Plasma Homocysteine Levels in Neuromyelitis Optica

C l i n M e d International Library Citation: Zhang L, Shu Y, Sun S, Lin Y, Wang Y, et al. (2014) Plasma Homocysteine Levels in Neuromyelitis Optica. Int J Neurol Neurother 1:010. doi.org/10.23937/2378-3001/1/1/1010 Received: September 30, 2014: Accepted: November 14, 2014: Published: November 04, 2014 Copyright: © 2014 Zhang L. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Zhang et al. Int J Neurol Neurother 2014, 1:1


Introduction
Neuromyelitis Optica (NMO) is an inflammatory demyelinating disease that preferentially affects optic nerve and spinal cord.Although the pathogenesis of NMO is not completely clear, some studies have suggested that oxidative injury is involved in NMO [1,2].Homocysteine (Hcy) is a non-essential sulfur-containing amino acid derived from methionine by demethylation.Recent studies indicate that homocysteine might cause neuronal damage by triggering oxidative injury and DNA damage [3][4][5][6].And homocysteine has been implicated in many kinds of neurologic diseases, such as multiple sclerosis (MS), stroke, and dementia [7][8][9].However, little is known about the relationship between Hcy and NMO.In the present study, we investigated whether there were any relationship between plasma Hcy and clinical features of NMO patients.using a GE 1.5T MR scanner (General Electric, Milwaukee, Wisconsin, USA).The slice thickness of the axial scans was 5 mm.Conventional MRI protocols were used in all patients: T1 with and without gadolinium enhancement (400/15.5 ms, TR/TE) and T2 (2500-3500/100 ms, TR/TE) for spinal cord MRI; and T1 with and without gadolinium enhancement (2128-2300/11.6-12.4ms, TR/ TE), T2 (4600-4640/97.8-102ms, TR/TE), and fluid-attenuated inversion recovery (FLAIR) (8800/120 ms, TR/TE) for brain MRI [11].Each patient in acute stage underwent MRI scanning at the time prior to corti costeroid treatment.Brain abnormalities were assessed with T2-FLAIR sequences.All of the MRI scans were analyzed by an experienced neuroradiologist and a neurologist.The final assessments were made by consensus.

Statistical analysis
The data were expressed as mean ± standard deviation (SD).Chi-square test and t-test were used for qualitative and quantitative data, respectively.Correlations between plasma Hcy and clinical and MRI features of NMO patients were analyzed by Pearson correlation analysis.Statistical analysis was performed by SPSS version 17.0.Values of p=0.05 were considered statistically significant.

Results
In our study, the patients with NMO had significantly higher Hcy level than that of healthy control (HC) (P<0.001)(Table 1).The average Hcy level of patients with NMO was in normal range.
In NMO patients, the Hcy level was not correlated with age, disease duration, Expanded Disability Status Scale (EDSS) score, relapse number, number of brain MRI lesions, or length of spinal cord MRI lesions (Table 2).Furthermore, we classified the NMO patients into different groups according to disease activity, gender, and occurrence of relapse.There were no differences between NMO patients in active and inactive stage, male and female, NMO-IgG positive and negative, or patients with and without relapse in follow-up (Table 3).
Finally, further analysis showed that the inactive NMO patients with relapse in follow-up had significantly higher Hcy level than those without relapse in follow-up (P=0.045), and no differences were found in Hcy levels between the active NMO patients with and without relapse in follow-up (Table 4).And for the patients in inactive stage with relapse in follow-up, there was at least one relapse that occurred in the first year of follow-up.

Discussion
Previous studies have demonstrated that Hcy might cause neuronal damage by triggering oxidative injury which is implicated in NMO [3][4][5][6].However, it is unclear whether Hcy play a role in pathogenesis of NMO.To our knowledge, this is the first study investigating the relationship between Hcy and NMO.In the present study, we found the level of Hcy elevated in NMO patients within normal range and the inactive NMO patients with relapse in followup had higher Hcy level.
Several researches have reported higher level of Hcy in patients with MS which has some common pathogenic mechanisms with NMO [7,[12][13][14][15].Although other studies did not found increased level of Hcy in patients with MS [16][17][18], a meta-analysis still suggested a significant association between MS and serum Hcy [19].But only a few associations were found between clinical features of MS and Hcy in these studies: two of them suggested an association between cognitive impairment in MS and Hcy [13,16], one found Hcy levels in patients with multiple sclerosis were associated with male gender while the other did not [12,17], and four studies investigated the relationship between EDSS score of MS and Hcy and found negative results [7,14,15,17].We found similar results when analyzing the association between clinical features of NMO and Hcy.It seems that the level of Hcy is not related to the severity, prognosis, and lesion extent of NMO.So the elevated Hcy levels in NMO patients might be just a secondary change.There might be other explanations.One could argue that Hcy does cause oxidative injury but its impact is not large enough to affect the severity, prognosis, and lesion extent of NMO.Besides, other factors that play more important role in oxidative injury in NMO may cover the effect of Hcy.But it is unlikely that Hcy within normal range can cause substantial oxidative injury.Besides, C677T polymorphism of MTHFR gene which is the main genetic factor of Hcy was not tested, so we could not exclude its effect on our results.Further analysis indicated that the inactive NMO patients with relapse within one year had higher Hcy level, while the same results were not found in active NMO patients.It is possible that the Hcy levels reflect the severity of oxidative injury only in inactive NMO patients but not in active NMO patients, since different mechanisms may be involved in different stages of disease.The elevated Hcy might indicate more severe oxidative injury, so the inactive NMO patients with higher Hcy levels might be more prone to relapse.However, the follow-up period varied from several months to several years in our study, so we still can not draw a conclusion that the level of Hcy in patients with NMO in inactive stage might be helpful to predict relapse.
Folate and vitamin B12 have fundamental roles in CNS function especially methionine synthase-mediated conversion of Hcy to methionine, which is essential for synthesis of DNA and RNA [20,21].Therefore, vitamin B12 and folate deficiency can lead to an increased level of Hcy [21].Some studies showed the relation between high level of serum Hcy and low levels of serum B12 and folate in patients with MS [15,22,23], while others did not [24,25].The levels of vitamin B12 and folate were tested in only thirteen patients in our study, among whom no deficiency in vitamin B12 or folate were detected.After searching our database of NMO, we found the levels of vitamin B12 and folate were tested in another nine patients that were not included in the present study because the level of Hcy was not tested.None of these nine patients had deficiency in vitamin B12 and only one of them had a level of folate below normal range.
.  There are some limitations in this study: (a) Oxidative stress biomarkers and the cerebrospinal fluid Hcy levels were not measured; (b) sequential change of Hcy levels was unavailable; (c) the followup period varied from several months to several years; (d) bias is inevitable in retrospec tive studies.
In conclusion, the elevated Hcy levels in NMO patients might be just a secondary change.

Ethics Statement
This research was approved by the ethics committee of the Third Affiliated Hospital of Sun Yat-sen University.All participants involved in this study provided written informed consent.

Table 1 :
Demographic characteristics and Hcy levels of NMO patients and controls.

Table 2 :
Results of Spearman correlation analysis in patients with NMO.

Table 3 :
Comparison of Hcy levels in NMO patients with different disease activity, gender, NMO-IgG seropositivity and occurrence of relapse.So vitamin B12 and folate deficiency is uncommon in patients with NMO.Besides, if vitamin B12 and folate deficiency played a role in the elevated level of Hcy in NMO, the level of Hcy should not be in normal range.Therefore, it is unlikely that the elevated level of Hcy in NMO is caused by vitamin B12 or folate deficiency.

Table 4 :
Comparison of clinical features and Hcy levels in active/inactive NMO patients with and without relapse in follow-up.Homocysteine; NMO: Neuromyelitis Optica; F: Female; M: Male; EDSS: Expanded Disability Status Scale; P1: NMO in active stage with relapse in follow-up vs NMO in active stage without relapse in follow-up; P2: NMO in inactive stage with relapse in follow-up vs NMO in inactive stage without relapse in follow-up.