Background
Neuromyelitis optica spectrum disorders (NMOSD) is a group of inflammatory demyelinating disorders, mediated by pathogenic autoantibodies (NMO-IgG) against astrocyte aquaporin-4 (AQP4), the main water channel of the central nervous system (CNS) [
1],[
2]. As it is well known that the spinal cord is one of the most frequently involved sites in NMOSD, especially longitudinally extensive spinal cord lesions have been observed in 72.4-100% of NMO [
3]-[
6], and are predominantly located in the cervical and upper thoracic region. Futhermore, the neurological function changes in spinal cord injury are considered as the clinical hallmark of the disease evolution [
5],[
6].
The current studies indicate atrophy is a common pattern during the disease course and a potential marker of clinical disability in all subtypes of multiple sclerosis (MS) [
7]-[
9]. Spinal cord atrophy (SCA), particularly atrophy of cervical cord, is considered to contribute to accumulation of disability and clinical outcome [
7],[
10]. SCA is expected to present in NMOSD. However, little attention has been paid to exploring the clinical features of SCA in NMOSD. Only a few sporadic studies have reported the frequent occurrence, locations of the SCA in exploring the features of spinal cord lesions with NMO patients [
4],[
11]-[
13]. Therefore, we investigated and compared the clinical, laboratory, and magnetic resonance imaging (MRI) characteristics between NMOSD with and without SCA.
Discussion
Although the spinal cord lesion is widely recognized as one of the predominant characteristics in NMOSD. However, the SCA has only been sparsely studied, and only focused on the locations, incidences and magnetic resonance imaging markers of SCA in NMOSD patients [
4],[
11]. To the best of our knowledge, this is the first study to investigate the clinical characteristics of SCA in Chinese NMOSD patients. In the present study, we confirmed that the SCA patients had more frequently cervical spinal cord lesions, more severe clinical disability, and longer disease duration. More importantly, our findings suggest inflammation play the important role in the development of SCA in NMOSD.
Previous reports revealed that the frequent occurrence of SCA in NMO patients was 52.2% or 57% [
4],[
11], respectively. However, in our study, the prevalence of SCA was 14.2% in adult Chinese patients with NMOSD. and SCA mainly located in the cervical spinal cord. Factors influencing variation may include differences in disease susceptibility, diagnostic criteria, sample size. The spinal cord, especially the cervical cord, has been identified as containing important ascending and descending pathways related to locomotion and sensation. Therefore, any degree of SCA may be associated with the presence of sensory, limb movements, or urinary symptoms [
7],[
10]. In our SCA patients, the clinical relevance of SCA in NMOSD was supported by the difference which we found EDSS score, particularly reaching disability milestones at clinical onset and last visit (EDSS ≥ 6.0); the time to reach EDSS 6.0 from onset; the more frequency and severity of clinical presentation including bowel or bladder dysfunction, movement disorders and sensory disturbances between the two group patients. Therefore, the neurological impairment to reach EDSS ≥ 6.0; residual EDSS score; a greater number of functional systems involved at onset as well as higher residual deficits in pyramidal, visual, sphincteric and sensory system, may be the predictors of favorable SCA. Besides, disease duration was also one of the vital factors contributing to SCA, this suggesting a cumulative effect with time of the pathologic processes leading to progressive and irreversible tissue lesion in the cord [
7],[
10].
More recent studies suggest a potential link inflammation with disease activity and clinical disability of NMO and MS [
25]-[
27]. The C-reactive protein(CRP) is an acute phase protein and a component of the innate immune system. Current studies indicate CRP was produced by astrocytes [
28]. it could assess the degree of inflammation, correlate with disease activity and clinical relapse in MS and NMO [
29]-[
31]. In our study, we found CRP and ESR in NMOSD patients with SCA were higher than those without SCA. These suggest that the SCA patients may have more severe systemic inflammatory reactions, and disease activity. Moreover, dysfunction of astrocytes occur early in NMO pathophysiological process, and trigger demyelination, myelin loss, neuron death, and promote SCA formation in NMOSD. Meanwhile, the innate immune system may also play a critical role in the initiation and progression of SCA by mediating the demyelination of neuronal axons, and initiating a cascade of immuno-inflammatory reactions. Although some studies reported hypercomplementemia (serum C4, CH50 and CSF - C5a, sC5b-9) was significantly higher in NMO patients, especially in anti-AQP4 antibody positive patients [
32]-[
34]. However, no significant difference was found in complements between the two groups. And few data showed the relationships between complements and SCA in NMOSD. So further work is needed to determine whether complements promotes SCA formation. AQP4 antibodies act as a radical initiator to induce the NMOSD lesion, and consistently play an important role in the pathological process by monitoring inflammatory tissue injury, demyelination, necrosis and axonal damage [
35]-[
37]. However, in the present study, there were no differences in the seropositivity of NMO-IgG between patients with and without SCA. So NMO-IgG might not be associated with SCA. But, due to technical reasons, we did not test the titer of NMO-IgG which were thought to be related to the disease progress and exacerbation [
6],[
38]. However, any suggestion of a positive link between the NMO-IgG titers and SCA must be prompt further research using the larger, prospective study design. Besides, although NMO-IgG and systemic inflammatory reactions were closely associated
with astrocytes and involved in the pathogenesis of NMOSD [
28],[
39]. However, our results suggest that they may be a two stage of the SCA disease course, or have potential mechanisms for "cross-talk" between the NMO-IgG and systemic inflammatory reactions.
Clearly, this study is not without limitations. Because of the technical conditions, the titers of some autoantibodies and NMO-IgG could not be tested; because only a limited number of patients with SCA, we were not able to make a comprehensive analysis on different anti-AQP4 antibody positive/negative of SCA.
Conclusions
The patients diagnosed as NMOSD with SCA have more severe disability, and longer disease duration. In the early phases of the disease, the SCA, specially concomitant cervical spinal cord lesions, may be an important indicator of disease severity, and a limited form event of NMOSD. Systemic inflammation occurs rapidly after the onset of SCA, and is considered as one of the important components of neurodegenerative processes in SCA. Thus, early and effective inhibition of systemic microinflammation is critical to prevent or minimize the development of the SCA in NMOSD. Measurements of SCA might help to predict disease severity and evaluate the therapeutic effects of NMOSD.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
YW, AW and XC: design, draft, interpretation of the data, conception and data collection. YL and LZ: clinical data collection. SS and BZ: biological indicators collection. ZK, XH and WQ: MRI re-evaluation and analysis of follow up MRI investigations. WC: statistical analysis. ZL: Revising manuscript and approving final version, study supervisor. All authors read and approved the final manuscript.