J Neurol DOI 10.1007/s00415-015-7844-y
ORIGINAL COMMUNICATION
Features of anti-aquaporin 4 antibody-seropositive Chinese patients with neuromyelitis optica spectrum optic neuritis Hongyang Li2 • Yanling Wang2 • Quangang Xu3 • Aidi Zhang4 • Huanfen Zhou1 Shuo Zhao1 • Hao Kang1 • Chunxia Peng1 • Shanshan Cao1 • Shihui Wei1
•
Received: 6 April 2015 / Revised: 1 July 2015 / Accepted: 1 July 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract The detection of anti-aquaporin-4 autoantibody (AQP-4 Ab) is crucial to detect patients who will develop neuromyelitis optica (NMO); however, there are few studies on the AQP-4 Ab serostatus of patients with neuromyelitis optica spectrum ON. We analyzed the clinical and paraclinical features of neuromyelitis optica spectrum ON patients in China according to the patients’ AQP4-Ab serostatus. 125 patients with recurrent and bilateral ON with simultaneous attacks were divided into AQP-4 Abseropositive and -seronegative groups. Demographic, clinical, serum autoantibody data, connective tissue disorders (CTDs), visual performance were compared. A Visual Acuity (VA) of less than 0.1 during acute ON attacks occurred more frequently in the seropositive group (p = 0.023); however, there was not a significant difference between groups on VA recovery after the first attack. The seropositive group experienced the worst outcome during the last attack (p = 0.017). Other co-existing autoimmunity antibodies (p \ 0.001) and CTDs (p \ 0.001) were more prevalent in seropositive patients. There were no significant differences on VA recovery and Hongyang Li and Yanling Wang were the co-first authors and they contributed equally. & Shihui Wei [email protected]; [email protected] 1
Department of Ophthalmology, The Chinese People’s Liberation Army General Hospital, Beijing, China
2
Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
3
Department of Neurology, The Chinese People’s Liberation Army General Hospital, Beijing, China
4
Department of Ophthalmology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
RNFLT combined with other autoantibodies or CTDs. The two groups did not differ significantly with regard to time to relapse, annualized relapse rates, time of diagnosis NMO, or RNFL. There were no significant differences on VA recovery and RNFLT combined with other autoantibodies or CTDs. RNFLT was thinner in NMO seropositive patients. Although AQP-4 Ab expression predicted poor visual outcome, positive patients were usually associated with mild symptoms at first onset. Anti-SSA/SSB antibody or Sjo¨gren syndrome may be associated with AQP-4 Ab in neuromyelitis optica spectrum ON. Keywords Optic neuritis Neuromyelitis optica spectrum Aquaporin 4 Connective tissue disorders
Introduction Optic neuritis (ON) is an inflammatory optic nerve injury which causes acute or sub-acute onset vision loss in children and young adults and is recognized as a leading cause of blindness in young adults [1]. ON can represent the first presentation of symptoms of multiple sclerosis (MS) or neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) [2]. Early differentiation of MS and NMO/ NMOSD symptoms in patients who first present with ON is important, as therapeutic options differ for each condition and the prognosis for NMO is usually worse than MS [3]. A specific IgG autoantibody, NMO-IgG, which selectively targets AQP4, has been found in up to 63 % of NMO patients [4]. In recent studies, AQP4 IgG has been found to be a highly specific, but moderately sensitive, biomarker of NMO pathology and has been found to distinguish NMO from MS [5]. Therefore, AQP4 IgG status is crucial for detecting patients who will develop NMO [6, 7]. It is also a
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sensitive and specific biomarker for the discrimination of NMO, classic MS, and other neurological diseases [8]. Moreover, poorer visual outcomes during acute ON attacks were found to be more frequent among seropositive patients compared to seronegative patients based on a population of 34 severe ON patients [9]. Seropositive and seronegative patients with MS or NMO/NMOSD might differ with regard to clinical presentation or prognosis [10]. Since AQP4-IgG was discovered only a few years ago, many previous studies did not categorize patients according to their AQP4-IgG serostatus [11], did not determine the clinical features and prognosis associated with AQP4-IgG at all [12], or only evaluated relatively few patients with short outcomes [13]. Reports showed that AQP4-Ab-positive NMO/NMOSD differed clinically and epidemiologically from seronegative disease, clinical features of seronegative disorder could be more similar to that of MS. However, there have been few reports on AQP4-Ab serostatus in patients with clinically isolated syndrome (CIS) manifesting as a single isolated ON (SION) [14, 15]. So the problem that features of AQP4 Ab-seropositive with NMOSD-ON should be resolved. In the present study, patients with recurrent and bilateral ON with simultaneous attacks were recruited as the AQP-4 Ab is more easily detected in RON and BON patients [16]. We analyzed the clinical and paraclinical features of ON patients in China according to the patients’ AQP-4 Ab serostatus, evaluated visual performance of AQP-4 Abseropositive patients within the NMOSD-ON population, and assessed whether the presence of the AQP-4 Ab had any clinical significance.
Methods Patients Patients with recurrent ON and bilateral ON simultaneous attacks were recruited from the Ophthalmology Department of The Chinese People’s Liberation Army General Hospital (PLAGH) and Beijing Friendship Hospital of Capital Medical University; a retrospective study had been performed. Recruitment was completed from May 2008 through December 2013. ON was the first symptom in all the participants. All the patients in research groups had with an episode of ON more than 12 months before the study inclusion time point. All the patients were treated with Methylprednisolone according to the suggestion with ONTT: Methylprednisolone (1.0 g) was taken through intravenous fluid therapy for 3 days, and then orally with the dose of 60 mg for 11 days [1]. Patients were excluded if they showed any evidence of compressive, vascular, toxic, metabolic, infiltrative, or
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hereditary optic neuropathy. We also excluded those who had retinal lesions or other causative ocular diseases or had the presence of significant refractive errors (3D of spherical equivalent refraction or 2D of astigmatism), intraocular pressure of 21 mmHg higher, glaucoma, retinal disease, a history of media opacification, ocular pathologies affecting the cornea, lens, or vitreous or laser therapy. Patients with the hepatitis viral infection, human immunodeficiency virus (HIV) infection, syphilitics, lymphoma, graft-versushost disease, lymphoma, human T-lymphotropic virus Type I, or previous head or neck radiation were also excluded [17]. We also excluded the patients who had taken corticosteroids when they collected blood samples for the measurements of AQP4-Ab. Patients whose most recent attack of ON had occurred less than 6 months previously were not included in the study. The results of VA involving to this study were all performed at least 3 months after the ON attack. Because the visual recovery has been relatively stable at that time. MS diagnosis was confirmed using the 2010 revisions to the McDonald Criteria [18]. NMO diagnosis met the Wingerchuk’s 2006 diagnostic criteria [19]. Diagnosis of a rheumatologic disease or syndrome was confirmed according to international classification criteria, such as rheumatoid (RM) [20]. Sjo¨gren’s syndrome (SS) [21], ankylosing spondylitis (AS) [22], systemic lupus erythematosus (SLE) [23], Wegner’s granulomatosis (WG) [24], Behcet’s disease (BD) [25], and anticardiolipin antibody syndrome (ACA) [26]. AQP-4 IgG testing All serum samples were analyzed for the presence of AQP4-IgG antibodies by an extracellular live cell-staining immunofluorescence technique using transiently transfected AQP4-expressing cells as previously described [27]. Sera were scored as positive or negative by two independent evaluators and titrated in doubling dilutions to determine the greatest dilution that remained positive. The assay evaluators were unaware of the clinical diagnosis. The patients were tested for AQP-4 Ab-positive (titer [1:10) at least twice. Blood and CSF tests Sera were drawn for antinuclear antibody (ANA), extractable nuclear antigen antibodies (SSA and SSB), rheumatoid factor (RF), anticardiolipin antibodies (ACLs and b2GPI), and lupus anticoagulant (A-ds DNA), Anti-Neutrophil Cytoplasmic Antibodies (ANCA), centromere/ kinetochore complex protein-B (CENP-B), Major Histocompatibility Complex-B27 (HLA-B27) in the Examination Center for Biomedical Research of PLAGH. 12 mL of
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CSF was collected in an ice bath and immediately centrifuged at 400G at 4 °C for 10 min, and the cell-free supernatant was frozen and stored in 0.5 mL aliquots at -80 °C until analysis. All biomarker analyses were performed by enzyme-linked immunosorbent assays (ELISA) using commercially available kits. Neuro-opthalmology testing Ophthalmic examinations including slit lamp examination and pupillary reactions in unilateral or bilateral asymmetric conditions allowed a quantitative measurement of whether the optic neuropathy was stable, improving, or worsening. VA was examined by the standard table of vision logarithms at 5 m. Those unable to read any letters at one meter were further examined by finger counts, hand movements, or perceiving light. SD-OCT examinations were carried out on a high-definition spectral domain optical coherence tomography (HDOCT) (Carl Zeiss Meditec, Dublin, USA). Both the Macular Cube 512 9 128 scan and RNFL measurement by the Optic Disc Cube 200 9 200 protocol were performed on all eyes. The orbit and brain MRI imaging were evaluated according to Paty criteria using MRI-3.0T (TW1WSPEED HDXT, GE, USA), post-contrast T1-weighted conventional spin-echo (TR = 680 ms; TE = 14 ms, FOV = 24, slice thickness = 3.0, interleaved), 5 min after the intravenous administration of 0.1 mmoL/kg gadopentetate dimeglumine.
Table 1 Epidemiologic and disease characteristics of patients with ON Number
125
Age (year, mean ± SD)
38.98 ± 15.40
Sex (male:female)
31:94
Duration (months, mean ± SD)
41.07 ± 47.06
AQP4 antibody-seropositive (N, %)
49 (39.2 %)
Patients meeting Wingerchuk’s 2006 criteria (N, %)
31 (24.8 %)
Cases of death, attack-related (N, %)
0 (0.0 %)
Recurrent ON onset (N, %)
96 (76.8 %)
Bilateral ON at first ON attack (N, %)
29 (23.2 %)
Intraocular pressure, mean ± SD, mmHg
15.97 ± 5.01
Clinical features according to the patients’ AQP4Ab The female to male ratio was 94:31 (n = 125) in the total cohort; it was significantly higher in seropositive patients compared to seronegative patients (Table 1). There were 43 (87.76 %) female patients who were seropositive and 51 (67.11 %) who were seronegative. 49.0 % patients fulfilled the diagnosis of NMO in the seropositive group and 10.5 % patients in the seronegative group (p \ 0.001). 12 patients relapsed to MS, including 11 (14.5 %) in the seronegative group and 1 (2.0 %) in the seropositive group (p = 0.027) (Table 2). There were no significant differences between the two groups in age, disease course, times of ON attacks, or number of recurrent and bilateral ON patients.
Statistical analysis CSF and MRI findings All statistical analyses were performed using the Statistical Program for Social Sciences statistical software (version 17.0; SPSS, Inc., Chicago, IL). Nonparametric tests (Wilcoxon tests or Mann–Whitney U tests) were used to compare the clinical data and other measurement data. The categorical data were analyzed using Chi-squared test or Fisher exact test. p values \0.05 were considered significant.
Results Patient demographics Our cohort included 125 patients (220 eyes) with ON. All patients underwent clinical diagnosis, AQP-4 Ab and other autoantibodies detection, OCT examination, and orbit/ brain MRI. There were 96 (76.8 %) patients with a unilateral bilateral relapsing ON, whereas 29 patients (23.2 %) had a history of bilateral simultaneous ON. 31 patients were relapsing to NMO. Demographic and ON disease characteristics identified via medical record review are presented in Table 1.
No significant difference in oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) between seropositive and seronegative groups was found (Table 3). CSF white cell numbers were 3.58 ± 6.82 (no./mm3) in the seropositive group and 3.15 ± 4.14 in the seronegative group (p = 0.982). CSF total cells numbers (no./mm3) were 29.22 ± 47.14 in the seropositive group and 12.36 ± 27.40 in the seronegative group (p = 0.447). In addition, there were no significant differences in CSF protein (g/L) and CSF IgG levels across the two groups either. 109 (87.20 %) patients presented with abnormal optic nerves based on the MRI (Fig. 1), including T2 lesions and Gad enhancing; however, there were no significant differences across the two groups (p = 0.343) (Table 3). Vision recovery and prognosis During the first documented ON attack, there were ON attacks in the right eye in 42 (47.7 %) in the seropositive group and 45 (32.6 %) in the seronegative group; it was more frequent among the seropositive patients than among
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J Neurol Table 2 Comparison of clinical features according to the patients’ AQP4-Ab serostatus
Seropositive
Seronegative
p level
Number of patients (n)
49
76
Eyes with optic neuritis history (n)
85
135
Age (year, mean ± SD)
36.53 ± 16.26
40.56 ± 14.72
0.13
Sex (male:female)
6/43
25/51
0.009**
Duration (months, mean ± SD)
41.81 ± 29.90
40.56 ± 47.35
0.079 0.509
Times of ON attacks (n, mean ± SD)
2.62 ± 1.68
2.55 ± 1.61
Recurrent ON onset (N, %)
39 (79.6 %)
57 (75.0 %)
0.553
Bilateral ON at first ON attack (N, %)
10 (20.4 %)
19 (25.0 %)
0.553
Time of diagnosis NMO (months, mean ± SD)
19.5 ± 20.51
27.75 ± 24.27
0.535
Meeting Wingerchuk’s 2006 criteria (N)
24 (49.0 %)
8 (10.5 %)
\0.001**
Meeting MS criteria (N)
1 (2.0 %)
11 (14.5 %)
0.027*
* p \ 0.05, ** p \ 0.01
Table 3 Comparison of CSF and MRI according to the patients’ AQP4-Ab serostatus
Seropositive
Seronegative
p level
Number of patients (n)
49
76
CSF-restricted OCB (n)
1
2
1.00
CSF cells (no./mm3)
29.22 ± 47.14
12.36 ± 27.40
0.447
Median CSF white cell count
3.58 ± 6.82
3.15 ± 4.14
0.982
CSF protein (g/L)
361.40 ± 139.70
404.11 ± 175.08
0.379 0.722
CSF IgG level
3.37 ± 1.80
3.27 ± 1.74
MRI total (N, %)
41 (83.7 %)
68 (89.5 %)
0.343
T2 lesion (N, %)
35 (71.4 %)
55 (72.4 %)
0.909
Gad enhancing (N, %)
28 (57.1 %)
37 (48.7 %)
0.355
CSF cerebrospinal fluid, OCB oligoclonal bands
Fig. 1 The sagittal plane and coronal plane MRI of the orbit. Coronal postgadolinium fat-saturated T1-weighted image showed the right optic nerve enhances along with enhancement of the optic sheath. Arrows the lesion part
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J Neurol Table 4 Comparison of Visual Performance according to the patients’ AQP4-Ab serostatus
Seropositive
Seronegative
p level
Number of patients (n)
49
76
Eyes with optic neuritis history (n)
88
138
Time of first to second attack (months)
11.16 ± 17.03
16.64 ± 30.64
0.46
42 (47.7 %)
45 (32.6 %)
0.023*
VA at first ON attacks in acute time B0.1 0.1–0.5
18 (20.5 %)
29 (21.5 %)
0.919
C0.5
28 (31.8 %)
64 (46.4 %)
0.03*
B0.1
31 (35.2 %)
38 (27.5 %)
0.221
0.1–0.5
17 (19.3 %)
32 (23.2 %)
0.491
C0.5
40 (45.5 %)
68 (49.3 %)
0.575
B0.1
46 (52.3 %)
50 (36.2 %)
0.017*
0.1–0.5
19 (21.6 %)
32 (23.2 %)
0.779
C0.5 RNFL (lm)
23 (26.1 %)
56 (40.6 %)
0.026*
VA recovery at first attack
VA recovery at last attack
Average thickness (mean ± SD)
70.89 ± 17.55
73.88 ± 18.20
0.251
Superior quadrant (mean ± SD)
84.26 ± 87.34
87.71 ± 28.43
0.358 0.361
Inferior quadrant (mean ± SD)
85.93 ± 30.82
88.77 ± 30.63
Nasal quadrant (mean ± SD)
61.56 ± 13.55
62.07 ± 12.00
0.486
Temporal quadrant (mean ± SD)
50.13 ± 10.69
53.45 ± 13.39
0.100
VA visual acuity * p \ 0.05, ** p \ 0.01
seronegative patients at the first ON acute (p = 0.023) (Table 4). No differences in visual recovery outcome were observed between seropositive and seronegative patients (Table 4). After the first ON attack, VA was: B0.1 in 31 (35.2 %) of seropositive patients and 38 (27.5 %) in the seronegative patients; 0.1–0.5 in 17 19.3 %) in the seropositive patients and 32 (23.2 %) in the seronegative patients. Complete remission (VA [0.5) was 40 (45.5 %) in the seropositive patients and 68 (49.3 %) in the seronegative patients. At the end of the observation period, VA was B0.1 on either the left or the right eye in 46 (52.3 %) patients in the seropositive patients and 50 (36.2 %) in the seronegative patients; it was more frequent among seropositive patients than among seronegative patients with the servers VA at the last ON attacks in acute time (p = 0.017) (Table 4). In addition, there were no significant differences between the two groups in time of first to second attack (months) and RNFLT (lm, average, superior, inferior, nasal, temporal quadrant thickness).
in 34 (69.4 %) of seropositive patients and 27 (35.5 %) of seronegative patients (p \ 0.001). There were 24 (49.0 %) patients, 16 (21.1 %) patients, 3 (5.00 %) patient, in the seropositive group, and seronegative group, respectively, with ANA titers equal to or greater than 1:160. SSA or SSB was positive in 19 (38.8 %) of seropositive patients and 10 (13.2 %) of seronegative patients, respectively. There were no significant differences across the two groups on frequency of ACL/b2-GPI, A-ds DNA, RF, ANCA, CEPD-B, and HLA-B27 levels (Table 5). There were 32 patients who fulfilled the clinical classification criteria for SS (25 patients), AS (3), SLE (2), RM (2), ACA (0), WG (0), and BD (0) (Table 5). The seropositive group showed a higher tendency to have CTD than the seronegative group (p \ 0.001). Seropositive patients had SS more frequently than seronegative patients and the differences between them were statistically significant.
Associations with autoantibody and CTD detection
Comparison of clinical features according to the patients’ AQP4-Ab serostatus in ON combined with CTDs was also performed (Table 6). There were no significant differences across the two groups in age, female to male ratio, numbers of patients relapsed to MS or NMO (Fig. 2), times of
Frequencies of autoantibodies and CTDs were assessed in the two groups of patients. Detailed results of autoantibody testing are presented in Table 5. Autoantibodies were found
Vision performance in ON combined with Ab or CTDs
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J Neurol Table 5 Comparison of autoimmunity according to the patients’ AQP4-Ab serostatus
Seropositive
Seronegative
p level
Number of patients (n)
49
76
Signs of existing autoimmunity (n)
23 (46.9 %)
9 (11.8 %)
AS
1 (2.0 %)
2 (2.6 %)
0.833
SS
19 (38.8 %)
6 (7.6 %)
\0.001**
SLE
2 (4.1 %)
0 (0.0 %)
0.152
WG
0 (0.0 %)
0 (0.0 %)
NA
ACA
0 (0.0 %)
0 (0.0 %)
NA
BD
0 (0.0 %)
0 (0.0 %)
NA
RM
1 (2.0 %)
1 (1.3 %)
1.00
Co-existing autoantibodies (n)
34 (69.4 %)
27 (35.5 %)
\0.001**
ANA
24 (49.0 %)
16 (21.1 %)
0.001**
SSA/SSB
19 (38.8 %)
10 (13.2 %)
0.001**
ACL/b2-GPI
5 (10.2 %)
7 (9.2 %)
1.00
\0.001**
A-ds DNA
3 (6.1 %)
0 (0.0 %)
0.058
RF ANCA
2 (4.1 %) 1 (2.0 %)
2 (2.6 %) 0 (0.0 %)
0.645 0.392
CENP-B
1 (2.0 %)
1 (1.3 %)
1.00
HLA-B27
6 (12.2 %)
4 (5.3 %)
1.188
ANA antinuclear antibody, SSA and SSB extractable nuclear antigen antibodies, RF rheumatoid factor, ACL anticardiolipin antibody, b2-GPI anti-b2-glycoprotein I, A-ds DNA antidouble-stranded DNA antibody, ANCA anti-neutrophil cytoplasmic antibodies, CENP-B centromere/kinetochore complex protein-B, HLAB27 major histocompatibility complex-B27, AS ankylosing spondylitis, RM rheumatoid, BD Behcet’s disease, WG Wegner’s granulomatosis, SLE systemic lupus erythematosus, ACA anticardiolipin antibody syndrome, SS Sjogren’s syndrome, NA not available * p \ 0.05, * *p \ 0.01
relapse, time of first to second attack, VA at first ON attacks in acute time or in remission time, or VA recovery at the last attack in the follow-up period and RNFLT (lm, average, superior, inferior, nasal, temporal quadrant thickness). 15 (44.1 %) patients in the seropositive group and 2 (7.4 %) patients in the seronegative group met Wingerchuk’s 2006 criteria (p = 0.001, Table 7). Vision performance according to AQP4-Ab serostatus in NMO patients Patients with NMO (n = 32, 55 eyes) were divided into two groups according to AQP-4 Ab serostatus and they underwent vision testing and OCT imaging. Peripapillary RNFL average thickness was reduced in seropositive patients (70.26 ± 19.90 lm) relative to seronegative patients (86.68 ± 0.63; p = 0.017). RNFL in the inferior quadrant and nasal quadrant thickness were significantly reduced in seropositive patients (inferior: 84.71 ± 30.79 lm; nasal: 108.73 ± 30.62 lm) relative to seronegative patients (inferior: 61.18 ± 15.52 lm; nasal: 70.36 ± 16.64 lm) (Table 8). There were no significant differences among the two groups across age, female to male ratio, time of diagnosis of NMO, times of relapse, time of first to second attack,
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VA at first ON attacks in acute time or in remission time, or VA recovery at the last attack in the follow-up period.
Discussion In this study the clinical and paraclinical features of ON according to the patients’ AQP4-Ab serostatus were analyzed in Chinese patients. We found a strong female predominance in this population of seropositive patients. The female/male ratio of the seropositive patients (7.17) was significantly higher than that reported in previous MS studies [28]. In the seronegative group (2.04), the ratio was in accordance with previous study in MS (2:1); this finding further supported the hypothesis that seropositive NMO is a distinct disease from MS. 49 % of patients in AQP-4 Abseropositive group developed NMO, which was significantly higher than the seronegative group (10.5 %). These results support previous findings that AQP-4 Ab is a specific biomarker for NMO [29]. AQP4 Ab is useful in predicting the severity of disease course and the probability of conversion to NMO at the first episode of isolated ON [30]. There were no significant differences between the two groups across median time to NMO diagnosis and the latency between the first ON attack and the second attack.
J Neurol Table 6 Comparison of visual performance according to the patients’ AQP4-Ab serostatus in ON combined with CTDs
Seropositive
Seronegative
p level
ON at onset (n)
23
9
Eyes with optic neuritis history (n)
39
16
Age (median, range; N)
39.41 ± 14.59
44.33 ± 15.59
Sex (male:female)
2:21
1/8
1.00
Duration (months)
40.83 ± 24.56
64.89 ± 107.14
0.45 0.557
0.338
Recurrent ON onset (N, %)
21/23 (91.3 %)
7/9 (77.8 %)
Bilateral ON at first ON attack (n, %)
2/23 (8.7 %)
2/9 (22.2 %)
0.557
Meeting Wingerchuk’s 2006 criteria (n)
7 (30.4 %)
0 (0.0 %)
0.149
Meeting MS criteria (n)
0 (0.0 %)
2 (22.2 %)
0.073
Times of relapse (n)
2.68 ± 1.36
3.00 ± 2.06
0.855
Time of first to second attack (months)
12.64 ± 16.89
20.44 ± 55.36
0.08
B0.1
27 (69.2 %)
12 (75.0 %)
0.754
0.1–0.5
8 (20.5 %)
3 (18.8 %)
1.00
4 (10.3 %)
1 (6.2 %)
1.00
B0.1
10 (25.6 %)
3 (18.8 %)
0.734
0.1–0.5
6 (15.4 %)
2 (12.5 %)
1.00
C0.5
23 (59.0 %)
11 (68.8 %)
0.498
16 (41.0 %)
6 (37.5 %)
0.808
VA at first ON attacks in acute time
C0.5 VA recovery at first attack
VA recovery at last attack B0.1 0.1–0.5
8 (20.5 %)
2 (12.5 %)
0.706
C0.5
15 (38.5 %)
8 (50.0 %)
0.431
RNFL (lm) Average thickness(mean ± SD)
71.25±18.77
76.88±24.01
0.369
Superior quadrant (mean ± SD)
85.00 ± 27.77
91.63 ± 35.09
0.685
Inferior quadrant (mean ± SD)
81.88 ± 29.62
95.56 ± 39.62
0.399
Nasal quadrant (mean ± SD)
61.60 ± 19.37
58.88 ± 12.32
0.298
Temporal quadrant (mean ± SD)
53.73 ± 11.40
57.50 ± 15.57
0.269
* p \ 0.05, ** p \ 0.01
Therefore, we suggest that the AQP-4 Ab would not likely determine the time to myelitis onset or latency of disease recurrence. VA of less than 0.1 during acute ON attacks was more frequent among seropositive patients. While visual recovery after an initial attack between the two groups was not significantly different, seropositive patients had more severe VA outcomes than seronegative patients at the final follow-up. Matiello et al. showed that AQP-4 Ab expression predicted poor visual outcome and development of NMO [31]. A multicentre study of 175 patients in Germany found that a VA of \0.1 was more common during acute ON attacks among AQP-4 Ab-seropositive patients [32]. In the current study, VA results were similar to that of previous studies; however, visual recovery during the remission period at the first ON attack was not significantly different between groups. Recent studies have found that a substantial number of NMO cases are usually associated
with mild symptoms or a benign long-term course [33, 34]; therefore, the outcome of a single isolated ON case cannot be determined according to VA recovery at first onset. In the current study, NMO started in most patients with unilateral ON. In a Swedish MS register, Burman et al. identified 472 patients with MS and found that the proportion of patients who developed a second attack of ON was 5.5 %; the percentage of bilateral simultaneous ON as the presenting symptom of MS was 0.42 %. They suggested that recurrent ON, whether unilateral or bilateral, is a common presentation of MS [35]. According to the McDonald diagnostic criteria, isolated recurrent ON affecting both optic nerves could have led to the diagnosis of MS [36, 37]. In recent studies, ON relapse (14.8 %) was found to be more likely in Chinese seropositive patients [8]. Optical coherence tomography (OCT) is a useful tool that can be used to evaluate the differences between NMO-
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Fig. 2 MS and NMO patients showed demyelinating cerebral and spinal lesions in MRI. a Focal multiple small lesions (arrow) seen on coronal T2-weighted image MRI of brain. b The spinal cord MRI, T2-
weighted image showed a high signal intensity long cord lesion extending from the C2 to the T6 level. Arrows the lesion part
ON and MS-ON [38, 39]. OCT showed more severe retinal damage after ON episodes in NMO compared to relapsing– remitting MS [40, 41]. In current study, OCT was also used to evaluate the severity of atrophy of the optic nerve in the two groups and there were no significant differences between seropositive and seronegative patients. Peripapillary RNFL average thickness was reduced in seropositive patients compared to seronegative patients in the NMO-ON patients. Based on these results, it seemed that AQP-4 Ab had effect on the severity of NMO-ON. There was few studies focus on RNFL after ON episodes in different AQP-4 antibody serostatus. In current study, OCT was also used to evaluate the severity of atrophy of optic nerve in two different serostatus groups of ON and NMO. RNFLT was not significantly different between two groups, and it was thinner in NMO seropositive patients due to the possible reasons as following: (1) layer of retina facilitated to study the functional zone of retina in detail. The densest area of optic nerve ganglion cells was macula, while other location existed deletion. Macula may be the best area to demonstrate the early damage of ischemic optic neuropathy and optic nerve head. Peripapillary RNFL of optic disc only represented the atrophy of optic nerve axons, and
optic disc edema could conceal the loss of optic nerve head axons [42]. (2) The sample size is small, especially NMO AQP-4 (?) group, only 8 patients with 11 eyes, and may affect the statistical results. (3) At the end of the observation period, the VA damage was more severe in AQP4(?) patients than AQP-4(-) patients, nevertheless, there were no significant differences on RNFLT, and indicated that the most sensitive area of vision should be in the macular region, and the most intensive region of optic nerve ganglion cells is macula. Nonetheless, we detected the peripapillary RNFL of optic disc instead of the thickness of macular RNFL and ganglion cell layer. In this study, autoantibodies and CTDs were frequently detected in both seropositive and seronegative patients. Coexisting autoimmune disorders, as well as sero-autoantibodies, were significantly more common in seropositive patients; SS and SLE were the most common CTDs and SSA and SSB were the most common autoantibodies in these patients. These findings are similar to previous studies which found that NMO could coexist with CTDs [43], particularly SS [44]; however, this association is rare in MS [45, 46], as the prevalence of MS with SS ranges from 0 to 3.3 % [47]. Since AQP-4 Ab is a sensitive bio-
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J Neurol Table 7 Comparison of visual performance according to the patients’ AQP4-Ab serostatus in ON combined with abnormal auto-Ab
Seropositive
Seronegative
ON at onset (n)
34
27
Eyes with optic neuritis history (n)
61
51
p level
Age (median, range; N)
35.63 ± 15.53
40.96 ± 14.69
Sex (male:female)
4/34
7/27
0.379 0.190
Duration (months)
41.09 ± 24.11
49.57 ± 68.42
0.251
Recurrent ON onset (N, %)
30 (88.2 %)
23 (85.2 %)
1.00
Bilateral ON at first ON attack (n, %)
4 (11.8 %)
4 (14.8 %)
1.00
Meeting Wingerchuk’s 2006 criteria (n)
15 (44.1 %)
2 (7.4 %)
0.001**
Meeting MS criteria (n)
0(0.0 %)
3 (11.1 %)
0.081
Times of relapse (n)
2.67 ± 1.51
3.04 ± 1.90
0.94
Time of first to second attack (months)
11.33 ± 15.66
20.79 ± 37.79
0.844
B0.1
44 (72.1 %)
43 (84.3 %)
0.123
0.1-0.5
11 (18.0 %)
7 (13.7 %)
0.537
6 (9.8 %)
1 (2.0 %)
0.124
B0.1
18 (29.5 %)
14 (27.5 %)
0.81
0.1-0.5
11 (18.0 %)
10 (19.6 %)
0.832
C0.5
32 (52.5 %)
27 (52.9 %)
0.959
31 (50.8 %)
23 (45.1 %)
0.546
VA at first ON attacks in acute time
C0.5 VA recovery at first attack
VA recovery at last attack B0.1 0.1-0.5
10 (16.4 %)
8 (15.7 %)
0.919
C0.5
20 (32.8 %)
20 (39.2 %)
0.479
RNFL (lm) Average thickness(mean ± SD)
71.19 ± 18.32
72.96 ± 14.43
0.626
Superior quadrant (mean ± SD)
83.85 ± 27.13
86.36 ± 28.70
0.653
Inferior quadrant (mean ± SD)
86.89 ± 31.99
87.68 ± 34.18
0.818
Nasal quadrant (mean ± SD)
62.49 ± 14.77
60.02 ± 10.86
0.586
Temporal quadrant (mean ± SD)
50.68 ± 11.65
53.72 ± 13.24
0.458
* p \ 0.05, ** p \ 0.01
marker for NMO, the results of our study are similar to previous studies. CSF findings in NMO have been found to differ significantly from those of classical MS [48, 49]. In the current study, there were no significant differences between the two groups on abnormal CSF proteins, CSF cells, or CSF IgG levels. These results are similar to previous research [50], providing further support for the hypothesis that seronegative NMO patients are not simply a clinical variant of MS patients. All the patients were examined though the orbits with MRI; 83.7 % of seropositive patients had an abnormal optic nerve compared to 89.5 % of
seronegative patients. There were no significant differences in optic nerve lesions between seropositive and seronegative patients. MRI lacks the specificity to distinguish AQP4 Ab status. For AQP4 assay, some patients were detected AQP4 on the ON first onset, and however some patients did not detect AQP4. In addition, although some patients were subjected to ON for a long time, AQP4 was not detected at first onset due to not in our hospital, and then detected when transferred to our hospital at the time of ON relapse. Therefore, these factors would affect the statistical results. Based on the above limitations, a multiple-center and prospective survey should be used in the future.
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J Neurol Table 8 Comparison of visual performance according to the patients’ AQP4-Ab serostatus in NMO patients
Seropositive
Seronegative
p level
ON at onset (n)
24
8
Eyes with optic neuritis history (n)
44
11
Age (median, range; N)
35.17 ± 16.17
30.75 ± 15.35
Sex (male:female)
2/22
1/7
1.00
Duration (months)
54.88 ± 33.69
35.38 ± 25.57
0.053
0.273
Recurrent ON onset (N, %)
19 (79.2 %)
6 (75.0 %)
1.00
Bilateral ON at first ON attack (n, %)
5 (20.8 %)
2 (25.0 %)
1.00
Time of diagnosis NMO
27.75 ± 20.29
19.50 ± 20.51
0.522
Times of relapse (n)
3.04 ± 1.99
1.88 ± 1.13
0.098
Time of first to second attack (months)
30.75 ± 21.92
11.88 ± 20.01
0.321
VA at first ON attacks in acute time B0.1
35 (79.5 %)
9 (81.8 %)
1.00
0.1–0.5
6 (13.6 %)
1 (9.1 %)
1.00
C0.5
3 (6.8 %)
1 (9.1 %)
1.00
12 (27.3 %)
3 (27.3 %)
1.00
0.1–0.5
7 (15.9 %)
0 (0.0 %)
0.323
C0.5
25 (56.8 %)
8 (72.7 %)
0.495
VA recovery at first attack B0.1
VA recovery at last attack B0.1
25 (56.8 %)
3 (27.3 %)
0.08
0.1–0.5
7 (15.9 %)
2 (18.2)
1.00
C0.5
12 (27.3 %)
6 (54.5 %)
0.148
RNFL (lm) Average thickness(mean ± SD)
70.26 ± 19.90
86.68 ± 18.63
0.017*
Superior quadrant (mean ± SD)
83.76 ± 30.41
101.81 ± 23.43
0.144
Inferior quadrant (mean ± SD)
84.71 ± 30.79
108.73 ± 30.62
0.039*
Nasal quadrant (mean ± SD)
61.18 ± 15.52
70.36 ± 16.64
0.041*
Temporal quadrant (mean ± SD)
50.29 ± 11.06
60.09 ± 17.38
0.070
* p \ 0.05, ** p \ 0.01
References
Conclusion Severe VA performance during acute ON attacks is more frequent among seropositive NMOSD-ON patients. It does not impact the aspect of VA recovery at first attack, RNFLT, time of diagnosis NMO or time to second attack. SSA/SSB autoimmunity antibodies and SS were more prevalent in seropositive patients. Acknowledgments This work is supported by National the 12th Five-Year Plan Science and Technology support project ‘‘clinical epidemiological studies of optic neuritis (number: 2012BAI08B06) and China Postdoctoral Science Foundation (No.: 2013M532109). Conflicts of interest competing interests.
All the authors declare that there are no
Ethical standard This study was approved by the People’s Liberation Army General Hospital Ethics Committee and was conducted following the Declaration of Helsinki in its currently applicable version. All individuals voluntarily participated in the study after a thorough oral and written information procedure. Oral and written consents were obtained from all participants.
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ORIGINAL COMMUNICATION
Features of anti-aquaporin 4 antibody-seropositive Chinese patients with neuromyelitis optica spectrum optic neuritis Hongyang Li2 • Yanling Wang2 • Quangang Xu3 • Aidi Zhang4 • Huanfen Zhou1 Shuo Zhao1 • Hao Kang1 • Chunxia Peng1 • Shanshan Cao1 • Shihui Wei1
•
Received: 6 April 2015 / Revised: 1 July 2015 / Accepted: 1 July 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract The detection of anti-aquaporin-4 autoantibody (AQP-4 Ab) is crucial to detect patients who will develop neuromyelitis optica (NMO); however, there are few studies on the AQP-4 Ab serostatus of patients with neuromyelitis optica spectrum ON. We analyzed the clinical and paraclinical features of neuromyelitis optica spectrum ON patients in China according to the patients’ AQP4-Ab serostatus. 125 patients with recurrent and bilateral ON with simultaneous attacks were divided into AQP-4 Abseropositive and -seronegative groups. Demographic, clinical, serum autoantibody data, connective tissue disorders (CTDs), visual performance were compared. A Visual Acuity (VA) of less than 0.1 during acute ON attacks occurred more frequently in the seropositive group (p = 0.023); however, there was not a significant difference between groups on VA recovery after the first attack. The seropositive group experienced the worst outcome during the last attack (p = 0.017). Other co-existing autoimmunity antibodies (p \ 0.001) and CTDs (p \ 0.001) were more prevalent in seropositive patients. There were no significant differences on VA recovery and Hongyang Li and Yanling Wang were the co-first authors and they contributed equally. & Shihui Wei [email protected]; [email protected] 1
Department of Ophthalmology, The Chinese People’s Liberation Army General Hospital, Beijing, China
2
Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
3
Department of Neurology, The Chinese People’s Liberation Army General Hospital, Beijing, China
4
Department of Ophthalmology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
RNFLT combined with other autoantibodies or CTDs. The two groups did not differ significantly with regard to time to relapse, annualized relapse rates, time of diagnosis NMO, or RNFL. There were no significant differences on VA recovery and RNFLT combined with other autoantibodies or CTDs. RNFLT was thinner in NMO seropositive patients. Although AQP-4 Ab expression predicted poor visual outcome, positive patients were usually associated with mild symptoms at first onset. Anti-SSA/SSB antibody or Sjo¨gren syndrome may be associated with AQP-4 Ab in neuromyelitis optica spectrum ON. Keywords Optic neuritis Neuromyelitis optica spectrum Aquaporin 4 Connective tissue disorders
Introduction Optic neuritis (ON) is an inflammatory optic nerve injury which causes acute or sub-acute onset vision loss in children and young adults and is recognized as a leading cause of blindness in young adults [1]. ON can represent the first presentation of symptoms of multiple sclerosis (MS) or neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) [2]. Early differentiation of MS and NMO/ NMOSD symptoms in patients who first present with ON is important, as therapeutic options differ for each condition and the prognosis for NMO is usually worse than MS [3]. A specific IgG autoantibody, NMO-IgG, which selectively targets AQP4, has been found in up to 63 % of NMO patients [4]. In recent studies, AQP4 IgG has been found to be a highly specific, but moderately sensitive, biomarker of NMO pathology and has been found to distinguish NMO from MS [5]. Therefore, AQP4 IgG status is crucial for detecting patients who will develop NMO [6, 7]. It is also a
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sensitive and specific biomarker for the discrimination of NMO, classic MS, and other neurological diseases [8]. Moreover, poorer visual outcomes during acute ON attacks were found to be more frequent among seropositive patients compared to seronegative patients based on a population of 34 severe ON patients [9]. Seropositive and seronegative patients with MS or NMO/NMOSD might differ with regard to clinical presentation or prognosis [10]. Since AQP4-IgG was discovered only a few years ago, many previous studies did not categorize patients according to their AQP4-IgG serostatus [11], did not determine the clinical features and prognosis associated with AQP4-IgG at all [12], or only evaluated relatively few patients with short outcomes [13]. Reports showed that AQP4-Ab-positive NMO/NMOSD differed clinically and epidemiologically from seronegative disease, clinical features of seronegative disorder could be more similar to that of MS. However, there have been few reports on AQP4-Ab serostatus in patients with clinically isolated syndrome (CIS) manifesting as a single isolated ON (SION) [14, 15]. So the problem that features of AQP4 Ab-seropositive with NMOSD-ON should be resolved. In the present study, patients with recurrent and bilateral ON with simultaneous attacks were recruited as the AQP-4 Ab is more easily detected in RON and BON patients [16]. We analyzed the clinical and paraclinical features of ON patients in China according to the patients’ AQP-4 Ab serostatus, evaluated visual performance of AQP-4 Abseropositive patients within the NMOSD-ON population, and assessed whether the presence of the AQP-4 Ab had any clinical significance.
Methods Patients Patients with recurrent ON and bilateral ON simultaneous attacks were recruited from the Ophthalmology Department of The Chinese People’s Liberation Army General Hospital (PLAGH) and Beijing Friendship Hospital of Capital Medical University; a retrospective study had been performed. Recruitment was completed from May 2008 through December 2013. ON was the first symptom in all the participants. All the patients in research groups had with an episode of ON more than 12 months before the study inclusion time point. All the patients were treated with Methylprednisolone according to the suggestion with ONTT: Methylprednisolone (1.0 g) was taken through intravenous fluid therapy for 3 days, and then orally with the dose of 60 mg for 11 days [1]. Patients were excluded if they showed any evidence of compressive, vascular, toxic, metabolic, infiltrative, or
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hereditary optic neuropathy. We also excluded those who had retinal lesions or other causative ocular diseases or had the presence of significant refractive errors (3D of spherical equivalent refraction or 2D of astigmatism), intraocular pressure of 21 mmHg higher, glaucoma, retinal disease, a history of media opacification, ocular pathologies affecting the cornea, lens, or vitreous or laser therapy. Patients with the hepatitis viral infection, human immunodeficiency virus (HIV) infection, syphilitics, lymphoma, graft-versushost disease, lymphoma, human T-lymphotropic virus Type I, or previous head or neck radiation were also excluded [17]. We also excluded the patients who had taken corticosteroids when they collected blood samples for the measurements of AQP4-Ab. Patients whose most recent attack of ON had occurred less than 6 months previously were not included in the study. The results of VA involving to this study were all performed at least 3 months after the ON attack. Because the visual recovery has been relatively stable at that time. MS diagnosis was confirmed using the 2010 revisions to the McDonald Criteria [18]. NMO diagnosis met the Wingerchuk’s 2006 diagnostic criteria [19]. Diagnosis of a rheumatologic disease or syndrome was confirmed according to international classification criteria, such as rheumatoid (RM) [20]. Sjo¨gren’s syndrome (SS) [21], ankylosing spondylitis (AS) [22], systemic lupus erythematosus (SLE) [23], Wegner’s granulomatosis (WG) [24], Behcet’s disease (BD) [25], and anticardiolipin antibody syndrome (ACA) [26]. AQP-4 IgG testing All serum samples were analyzed for the presence of AQP4-IgG antibodies by an extracellular live cell-staining immunofluorescence technique using transiently transfected AQP4-expressing cells as previously described [27]. Sera were scored as positive or negative by two independent evaluators and titrated in doubling dilutions to determine the greatest dilution that remained positive. The assay evaluators were unaware of the clinical diagnosis. The patients were tested for AQP-4 Ab-positive (titer [1:10) at least twice. Blood and CSF tests Sera were drawn for antinuclear antibody (ANA), extractable nuclear antigen antibodies (SSA and SSB), rheumatoid factor (RF), anticardiolipin antibodies (ACLs and b2GPI), and lupus anticoagulant (A-ds DNA), Anti-Neutrophil Cytoplasmic Antibodies (ANCA), centromere/ kinetochore complex protein-B (CENP-B), Major Histocompatibility Complex-B27 (HLA-B27) in the Examination Center for Biomedical Research of PLAGH. 12 mL of
J Neurol
CSF was collected in an ice bath and immediately centrifuged at 400G at 4 °C for 10 min, and the cell-free supernatant was frozen and stored in 0.5 mL aliquots at -80 °C until analysis. All biomarker analyses were performed by enzyme-linked immunosorbent assays (ELISA) using commercially available kits. Neuro-opthalmology testing Ophthalmic examinations including slit lamp examination and pupillary reactions in unilateral or bilateral asymmetric conditions allowed a quantitative measurement of whether the optic neuropathy was stable, improving, or worsening. VA was examined by the standard table of vision logarithms at 5 m. Those unable to read any letters at one meter were further examined by finger counts, hand movements, or perceiving light. SD-OCT examinations were carried out on a high-definition spectral domain optical coherence tomography (HDOCT) (Carl Zeiss Meditec, Dublin, USA). Both the Macular Cube 512 9 128 scan and RNFL measurement by the Optic Disc Cube 200 9 200 protocol were performed on all eyes. The orbit and brain MRI imaging were evaluated according to Paty criteria using MRI-3.0T (TW1WSPEED HDXT, GE, USA), post-contrast T1-weighted conventional spin-echo (TR = 680 ms; TE = 14 ms, FOV = 24, slice thickness = 3.0, interleaved), 5 min after the intravenous administration of 0.1 mmoL/kg gadopentetate dimeglumine.
Table 1 Epidemiologic and disease characteristics of patients with ON Number
125
Age (year, mean ± SD)
38.98 ± 15.40
Sex (male:female)
31:94
Duration (months, mean ± SD)
41.07 ± 47.06
AQP4 antibody-seropositive (N, %)
49 (39.2 %)
Patients meeting Wingerchuk’s 2006 criteria (N, %)
31 (24.8 %)
Cases of death, attack-related (N, %)
0 (0.0 %)
Recurrent ON onset (N, %)
96 (76.8 %)
Bilateral ON at first ON attack (N, %)
29 (23.2 %)
Intraocular pressure, mean ± SD, mmHg
15.97 ± 5.01
Clinical features according to the patients’ AQP4Ab The female to male ratio was 94:31 (n = 125) in the total cohort; it was significantly higher in seropositive patients compared to seronegative patients (Table 1). There were 43 (87.76 %) female patients who were seropositive and 51 (67.11 %) who were seronegative. 49.0 % patients fulfilled the diagnosis of NMO in the seropositive group and 10.5 % patients in the seronegative group (p \ 0.001). 12 patients relapsed to MS, including 11 (14.5 %) in the seronegative group and 1 (2.0 %) in the seropositive group (p = 0.027) (Table 2). There were no significant differences between the two groups in age, disease course, times of ON attacks, or number of recurrent and bilateral ON patients.
Statistical analysis CSF and MRI findings All statistical analyses were performed using the Statistical Program for Social Sciences statistical software (version 17.0; SPSS, Inc., Chicago, IL). Nonparametric tests (Wilcoxon tests or Mann–Whitney U tests) were used to compare the clinical data and other measurement data. The categorical data were analyzed using Chi-squared test or Fisher exact test. p values \0.05 were considered significant.
Results Patient demographics Our cohort included 125 patients (220 eyes) with ON. All patients underwent clinical diagnosis, AQP-4 Ab and other autoantibodies detection, OCT examination, and orbit/ brain MRI. There were 96 (76.8 %) patients with a unilateral bilateral relapsing ON, whereas 29 patients (23.2 %) had a history of bilateral simultaneous ON. 31 patients were relapsing to NMO. Demographic and ON disease characteristics identified via medical record review are presented in Table 1.
No significant difference in oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) between seropositive and seronegative groups was found (Table 3). CSF white cell numbers were 3.58 ± 6.82 (no./mm3) in the seropositive group and 3.15 ± 4.14 in the seronegative group (p = 0.982). CSF total cells numbers (no./mm3) were 29.22 ± 47.14 in the seropositive group and 12.36 ± 27.40 in the seronegative group (p = 0.447). In addition, there were no significant differences in CSF protein (g/L) and CSF IgG levels across the two groups either. 109 (87.20 %) patients presented with abnormal optic nerves based on the MRI (Fig. 1), including T2 lesions and Gad enhancing; however, there were no significant differences across the two groups (p = 0.343) (Table 3). Vision recovery and prognosis During the first documented ON attack, there were ON attacks in the right eye in 42 (47.7 %) in the seropositive group and 45 (32.6 %) in the seronegative group; it was more frequent among the seropositive patients than among
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J Neurol Table 2 Comparison of clinical features according to the patients’ AQP4-Ab serostatus
Seropositive
Seronegative
p level
Number of patients (n)
49
76
Eyes with optic neuritis history (n)
85
135
Age (year, mean ± SD)
36.53 ± 16.26
40.56 ± 14.72
0.13
Sex (male:female)
6/43
25/51
0.009**
Duration (months, mean ± SD)
41.81 ± 29.90
40.56 ± 47.35
0.079 0.509
Times of ON attacks (n, mean ± SD)
2.62 ± 1.68
2.55 ± 1.61
Recurrent ON onset (N, %)
39 (79.6 %)
57 (75.0 %)
0.553
Bilateral ON at first ON attack (N, %)
10 (20.4 %)
19 (25.0 %)
0.553
Time of diagnosis NMO (months, mean ± SD)
19.5 ± 20.51
27.75 ± 24.27
0.535
Meeting Wingerchuk’s 2006 criteria (N)
24 (49.0 %)
8 (10.5 %)
\0.001**
Meeting MS criteria (N)
1 (2.0 %)
11 (14.5 %)
0.027*
* p \ 0.05, ** p \ 0.01
Table 3 Comparison of CSF and MRI according to the patients’ AQP4-Ab serostatus
Seropositive
Seronegative
p level
Number of patients (n)
49
76
CSF-restricted OCB (n)
1
2
1.00
CSF cells (no./mm3)
29.22 ± 47.14
12.36 ± 27.40
0.447
Median CSF white cell count
3.58 ± 6.82
3.15 ± 4.14
0.982
CSF protein (g/L)
361.40 ± 139.70
404.11 ± 175.08
0.379 0.722
CSF IgG level
3.37 ± 1.80
3.27 ± 1.74
MRI total (N, %)
41 (83.7 %)
68 (89.5 %)
0.343
T2 lesion (N, %)
35 (71.4 %)
55 (72.4 %)
0.909
Gad enhancing (N, %)
28 (57.1 %)
37 (48.7 %)
0.355
CSF cerebrospinal fluid, OCB oligoclonal bands
Fig. 1 The sagittal plane and coronal plane MRI of the orbit. Coronal postgadolinium fat-saturated T1-weighted image showed the right optic nerve enhances along with enhancement of the optic sheath. Arrows the lesion part
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J Neurol Table 4 Comparison of Visual Performance according to the patients’ AQP4-Ab serostatus
Seropositive
Seronegative
p level
Number of patients (n)
49
76
Eyes with optic neuritis history (n)
88
138
Time of first to second attack (months)
11.16 ± 17.03
16.64 ± 30.64
0.46
42 (47.7 %)
45 (32.6 %)
0.023*
VA at first ON attacks in acute time B0.1 0.1–0.5
18 (20.5 %)
29 (21.5 %)
0.919
C0.5
28 (31.8 %)
64 (46.4 %)
0.03*
B0.1
31 (35.2 %)
38 (27.5 %)
0.221
0.1–0.5
17 (19.3 %)
32 (23.2 %)
0.491
C0.5
40 (45.5 %)
68 (49.3 %)
0.575
B0.1
46 (52.3 %)
50 (36.2 %)
0.017*
0.1–0.5
19 (21.6 %)
32 (23.2 %)
0.779
C0.5 RNFL (lm)
23 (26.1 %)
56 (40.6 %)
0.026*
VA recovery at first attack
VA recovery at last attack
Average thickness (mean ± SD)
70.89 ± 17.55
73.88 ± 18.20
0.251
Superior quadrant (mean ± SD)
84.26 ± 87.34
87.71 ± 28.43
0.358 0.361
Inferior quadrant (mean ± SD)
85.93 ± 30.82
88.77 ± 30.63
Nasal quadrant (mean ± SD)
61.56 ± 13.55
62.07 ± 12.00
0.486
Temporal quadrant (mean ± SD)
50.13 ± 10.69
53.45 ± 13.39
0.100
VA visual acuity * p \ 0.05, ** p \ 0.01
seronegative patients at the first ON acute (p = 0.023) (Table 4). No differences in visual recovery outcome were observed between seropositive and seronegative patients (Table 4). After the first ON attack, VA was: B0.1 in 31 (35.2 %) of seropositive patients and 38 (27.5 %) in the seronegative patients; 0.1–0.5 in 17 19.3 %) in the seropositive patients and 32 (23.2 %) in the seronegative patients. Complete remission (VA [0.5) was 40 (45.5 %) in the seropositive patients and 68 (49.3 %) in the seronegative patients. At the end of the observation period, VA was B0.1 on either the left or the right eye in 46 (52.3 %) patients in the seropositive patients and 50 (36.2 %) in the seronegative patients; it was more frequent among seropositive patients than among seronegative patients with the servers VA at the last ON attacks in acute time (p = 0.017) (Table 4). In addition, there were no significant differences between the two groups in time of first to second attack (months) and RNFLT (lm, average, superior, inferior, nasal, temporal quadrant thickness).
in 34 (69.4 %) of seropositive patients and 27 (35.5 %) of seronegative patients (p \ 0.001). There were 24 (49.0 %) patients, 16 (21.1 %) patients, 3 (5.00 %) patient, in the seropositive group, and seronegative group, respectively, with ANA titers equal to or greater than 1:160. SSA or SSB was positive in 19 (38.8 %) of seropositive patients and 10 (13.2 %) of seronegative patients, respectively. There were no significant differences across the two groups on frequency of ACL/b2-GPI, A-ds DNA, RF, ANCA, CEPD-B, and HLA-B27 levels (Table 5). There were 32 patients who fulfilled the clinical classification criteria for SS (25 patients), AS (3), SLE (2), RM (2), ACA (0), WG (0), and BD (0) (Table 5). The seropositive group showed a higher tendency to have CTD than the seronegative group (p \ 0.001). Seropositive patients had SS more frequently than seronegative patients and the differences between them were statistically significant.
Associations with autoantibody and CTD detection
Comparison of clinical features according to the patients’ AQP4-Ab serostatus in ON combined with CTDs was also performed (Table 6). There were no significant differences across the two groups in age, female to male ratio, numbers of patients relapsed to MS or NMO (Fig. 2), times of
Frequencies of autoantibodies and CTDs were assessed in the two groups of patients. Detailed results of autoantibody testing are presented in Table 5. Autoantibodies were found
Vision performance in ON combined with Ab or CTDs
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J Neurol Table 5 Comparison of autoimmunity according to the patients’ AQP4-Ab serostatus
Seropositive
Seronegative
p level
Number of patients (n)
49
76
Signs of existing autoimmunity (n)
23 (46.9 %)
9 (11.8 %)
AS
1 (2.0 %)
2 (2.6 %)
0.833
SS
19 (38.8 %)
6 (7.6 %)
\0.001**
SLE
2 (4.1 %)
0 (0.0 %)
0.152
WG
0 (0.0 %)
0 (0.0 %)
NA
ACA
0 (0.0 %)
0 (0.0 %)
NA
BD
0 (0.0 %)
0 (0.0 %)
NA
RM
1 (2.0 %)
1 (1.3 %)
1.00
Co-existing autoantibodies (n)
34 (69.4 %)
27 (35.5 %)
\0.001**
ANA
24 (49.0 %)
16 (21.1 %)
0.001**
SSA/SSB
19 (38.8 %)
10 (13.2 %)
0.001**
ACL/b2-GPI
5 (10.2 %)
7 (9.2 %)
1.00
\0.001**
A-ds DNA
3 (6.1 %)
0 (0.0 %)
0.058
RF ANCA
2 (4.1 %) 1 (2.0 %)
2 (2.6 %) 0 (0.0 %)
0.645 0.392
CENP-B
1 (2.0 %)
1 (1.3 %)
1.00
HLA-B27
6 (12.2 %)
4 (5.3 %)
1.188
ANA antinuclear antibody, SSA and SSB extractable nuclear antigen antibodies, RF rheumatoid factor, ACL anticardiolipin antibody, b2-GPI anti-b2-glycoprotein I, A-ds DNA antidouble-stranded DNA antibody, ANCA anti-neutrophil cytoplasmic antibodies, CENP-B centromere/kinetochore complex protein-B, HLAB27 major histocompatibility complex-B27, AS ankylosing spondylitis, RM rheumatoid, BD Behcet’s disease, WG Wegner’s granulomatosis, SLE systemic lupus erythematosus, ACA anticardiolipin antibody syndrome, SS Sjogren’s syndrome, NA not available * p \ 0.05, * *p \ 0.01
relapse, time of first to second attack, VA at first ON attacks in acute time or in remission time, or VA recovery at the last attack in the follow-up period and RNFLT (lm, average, superior, inferior, nasal, temporal quadrant thickness). 15 (44.1 %) patients in the seropositive group and 2 (7.4 %) patients in the seronegative group met Wingerchuk’s 2006 criteria (p = 0.001, Table 7). Vision performance according to AQP4-Ab serostatus in NMO patients Patients with NMO (n = 32, 55 eyes) were divided into two groups according to AQP-4 Ab serostatus and they underwent vision testing and OCT imaging. Peripapillary RNFL average thickness was reduced in seropositive patients (70.26 ± 19.90 lm) relative to seronegative patients (86.68 ± 0.63; p = 0.017). RNFL in the inferior quadrant and nasal quadrant thickness were significantly reduced in seropositive patients (inferior: 84.71 ± 30.79 lm; nasal: 108.73 ± 30.62 lm) relative to seronegative patients (inferior: 61.18 ± 15.52 lm; nasal: 70.36 ± 16.64 lm) (Table 8). There were no significant differences among the two groups across age, female to male ratio, time of diagnosis of NMO, times of relapse, time of first to second attack,
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VA at first ON attacks in acute time or in remission time, or VA recovery at the last attack in the follow-up period.
Discussion In this study the clinical and paraclinical features of ON according to the patients’ AQP4-Ab serostatus were analyzed in Chinese patients. We found a strong female predominance in this population of seropositive patients. The female/male ratio of the seropositive patients (7.17) was significantly higher than that reported in previous MS studies [28]. In the seronegative group (2.04), the ratio was in accordance with previous study in MS (2:1); this finding further supported the hypothesis that seropositive NMO is a distinct disease from MS. 49 % of patients in AQP-4 Abseropositive group developed NMO, which was significantly higher than the seronegative group (10.5 %). These results support previous findings that AQP-4 Ab is a specific biomarker for NMO [29]. AQP4 Ab is useful in predicting the severity of disease course and the probability of conversion to NMO at the first episode of isolated ON [30]. There were no significant differences between the two groups across median time to NMO diagnosis and the latency between the first ON attack and the second attack.
J Neurol Table 6 Comparison of visual performance according to the patients’ AQP4-Ab serostatus in ON combined with CTDs
Seropositive
Seronegative
p level
ON at onset (n)
23
9
Eyes with optic neuritis history (n)
39
16
Age (median, range; N)
39.41 ± 14.59
44.33 ± 15.59
Sex (male:female)
2:21
1/8
1.00
Duration (months)
40.83 ± 24.56
64.89 ± 107.14
0.45 0.557
0.338
Recurrent ON onset (N, %)
21/23 (91.3 %)
7/9 (77.8 %)
Bilateral ON at first ON attack (n, %)
2/23 (8.7 %)
2/9 (22.2 %)
0.557
Meeting Wingerchuk’s 2006 criteria (n)
7 (30.4 %)
0 (0.0 %)
0.149
Meeting MS criteria (n)
0 (0.0 %)
2 (22.2 %)
0.073
Times of relapse (n)
2.68 ± 1.36
3.00 ± 2.06
0.855
Time of first to second attack (months)
12.64 ± 16.89
20.44 ± 55.36
0.08
B0.1
27 (69.2 %)
12 (75.0 %)
0.754
0.1–0.5
8 (20.5 %)
3 (18.8 %)
1.00
4 (10.3 %)
1 (6.2 %)
1.00
B0.1
10 (25.6 %)
3 (18.8 %)
0.734
0.1–0.5
6 (15.4 %)
2 (12.5 %)
1.00
C0.5
23 (59.0 %)
11 (68.8 %)
0.498
16 (41.0 %)
6 (37.5 %)
0.808
VA at first ON attacks in acute time
C0.5 VA recovery at first attack
VA recovery at last attack B0.1 0.1–0.5
8 (20.5 %)
2 (12.5 %)
0.706
C0.5
15 (38.5 %)
8 (50.0 %)
0.431
RNFL (lm) Average thickness(mean ± SD)
71.25±18.77
76.88±24.01
0.369
Superior quadrant (mean ± SD)
85.00 ± 27.77
91.63 ± 35.09
0.685
Inferior quadrant (mean ± SD)
81.88 ± 29.62
95.56 ± 39.62
0.399
Nasal quadrant (mean ± SD)
61.60 ± 19.37
58.88 ± 12.32
0.298
Temporal quadrant (mean ± SD)
53.73 ± 11.40
57.50 ± 15.57
0.269
* p \ 0.05, ** p \ 0.01
Therefore, we suggest that the AQP-4 Ab would not likely determine the time to myelitis onset or latency of disease recurrence. VA of less than 0.1 during acute ON attacks was more frequent among seropositive patients. While visual recovery after an initial attack between the two groups was not significantly different, seropositive patients had more severe VA outcomes than seronegative patients at the final follow-up. Matiello et al. showed that AQP-4 Ab expression predicted poor visual outcome and development of NMO [31]. A multicentre study of 175 patients in Germany found that a VA of \0.1 was more common during acute ON attacks among AQP-4 Ab-seropositive patients [32]. In the current study, VA results were similar to that of previous studies; however, visual recovery during the remission period at the first ON attack was not significantly different between groups. Recent studies have found that a substantial number of NMO cases are usually associated
with mild symptoms or a benign long-term course [33, 34]; therefore, the outcome of a single isolated ON case cannot be determined according to VA recovery at first onset. In the current study, NMO started in most patients with unilateral ON. In a Swedish MS register, Burman et al. identified 472 patients with MS and found that the proportion of patients who developed a second attack of ON was 5.5 %; the percentage of bilateral simultaneous ON as the presenting symptom of MS was 0.42 %. They suggested that recurrent ON, whether unilateral or bilateral, is a common presentation of MS [35]. According to the McDonald diagnostic criteria, isolated recurrent ON affecting both optic nerves could have led to the diagnosis of MS [36, 37]. In recent studies, ON relapse (14.8 %) was found to be more likely in Chinese seropositive patients [8]. Optical coherence tomography (OCT) is a useful tool that can be used to evaluate the differences between NMO-
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J Neurol
Fig. 2 MS and NMO patients showed demyelinating cerebral and spinal lesions in MRI. a Focal multiple small lesions (arrow) seen on coronal T2-weighted image MRI of brain. b The spinal cord MRI, T2-
weighted image showed a high signal intensity long cord lesion extending from the C2 to the T6 level. Arrows the lesion part
ON and MS-ON [38, 39]. OCT showed more severe retinal damage after ON episodes in NMO compared to relapsing– remitting MS [40, 41]. In current study, OCT was also used to evaluate the severity of atrophy of the optic nerve in the two groups and there were no significant differences between seropositive and seronegative patients. Peripapillary RNFL average thickness was reduced in seropositive patients compared to seronegative patients in the NMO-ON patients. Based on these results, it seemed that AQP-4 Ab had effect on the severity of NMO-ON. There was few studies focus on RNFL after ON episodes in different AQP-4 antibody serostatus. In current study, OCT was also used to evaluate the severity of atrophy of optic nerve in two different serostatus groups of ON and NMO. RNFLT was not significantly different between two groups, and it was thinner in NMO seropositive patients due to the possible reasons as following: (1) layer of retina facilitated to study the functional zone of retina in detail. The densest area of optic nerve ganglion cells was macula, while other location existed deletion. Macula may be the best area to demonstrate the early damage of ischemic optic neuropathy and optic nerve head. Peripapillary RNFL of optic disc only represented the atrophy of optic nerve axons, and
optic disc edema could conceal the loss of optic nerve head axons [42]. (2) The sample size is small, especially NMO AQP-4 (?) group, only 8 patients with 11 eyes, and may affect the statistical results. (3) At the end of the observation period, the VA damage was more severe in AQP4(?) patients than AQP-4(-) patients, nevertheless, there were no significant differences on RNFLT, and indicated that the most sensitive area of vision should be in the macular region, and the most intensive region of optic nerve ganglion cells is macula. Nonetheless, we detected the peripapillary RNFL of optic disc instead of the thickness of macular RNFL and ganglion cell layer. In this study, autoantibodies and CTDs were frequently detected in both seropositive and seronegative patients. Coexisting autoimmune disorders, as well as sero-autoantibodies, were significantly more common in seropositive patients; SS and SLE were the most common CTDs and SSA and SSB were the most common autoantibodies in these patients. These findings are similar to previous studies which found that NMO could coexist with CTDs [43], particularly SS [44]; however, this association is rare in MS [45, 46], as the prevalence of MS with SS ranges from 0 to 3.3 % [47]. Since AQP-4 Ab is a sensitive bio-
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J Neurol Table 7 Comparison of visual performance according to the patients’ AQP4-Ab serostatus in ON combined with abnormal auto-Ab
Seropositive
Seronegative
ON at onset (n)
34
27
Eyes with optic neuritis history (n)
61
51
p level
Age (median, range; N)
35.63 ± 15.53
40.96 ± 14.69
Sex (male:female)
4/34
7/27
0.379 0.190
Duration (months)
41.09 ± 24.11
49.57 ± 68.42
0.251
Recurrent ON onset (N, %)
30 (88.2 %)
23 (85.2 %)
1.00
Bilateral ON at first ON attack (n, %)
4 (11.8 %)
4 (14.8 %)
1.00
Meeting Wingerchuk’s 2006 criteria (n)
15 (44.1 %)
2 (7.4 %)
0.001**
Meeting MS criteria (n)
0(0.0 %)
3 (11.1 %)
0.081
Times of relapse (n)
2.67 ± 1.51
3.04 ± 1.90
0.94
Time of first to second attack (months)
11.33 ± 15.66
20.79 ± 37.79
0.844
B0.1
44 (72.1 %)
43 (84.3 %)
0.123
0.1-0.5
11 (18.0 %)
7 (13.7 %)
0.537
6 (9.8 %)
1 (2.0 %)
0.124
B0.1
18 (29.5 %)
14 (27.5 %)
0.81
0.1-0.5
11 (18.0 %)
10 (19.6 %)
0.832
C0.5
32 (52.5 %)
27 (52.9 %)
0.959
31 (50.8 %)
23 (45.1 %)
0.546
VA at first ON attacks in acute time
C0.5 VA recovery at first attack
VA recovery at last attack B0.1 0.1-0.5
10 (16.4 %)
8 (15.7 %)
0.919
C0.5
20 (32.8 %)
20 (39.2 %)
0.479
RNFL (lm) Average thickness(mean ± SD)
71.19 ± 18.32
72.96 ± 14.43
0.626
Superior quadrant (mean ± SD)
83.85 ± 27.13
86.36 ± 28.70
0.653
Inferior quadrant (mean ± SD)
86.89 ± 31.99
87.68 ± 34.18
0.818
Nasal quadrant (mean ± SD)
62.49 ± 14.77
60.02 ± 10.86
0.586
Temporal quadrant (mean ± SD)
50.68 ± 11.65
53.72 ± 13.24
0.458
* p \ 0.05, ** p \ 0.01
marker for NMO, the results of our study are similar to previous studies. CSF findings in NMO have been found to differ significantly from those of classical MS [48, 49]. In the current study, there were no significant differences between the two groups on abnormal CSF proteins, CSF cells, or CSF IgG levels. These results are similar to previous research [50], providing further support for the hypothesis that seronegative NMO patients are not simply a clinical variant of MS patients. All the patients were examined though the orbits with MRI; 83.7 % of seropositive patients had an abnormal optic nerve compared to 89.5 % of
seronegative patients. There were no significant differences in optic nerve lesions between seropositive and seronegative patients. MRI lacks the specificity to distinguish AQP4 Ab status. For AQP4 assay, some patients were detected AQP4 on the ON first onset, and however some patients did not detect AQP4. In addition, although some patients were subjected to ON for a long time, AQP4 was not detected at first onset due to not in our hospital, and then detected when transferred to our hospital at the time of ON relapse. Therefore, these factors would affect the statistical results. Based on the above limitations, a multiple-center and prospective survey should be used in the future.
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J Neurol Table 8 Comparison of visual performance according to the patients’ AQP4-Ab serostatus in NMO patients
Seropositive
Seronegative
p level
ON at onset (n)
24
8
Eyes with optic neuritis history (n)
44
11
Age (median, range; N)
35.17 ± 16.17
30.75 ± 15.35
Sex (male:female)
2/22
1/7
1.00
Duration (months)
54.88 ± 33.69
35.38 ± 25.57
0.053
0.273
Recurrent ON onset (N, %)
19 (79.2 %)
6 (75.0 %)
1.00
Bilateral ON at first ON attack (n, %)
5 (20.8 %)
2 (25.0 %)
1.00
Time of diagnosis NMO
27.75 ± 20.29
19.50 ± 20.51
0.522
Times of relapse (n)
3.04 ± 1.99
1.88 ± 1.13
0.098
Time of first to second attack (months)
30.75 ± 21.92
11.88 ± 20.01
0.321
VA at first ON attacks in acute time B0.1
35 (79.5 %)
9 (81.8 %)
1.00
0.1–0.5
6 (13.6 %)
1 (9.1 %)
1.00
C0.5
3 (6.8 %)
1 (9.1 %)
1.00
12 (27.3 %)
3 (27.3 %)
1.00
0.1–0.5
7 (15.9 %)
0 (0.0 %)
0.323
C0.5
25 (56.8 %)
8 (72.7 %)
0.495
VA recovery at first attack B0.1
VA recovery at last attack B0.1
25 (56.8 %)
3 (27.3 %)
0.08
0.1–0.5
7 (15.9 %)
2 (18.2)
1.00
C0.5
12 (27.3 %)
6 (54.5 %)
0.148
RNFL (lm) Average thickness(mean ± SD)
70.26 ± 19.90
86.68 ± 18.63
0.017*
Superior quadrant (mean ± SD)
83.76 ± 30.41
101.81 ± 23.43
0.144
Inferior quadrant (mean ± SD)
84.71 ± 30.79
108.73 ± 30.62
0.039*
Nasal quadrant (mean ± SD)
61.18 ± 15.52
70.36 ± 16.64
0.041*
Temporal quadrant (mean ± SD)
50.29 ± 11.06
60.09 ± 17.38
0.070
* p \ 0.05, ** p \ 0.01
References
Conclusion Severe VA performance during acute ON attacks is more frequent among seropositive NMOSD-ON patients. It does not impact the aspect of VA recovery at first attack, RNFLT, time of diagnosis NMO or time to second attack. SSA/SSB autoimmunity antibodies and SS were more prevalent in seropositive patients. Acknowledgments This work is supported by National the 12th Five-Year Plan Science and Technology support project ‘‘clinical epidemiological studies of optic neuritis (number: 2012BAI08B06) and China Postdoctoral Science Foundation (No.: 2013M532109). Conflicts of interest competing interests.
All the authors declare that there are no
Ethical standard This study was approved by the People’s Liberation Army General Hospital Ethics Committee and was conducted following the Declaration of Helsinki in its currently applicable version. All individuals voluntarily participated in the study after a thorough oral and written information procedure. Oral and written consents were obtained from all participants.
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