve remission and
prevent relapses, including associations of drugs at the acute phase, plasma exchange,
and therapeutic failure to change the immunosuppressive drug. To describe the long-term
outcome, we considered the total number of relapses, the classification according
to Kurtzke, EDSS (Expanded Disability Status Scale), and the last follow-up. We subdivided
all the disabilities into four groups: (1) permanent physical impairments (handicapped
and needing bracing, wheelchair, or bedridden); (2) permanent visual impairment (unilateral
or bilateral); (3) permanent sphincter deficiency (neurogenic bladder or ostomy);
and (4) locked-in syndrome (permanent vegetative state).
Our numerical results are shown as means, percentages, and standard deviations. Nonparametric
statistics with a direct counting method were performed and results were compared
using the chi-square test or Fisher's exact probability test (when the criteria for
the chi-square test were not fulfilled). Odds Ratios (ORs) were obtained to compare results. A p=0.05 was considered to be the limit of
significance for allelic comparisons.
RESULTS
According to the latest demographic Brazilian census, carried out in 2010, the population
of the state of Goiás was 6,003,788 inhabitants, of whom 50.34% were women and 49.66%
were men. We found 48 cases of people with NMOSD who were living in Goiás on the day
of the prevalence study (October 1, 2020), which represented an estimated prevalence
of 0.79/per 100,000 inhabitants. Also according to this demographic census, among
the population of Goiás, 41% self-identified their skin color as white, 6.53% as black,
50.1% as mulatto (mixed race), and 0.14% as Amerindian ethnicity.
Regarding demyelinating diseases, 9.37% (48 cases) of the patients were diagnosed
with NMOSD ([Table 1 ]). These individuals had a mean age of 43.29±15.51 years of age. There was a marked
predominance of females (81.2%), and skin color was self-reported as white by 16.6%,
black by 31.3%, and mulatto (mixed race) by 52.1%. Self-declared Amerindian ancestry
was significantly higher (68.75 vs. 31.25% for other ancestries; p<0.039). The overall
median age at NMOSD onset was 36.71±15.98 years of age, with a range from 9 to 66
years. The median length of time from disease onset to the time of study enrollment
was 81.73±57.30 months.
Table 1
The phenotype of the patients with neuromyelitis optica spectrum disorders in Midwestern
Brazil.
Demographic characteristics
Clinical manifestations
Radiological and laboratory features
Average±SD
Min-Max
Initial clinical event
Prevalence, %
Prevalence, %
Current age (years)
43.29±15.51
14.00–71.00
LETM+area postrema syndrome
2.1
Radiological cumulative features/ affected segments
Age at onset (years)
36.71±15.98
9.00–66.00
LETM+brainstem syndrome
2.1
Orbit resonance/ optic neuritis
64.6
Time of disease (months)
81.73±57.30
8.00–240.00
LETM (alone)
35.4
Brain resonance
22.9
n
Prevalence, %
Simultaneous ON+LETM
20.8
Cervical spinal cord
43.8
Gender
ON (alone)
35.4
Dorsal (thoracic) spinal cord
56.3
Female
39
81.2
Area postrema syndrome
4.2
Lumbar spinal cord
16.7
Male
9
18.8
Comorbidities
Laboratory features/ serological tests
Skin color
Hypertension
27.1
AQP4-IgG serostatus positive
35.4
White
8
16.6
Diabetes
10.4
Oligoclonal bands positive
22.9
Black
15
31.3
Thyroid dysfunction
10.4
Antinuclear antibody (ANA) positive
22.9
Mulatto
25
52.1
Most frequent autoimmune comorbidities
AQP4-IgG seropositivity adjusted prevalence
Ancestry
Scleroderma
4.2
Female
88.2
African
11
22.91
Lupus erythematosus
6.3
Male
11.8
Amerindian
33
68.75
Sjögren disease
6.3
Amerindian ancestry
41.2
European
4
8.34
Vitiligo
4.2
Other ancestries
58.8
NMOSD: neuromyelitis optica spectrum disorders; n: absolute requirement; %: relative
frequency; SD: standard deviation; Mulatto: mixed skin color classification of people
who are born with one white parent and one parent of another skin color; Amerindian:
native indigenous ethnic groups of the Americas; LETM: longitudinally extensive transverse
myelitis; area postrema: situated in the dorsal medulla oblongata, the lower part
of the brainstem; it is a structure whose functions include control over vomiting
and hiccups; ON: optic neuritis; AQP4-IgG: specific immunoglobulin for the water channel
aquaporin-4.
The most common onset manifestations were longitudinally extensive transverse myelitis
(LETM) alone on ≥3 vertebral segments (35.4%) or only optic neuritis (ON) (35.4%).
The prevalences of the initial clinical event are also shown in [Table 1 ] and [Figures 1 ], [2 ], and [3 ]. There was a predominance of a relapsing course: 72.9% of the individuals had 2-4
relapses ([Table 2 ]). The most frequent autoimmune comorbidities and systemic diseases were sclerodermas,
lupus erythematosus, Sjögren disease, vitiligo, hypertension, diabetes, and thyroid
dysfunctions ([Table 1 ]). No significant differences were found regarding serological status, gender, or
ancestry ([Table 1 ]). The other serological tests were on antinuclear antibodies (22.9%) and the presence
of oligoclonal bands in cerebrospinal fluid (22.9%).
Figure 1 Orbital resonance showing bilateral longitudinally extensive optic neuritis. Axial
section with T2-weighted acquisition.
Figure 2 Brain resonance shows lesions in the brainstem and area postrema. Coronal and axial
sections with T2-weighted acquisition.
Figure 3 Spinal cord resonance showing longitudinally extensive transverse myelitis in cervical-thoracic
segments (more than 3 vertebral segments). Sagittal section with T1 and T2-weighted
acquisition.
Table 2
Treatments and outcomes among patients with neuromyelitis optica spectrum disorders
in Midwestern Brazil.
Treatment strategies to improve remission and prevent relapses
Description and classification of the outcome and the permanent disabilities at last
follow-up
%
%
%
Acute pharmacological treatment (onset or relapse)
Total number of relapses
Permanent physical deficiency
Only high dose of IVMP
81.2
1 (monophasic course)
10.4
No physical impairments
60.4
Cyclophosphamide+IVMP
60.3
2 to 4
72.9
Mild handicapped - needs bracing
20.1
Intravenous immunoglobulin+IVMP
10.4
≥5
16.7
Moderate handicapped - wheelchair
35.4
Mycophenolate+IVMP
20.1
Long-term outcome
Severe handicapped - bedridden
20.1
Plasma exchange in acute treatment (in association with drugs)
20.8
Healthy
16.7
Permanent visual deficiency
First maintenance treatment for preventing relapses in NMOSD
Impairments, limitations, and restrictions
77.1
No visual impairment
58.3
Beta-interferon or glatiramer (misdiagnosis as multiple sclerosis)
14.6
Death
60.2
Unilateral
33.3
Isolated prednisone
12.5
Classification according to EDSS at the last follow-up
Bilateral
80.4
Azathioprine
68.7
No impairment/ no disability (EDSS 0–1.5)
10.4
Permanent sphincter deficiency
Rituximab
40.2
Mild disability (EDSS 2.0–2.5)
12.5
No sphincter impairment
77.1
Exchange of immunosuppressive therapy with a second drug
Moderate disability (EDSS 3.0–4.0)
45.9
Neurogenic bladder
18.7
Never changed the immunosuppressive drug (good response)
70.8
Severe disability/partial dependence (EDSS 4.5–6.5)
18.8
Ostomy
40.2
Therapeutic failure of the first drug and needed to change to azathioprine
14.6
Profound disability/total dependence (EDSS 7.0–9.5)
60.2
Locked-in syndrome
Therapeutic failure of the first drug and needed to change to rituximab
14.6
Death caused by NMOSD (EDSS 10)
60.2
Permanent vegetative state
20.1
NMOSD: neuromyelitis optica spectrum disorders; IVMP: intravenous methylprednisolone;
%: relative frequency; EDSS: Expanded Disability Status Scale (an outcome measurement
that classifies demyelinating diseases, created by Kurtzke in 1983).
Magnetic Resonance Imaging (MRI) identified LETM spinal cord lesions in 35 cases (73%),
and the cervicothoracic segment was the one most often affected. Spinal cord MRI showed
that involvement of both the cervical and the dorsal spinal was significantly more
common than involvement of only one of these two segments (40% both vs. 20% only cervical
and 17% only dorsal). The cumulative frequency of segments affected in the spinal
cord was 43.8% cervical, 56.3% dorsal, and 16.7% lumbar. Brain MRI examinations exhibited
typical NMOSD in 22.9% of the patients. More than 64% of the NMOSD patients had optic
nerve injuries ([Table 1 ]). The classical association between myelitis and optic neuritis, as first described
by Devic in 1894, was found in 15 cases (31.3%).
In this study, disability in terms of EDSS was predominantly moderate (EDSS 3.0–4.0),
which accounted for 45.9% of the cases; while 25% had worse classifications (EDSS
4.5–6.5 and 7.0–9.5) with limited mobility, as detailed in [Table 2 ].
The majority of the patients had been on immunosuppressive treatment with azathioprine
since receiving their diagnoses with NMOSD. Before the current NMOSD criteria, 14.6%
of the patients had been misdiagnosed as presenting multiple sclerosis and received
interferon and glatiramer, which worsened the clinical picture. After the NMOSD criteria
definition, they were switched to azathioprine or rituximab, as detailed in [Table 2 ].
Most of the patients (70.8%) never had any changes to their immunosuppressive drug,
which means that a good therapeutic response had been achieved. We considered that
a good therapeutic response consisted of the absence of new relapses, partial recovery,
or improvement of EDSS. Despite the good therapeutic responses seen in this study,
the diagnoses were made too late, and consequently, the specific immunosuppressive
treatment was also started too late, after permanent impairments had already occurred
(77.1%), and there was a death rate of 6.2%. The majority (84%) of the patients had
developed permanent disability: 52% became physically handicapped, 54% acquired permanent
visual impairment (25% with bilateral and 75% with unilateral amaurosis), and 30%
developed sphincter deficiency (82% with neurogenic bladder and 18% with ostomy).
It was seen that 68.75% of the patients considered themselves to be Amerindians (descendants
of Native Americans), while other ancestries accounted for the remaining 31.25%. Thus,
the present study showed, for the first time, that there was a higher prevalence of
this disease among descendants of the indigenous population (p<0.039) than among individuals
of other ancestries.
DISCUSSION
The classical worldwide epidemiological research described the overrepresentation
of east Asians and Afro-descendants among patients with NMO/NMOSD[1 ],[2 ],[5 ],[7 ],[10 ],[13 ]. The higher prevalence of Amerindian ancestry seen in our study conducted in the
Brazil Midwestern region also differs from the findings of other Brazilian NMO studies
which were conducted in other regions of this country of continental dimensions.
A study on genetic ancestry, conducted in 2013, which brought together data from five
reference centers for demyelinating diseases in Brazil, showed that European ancestry
was predominant in Brazil. However, that study[18 ] also showed that the vast majority of patients with European ancestry were living
in the southeastern region (80.5%; 87 cases), followed by the northeastern region
(13%; 14 cases), while only 6.5% (7 cases) came from the state of Goiás, in the Midwestern
region of Brazil. That study[18 ], with a mixed group from different regions of Brazil, also identified that 68.7%
were of European ancestry, 20.5% were of African ancestry and only 10.8% were of Amerindian
ancestry. However, another study in the southeastern region of Brazil, showed that
there was a predominance of Caucasians (54.9%) and that only 0.9% were Amerindians[14 ]. Principal component analysis has shown that groups of NMOSD patients in different
Brazilian regions have differences in ancestry and phenotype[18 ].
A literature review[19 ] evaluated the phenotypic characteristics of the Brazilian NMO case series, covering
the period from 2002 to 2014, five studies were found, out of which four were carried
out in the southeastern region (two in Rio de Janeiro[20 ],[21 ] and two in São Paulo[22 ],[23 ]) and one was carried out in the federal capital, Brasília[19 ]. All of these five studies described the predominance of NMOSD among individuals
of non-white skin color, but none of them described their ancestry.
According to the national census of 2010, 46.7% of Brazilians identified themselves
as being of mixed ancestry[14 ]. The state of Goiás, located in the Midwestern region, is at the “heart of Brazil”
and surrounds the Brasilia federal district. It is the seventh-largest state in Brazil,
with an approximate area of 340,126 km[2 ]
[14 ]. According to an autosomal genetic study, the population of Goiás is derived from
miscegenation between three main ancestral groups: 3% native Amerindians, 83.7% Europeans
(mainly Portuguese), and 13.3% afro-descendants, typically from sub-Saharan Africa[16 ],[17 ]. The prevalence of multiple sclerosis in the state of Goiás had been reported to
be 22.4/100.000[15 ], but the prevalence of NMOSD remained unknown until now. Through the present research,
it was shown that the estimated prevalence of NMOSD in Goiás was 0.79/per 100,000
inhabitants.
Although the predominance of HLA-DRB1*03 and DRB3 in mulattos with NMO/NMOSD in southeastern
Brazil has been well described[24 ], little is known about the possible HLA haplotypes of Amerindians, or about their
correlations with the incidence and prevalence of this disease. Thus, the Amerindian
genotype may resemble that of afro-descendants due to the high miscegenation of the
Brazilian population, especially in the central-western region, where the proportions
of Amerindians and blacks are high[14 ].
Other epidemiological features shown among the NMO/NMOSD patients in the present study
corroborate the results described by Flanagan et al.[10 ], with a predominantly female (81.2%) and non-Caucasian (83.3%) population. The profile
identified among patients who were followed up for 20 years of age at a reference
center in São Paulo, southeastern Brazil, was that NMOSD accounted for 15.3% of demyelinating
disorders[24 ].
35% of the patients with NMOSD were positive for autoantibodies, with no significant
differences in their concentrations between the groups. This proportion may have resulted
from the following events: [I] 77% of the patients were taking azathioprine, which
has the role of suppressing the immune response and may decrease the detection of
autoantibodies through laboratory tests[1 ]; [II] the low sensitivity of the ELISA used in this study (60%) led to the occurrence
of false negatives[25 ]; and [III] patients in the early stages of the disease may not yet have seroconverted
or, because they are in the process of seroconverting, they may have low concentrations
of AQP4-IgG, especially if the laboratory test used presented low sensitivity[26 ]–[30 ]. Thus, it is extremely necessary to improve the laboratory test for detection of
AQP4-IgG that is used by the state government of Goiás.
In conclusion, this study reported on the demographics, clinical characteristics,
treatments, and outcomes of neuromyelitis optica spectrum disorder (NMOSD) at a tertiary-level
reference center in Goiás, Midwestern Brazil, over the last 24 months. A higher prevalence
of this disease was found among Amerindian descendants. The estimated prevalence of
NMOSD in Goiás was 0.79/per 100,000 inhabitants, and NMOSD accounted for 9.37% of
the cases of demyelinating diseases seen in the reference center (CRIEM.) The predominant
phenotype of NMOSD in Goiás consists of women, non-whites, the median age of onset
in the fourth decade of life, relapsing course, and permanent moderate disability.
These data may be useful in assessing the overall status of NMOSD among Amerindian
descendants. Thus, studies on Amerindian HLA should be conducted to more accurately
determine the reasons that lead to the higher prevalence of NMOSD among the descendants
of native Americans.
