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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 5  |  Issue : 1  |  Page : 1-8

Assessment of normal-appearing brain white matter in patients with optic neuritis and multiple sclerosis by magnetic resonance spectroscopy


1 Department of Neurology, Faculty of Medicine, Al Azhar University, Damietta, Egypt
2 Department of Radiodiagnosis, Faculty of Medicine, Al Azhar University, Damietta, Egypt
3 Department of Neurology, Faculty of Medicine, Al Azhar University, Cairo, Egypt

Date of Submission07-Jan-2020
Date of Decision08-Jan-2020
Date of Acceptance15-Jan-2020
Date of Web Publication21-Apr-2021

Correspondence Address:
MBBCh, MSc Mohammed M.A.H Elgezery
Department of Neurology, Assistant Lecturer Al-Azhar University Damietta; Martyr Muhammad Hani Lashin Street, Kafr Elztate City, Garbea Governorate, 31611 kafr elzyate City
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_3_21

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  Abstract 


Background Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system, characterized pathologically by disseminated areas of demyelination and variable degrees of axonal loss and glial scarring. Typical optic neuritis may be associated with MS and is the most common type of optic neuritis. Nonconventional MRI such as magnetic resonance spectroscopy (MRS) has been used to enhance our knowledge of the pathophysiology of MS.
Objectives To evaluate metabolic changes of brain normal-appearing white matter among patients either presented with optic neuritis alone or those already diagnosed as having MS.
Patients and methods This is a cross-sectional study that was carried out on 30 patients with MS and 30 patients with typical optic neuritis attending neurology MS clinic of Al Azhar University Hospitals. All patients were subjected to the following: detailed history talking, assessment of disease severity by the Expanded Disability Status Scale, routine laboratory investigations, radiological evaluation (MS protocol), and MRS.
Results The results of the study revealed significant metabolic changes by MRS in patients with optic neuritis and MS.
Conclusion MRS provides advanced insights into the pathogenesis of optic neuritis and MS by obtaining information on the microenvironment within the brain. This enhances the understanding of the mechanisms involved in disease progression. MRS opens a window to detect early conversion of patient of the typical optic neuritis into MS.

Keywords: magnetic resonance spectroscopy, multiple sclerosis, normal-appearing white matter, optic neuritis


How to cite this article:
Elgezery MM, Ebrahim EM, Shakweer MM, Ibrahim AF. Assessment of normal-appearing brain white matter in patients with optic neuritis and multiple sclerosis by magnetic resonance spectroscopy. Sci J Al-Azhar Med Fac Girls 2021;5:1-8

How to cite this URL:
Elgezery MM, Ebrahim EM, Shakweer MM, Ibrahim AF. Assessment of normal-appearing brain white matter in patients with optic neuritis and multiple sclerosis by magnetic resonance spectroscopy. Sci J Al-Azhar Med Fac Girls [serial online] 2021 [cited 2021 Jun 14];5:1-8. Available from: http://www.sjamf.eg.net/text.asp?2021/5/1/1/314072




  Introduction Top


Multiple sclerosis (MS) is a progressive and highly debilitating disease that places a high burden both on individual patients and on society [1]. MS has a complex relapse and remission course; involving demyelination, remyelination, axonal loss, gliosis, and inflammation, which can be sporadic or exist simultaneously. These abnormalities have been demonstrated both in lesions and in normal-appearing white matter (NAWM) [2].

MS occurs with a variety of different symptoms such as vision problems, changes in sensation, and muscle weakness [3]. The visual system is highly susceptible to damage from MS [4]. In fact, optic neuritis is a common ophthalmological feature in patients with MS [5].

A monophasic clinical episode with patient-reported symptoms and objective findings reflecting a focal or multifocal inflammatory demyelinating event in the central nervous system, developing acutely or subacutely, with a duration of at least 24 h, with or without recovery, and in the absence of fever or infection, similar to a typical MS relapse (attack and exacerbation) but in a patient not known to have MS is classified as clinically isolated syndrome [6].

White matter changes in NAWM are present and can be present before white matter lesion (WML) develops. This suggests that WML develops gradually, and that visually appreciable WMLs are only the tip of the iceberg of white matter pathology [7].

Nonconventional MRI techniques, such as magnetic resonance spectroscopy (MRS), have been used to enhance our knowledge of the pathophysiology of MS. These techniques may offer data on the structural and biochemical changes occurring within and outside macroscopic MS lesions (demyelination, axonal loss, and inflammation), namely, in the NAWM [2]. MRS has become a valuable tool for assessing demyelination and axonal damage in the brain of patients with MS [8].


  Aim Top


The aim was to evaluate metabolic changes of brain NAWM among patients either presented with optic neuritis alone or those already diagnosed as having MS.


  Patients and methods Top


Study approval

The current study was approved by ethical committee, Faculty of Medicine, Al Azhar University, Egypt. A written informed consent was taken from all participants after a clear explanation of all study steps.

Study design

A cross-sectional randomized case–control study was conducted.

Patients

The study included 90 patients, comprising 30 patients with MS, 30 patients with typical optic neuritis attending Neurology MS clinics of Al Azhar University Hospitals, and 30 healthy volunteers of similar age and sex distribution as patients in the period from January 2019 to June 2020.

Inclusion criteria

Patients with relapsing-remitting multiple sclerosis (RRMS) according to McDonald criteria 2017 [6], patients with typical optic neuritis with normal MRI brain, and patients with typical optic neuritis with abnormal MRI brain (not fulfilling criteria for diagnosis of MS according to McDonald criteria 2017) were included. All patients aged from 18 to 50 years.

Exclusion criteria

(a) Patients with MRI white matter abnormalities that interfere with results such as vascular disorder, braininjury, carbon monoxide poisoning, hypoglycemia, normal pressure hydrocephalus, and other metabolic and toxic disorders were excluded. (b) In patients of group II, we also excluded patients who had a history of any previous neurological sign or symptom that could possibly be interpreted as a demyelinating event.

Study population and procedure: the 90 patients were divided into three groups:

Group I included 30 patients with RRMS (10 males and 20 females), with mean age of 33.733±4.646 years, with different disease duration.

Group II included 30 patients (nine males and 21 females) presenting with a first neurological event (typical optic neuritis).

Patients in group II were classified into two subgroups according to finding on brain MRI: subgroup IIA had no lesions on MRI and included 15 patients (five males and 10 females), with mean±SD age of 28.933±5.922 years, and subgroup IIB included patients having MRI lesions and included 15 patients (four males and 11 female), with mean±SD age of 31.133±8.070 years.

Group III included 30 healthy volunteers (10 males and 20 females), with mean±SD age of 33.733±4.820 years.

All patients were subjected to the following: detailed history taking, assessment of disease severity by the Expanded Disability Status Scale (EDSS) [9], and radiological evaluation.

Radiological evaluation included the following:
  1. MRI brain: all groups underwent conventional MRI (T1, T2, Flair) with contrast on 1.5 T unit using MRI machine (Philips, Achieva 1.5 Tesla-XR, the Netherlands 2010) using standard imaging head coil with standardized postprocessing protocol.
  2. MRS: single-voxel localization proton MRS was performed using a spin-echo mode sequence (SE) for all patient and control groups.


MRS was done on the following:
  1. NAWM in centrum semiovale − corpus callosum.
  2. Areas with demyelinating lesions.


Metabolites measured are N-acetylaspartate (NAA), myoinositol (M-Ins), choline (Cho), creatine (Cr), and ratio measured as follows: NAA/Cr, M-Ins/Cr, Cho/Cr, and NAA/Cho.

Statistical analysis

The collected data were organized, tabulated, and statistically analyzed using statistical package for the social sciences (SPSS), version 24 (SPSS Inc., Chicago, Illinois, USA), running on IBM-compatible computer. Quantitative data were represented as mean and SD. Qualitative data were represented as relative frequency and percentage. Comparison between groups was done by Student sample (t) test or χ2 test for quantitative and qualitative data, respectively. Significant result is considered if P value less than 0.05, and highly significant result is considered if P value less than 0.001.


  Results Top


There was a highly significant decrease of NAA and NAA/Cho in subgroup IIA in comparison with group III. There was a significant decrease of NAA/Cr in subgroup IIA in comparison with group III, and also there was a highly significant increase of Cho in subgroup IIA in comparison with group III. There were significant increases in M-Ins, M-Ins/Cr ratio, and Cho/Cr ratio in subgroup IIA in comparison with group III ([Table 1]).
Table 1 Comparison between metabolites resonance intensities and ratios of magnetic resonance spectroscopy between subgroup IIA and group III

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There was a highly significant decrease of NAA, NAA/Cr ratio, and NAA/Cho in subgroup IIB (NAWM) in comparison with group III and a highly significant increase of Cho, Cho/Cr ratio, M-Ins, and M-Ins/Cr ratio in subgroup IIB in comparison with group III ([Table 2]).
Table 2 Comparison between metabolites resonance intensities and ratios of magnetic resonance spectroscopy between subgroup IIB (normal-appearing white matter) and group III

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There was a highly significant decrease of NAA, NAA/Cr ratio, and NAA/Cho in group I in comparison with subgroup IIA, and a highly significant increase of Cho, Cho/Cr ratio, M-Ins, and M-Ins/Cr ratio in group I in comparison with subgroup IIA ([Table 3]).
Table 3 Comparison between metabolites resonance intensities and ratios of magnetic resonance spectroscopy between group I and subgroup IIA

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There was a highly significant decrease of NAA, NAA/Cr ratio, and NAA/Cho in group I in comparison with subgroup IIB (NAWM) and significant decrease of M-ins/Cr in group I in comparison with subgroup IIB (NAWM). There was a highly significant increase of Cho and Cho/Cr ratio in group I in comparison with subgroup IIB (NAWM) ([Table 4]).
Table 4 Comparison between metabolites resonance intensities and ratios of magnetic resonance spectroscopy between group I and subgroup IIB (normal-appearing white matter)

Click here to view


There was a negative correlation between EDSS and tNAA resonance intensities, tNAA/Cr ratio, and tNAA/Cho ratio and a positive correlation with M-Ins and M-Ins/Cr ([Table 5]).
Table 5 Correlation between metabolites resonance intensities and ratios of magnetic resonance spectroscopy in group I and Expanded Disability Status Scale

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There was a negative correlation between NAA and EDSS ([Figure 1]).
Figure 1 Correlation between NAA and EDSS. EDSS, Expanded Disability Status Scale; tNAA, total N-acetylaspartate.

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Magnetic resonance spectroscopy images from selected cases

[Figure 2] shows decreased NAA peaks at the voxels related to plaques. Cho/Cr ratio is increased, whereas NAA/Cr ratio prominently decreased at center of the plaque (RRMS patient).
Figure 2 MRS, TE (144 mm sec) − MS group. MRS, magnetic resonance spectroscopy; MS, multiple sclerosis.

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[Figure 3] shows marked decreased NAA (evidence of axonal damage). Cho/Cr ratio is seen increased, whereas NAA/Cr ratio prominently decreased at center of the plaque (RRMS patient).
Figure 3 MRS, TE (144 mm sec) − MS group. MRS, magnetic resonance spectroscopy; MS, multiple sclerosis.

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[Figure 4] (a, b) shows normal brain MRI (axial flair – axial T2), and (c) shows increased Cho/Cr ratio, decreased NAA, and mild decreased NAA/Cr ratio at NAWM (patient with optic neuritis).
Figure 4 (a) Axial T2. (b) Axial flair. (c) MRS, TE (144 mm/s) − optic neuritis group. MRS, magnetic resonance spectroscopy.

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  Discussion Top


In this study, we evaluated brain NAWM metabolic changes by MRS in patient with optic neuritis and patient with MS, and we found that the NAA, NAA/Cr, and NAA/Cho in MS group and optic neuritis group is decreased than the control group, and in comparison with each other, our results found optic neuritis subgroup IIB more decreased than MS group, and MS group more decreased than optic neuritis subgroup IIA. This result is compatible with Ruiz-Pena et al. [10], which stated that in the early stages of the MS, NAA/Cr ratios determined by MRS, in NAWM and WMLs, were lower in MS patients than in healthy controls. Arnold et al. [11], Larsson et al. [12], and Miller et al. [13] found that a reduction of NAA levels in patients with MS was correlated with axonal loss. Wattjes et al. [14] and Brief et al. [15] compared NAA/cho and NAA/Cr ratios in the lesions and NAWM in patients versus controls and found that ratios were clearly reduced. Our study is not compatible with Kirov et al. [16] and Brex et al. [17], as they found that NAA levels were not significantly different. These divergent results may be explained by the very small and heterogeneous patient cohorts in their samples.

Cho and Cho/Cr ratio in MS group and optic neuritis groups is increased than control group, and in comparison with each other, our result found optic neuritis subgroup IIB more increased than MS group, and group MS more increased than subgroup IIA. Kirov et al. [16] and Brex et al. [17] reported that cho-containing compounds in MS have been shown to be increased in acute and chronic lesions as well as in NAWM. It has been suggested that it may imply active or recent demyelination because of the abundance of Cho-containing compounds in myelin. These are present in all cell membranes and elevations could be owing to the turnover of cells involved in the inflammatory process.

Butteriss et al. [18] reports elevation of Cho in chronic MS plaque, probably reflecting the associated gliotic process. Increased Cho/Cr has also been described in MS as a result of abnormal cellular membrane mobility owing to demyelination [19]. In the study by Yetkin et al. [20], MRS was performed in recently diagnosed patients with RRMS and in control group, and it was found that Cho/Cr ratio was not significantly different, which not convenient with our study. This result could be explained by the time of MRS examination, which was at remission periods in patients with MS. Moreover, reduced membrane turnover might affect Cho levels, which may be attributed to the neuroprotective effect of beta-IFN treatment.

M-Ins and M-Ins/Cr ratio is increased in both MS group and optic neuritis group IIB than control group. M-Ins and M-Ins/Cr is decreased in optic neuritis group IIA than control group .M-Ins/Cr is increased in MS group than optic neuritis groups. Our result is harmonious with Pokryszko-Dragan et al. [21], who reported that analysis of MRS measurements in patients with MS in comparison with the controls showed increased M-Ins/Cr within NAWM as well as gray matter. Fernando et al. [22] reported that M-Ins in NAWM is elevated at an early clinical stage within 6 months of onset with a clinically isolated syndrome and in the subgroup can already be diagnosed as having MS at this time. M-Ins is synthesized primarily in glial cells, cannot cross the BBB, and considered to be a glial marker [23]. This result is not matched with Brex et al. [17], as there were no significant differences regarding M-Ins. The small sample size is likely to account for the negative result.

In this study, there was no significant change between studied groups regarding Cr. The concentration of Cr is typically stable and unaffected by the disease process; the other metabolites are expressed as a ratio relative to Cr as a mean of normalization [24].

The present work showed there was a negative correlation between EDSS and tNAA resonance intensities, tNAA/Cr ratio, and tNAA/Cho ratio and a positive correlation with M-Ins and M-Ins/Cr. Rovira and Alonso [25] demonstrated correlations in 1H-MRS findings with clinical disability. This clearly indicates neuroaxonal damage as a mechanism of disability, as patients with long disease duration, SPMS, and patients with RRMS and advanced clinical disability have the greatest NAA loss. This result also matched with Yetkin et al. [20], which reflect both the damaging innate central nervous system immune process (increase in M-Ins) and the neurodegeneration that causes long-term disability (reduced NAA). This result in NAWM was indeed significantly associated with future disease progression.


  Conclusion Top


MRS provides advanced insights into the pathogenesis of optic neuritis and MS by obtaining information on the microenvironment within the brain. This enhances the understanding of the mechanisms involved in disease progression. MRS may open widow to detect early conversion of patient of the typical optic neuritis into MS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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