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Is there any relation between cervical cord plaques and discopathy in patients with multiple sclerosis?

Clinical Neurology and Neurosurgery

Abstract

Introduction

Multiple sclerosis (MS) is the most common chronic autoimmune demyelinating disease of the central nervous system. The purpose of this study is to determine the relationship between the site of the cervical discopathy and cervical spinal cord plaque in MS patients.

Methods

This retrospective study included all patients with a definite diagnosis of MS who were treated at an outpatient clinic between September 2004 and September 2011. All patients underwent cervical magnetic resonance imaging (MRI) for primary investigation of the disease. Cervical MRI scans were evaluated for detection of any evidence of cervical discopathy and cervical MS plaques. Any correlation between the site of the MS lesions and discopathy was recorded.

Results

from 536 patients who were involved in the study, 214 patients had both cervical discopathy and cervical cord plaques, in this group 148 (69.1% of patients) had cervical plaque at the same site of cervical discopathy. The number of patients with cervical cord plaque and discopathy at same site was significantly higher than those with plaque and discopathy at different sites (p < 0.05).

Conclusion

The study data suggests a possible correlation between cervical discopathy and cervical MS plaque.

Keywords: cervical cord lesions, discopathy, multiple sclerosis, spinal cord symptoms, MRI.

1. Introduction

Multiple sclerosis (MS) is the most common chronic autoimmune demyelinating disease of the central nervous system (CNS). This condition predominantly affects the white matter of the brain, but it also parts of the gray matter[1] and [2]. It is one of the most important causes of non-traumatic disability in adults especially females, affecting about two million people worldwide [3] .

The primary diagnosis of MS and further monitoring and follow up of the disease is based on central nervous system magnetic resonance imaging (MRI) findings, which allow an early diagnosis of MS according to the diagnostic criteria[4] and [5]. It has been proposed that neuro-axonal loss is the leading cause of permanent disability that occurs in the primary stages of the disease[6] and [7]. Molecular and cellular mechanisms contributing to neurodegeneration are still poorly understood [8] .

Disk herniation may coexist with MS and may distort the diagnosis [9] . It seems that compression of the cervical spinal cord secondary to cervical spondylosis or disc herniation may result in acute or chronic myelopathy [9] .

Terminology of disk herniation describes an intact but thinned annulus fibrosus or frank rupture and extrusion of nucleus pulposus through the site of the defect. Herniation occurs most commonly at the level of C5-6 and C6-C7[10] and [11]. In this study Cervical discopathy is characterized by: thinning and protrusion of an intervertebral disk, herniation of nucleus pulposus, and new bone formation involving apophyseal joints and adjacent vertebrae. [12]

The purpose of this study is to determine the relationship between the site of cervical discopathy and cervical spinal cord plaque (which are especially common in the cervical cord opposite the C2 or C3 vertebra) [13] in an outpatient clinic for MS patients.

2. Patients and Methods

All patients with a definite diagnosis of MS who were visited at the outpatient clinic between September 2004 and September 2011 were included in this retrospective study. All referred patients were visited by an expert neurologist and if the definite diagnosis of MS were reached based on the McDonald criteria, they were included in this study [14] . All patients received the required treatment according to their condition. Using a data collection form, demographic data and information on the primary presentation of the disease, history and type of attacks and treatments were gathered.

All patients underwent a cervical MRI for primary investigation of the disease and again during the study when the patients had any new complaint. The MRI of the patients was reviewed for detection of cervical cord lesions and any sign of cervical discopathy.

We had two reviewers, first the radiologist of the MRI centre, who is expert in this field and also the neurologist who visited the patients. We reviewed the abnormal MRIs with the other radiologist for confirmation of both discopathy and plaque.

We selected the patients with both cervical cord plaques and cervical discopathy, then we divided these patients into two groups, the patients whose cervical plaques and discopathy were in the same site (group one) and the patients with plaques and discopathy in different sites (group two). Any correlation between the site of lesion and discopathy was investigated. The patients who were diagnosed as CIS (Clinically isolate syndrome) or RIS (Radiological isolated syndrome), were excluded from the study.

The patients with Expanded Disability Status Scale (EDSS) more than 6 were excluded from the study too.

The patients with remitting-relapsing MS and Progressive MS were included. We also investigated the presence of correlation between discopathy and cervical cord plaques in these groups of the patients too.

The study was approved by the Institutional Review Board and the Ethics Committee of Shiraz University of Medical Sciences. All of the patients gave informed consent to be included in this study. Descriptive statistics and chi-squared test by SPSS software version 15 were used for statistical analysis. A P-value of less than 0.05 was considered to be statistically significant.

3. Results

Overall, 536 patients (Female = 441 [82.3%] other males [17.7%], Mean age = 30.2 years, Ranges 16-61 years) were involved in this study.

Of these patients, 471 (87.9%) of them had cervical cord plaques on cervical MRI. Both discopathy and cervical plaques were seen in 214 (39.9%) of the patients. In this group 148 (69.1% of patients) had cervical plaque at the same site of cervical discopathy. (Group 1)

In 66 patients, cervical plaque and discopathy did not have any correlation regarding the site of the lesion. (Group 2)

The number of patients with plaque and discopathy at same site (group 1) was significantly higher than those with plaque and discopathy at different sites (group2) ( Table 1 ) (p < 0.05). There was not significant correlation between sex of the patients and presence of discopathy in this study, but there was a significant positive correlation between age and presence of cervical discopathy and also cervical disk plaques. (P < 0.05).

Table 1 Prevalence of cervical core lesions and discopathy in the patients.

Characteristics of the patient (N= 536) Count (Percent) P-value
Cervical discopathy 214 (39.9%)  
Cervical cord plaques 471 (87.8%)  
Cervical plaque and discopathy in the same level 148 (31.4%) (percent compared to the total patients with cervical plaques) < 0.05
Cervical plaque and discopathy in different level 66 (14%) (percent compared to the total patients with cervical plaques)  

Presence of spinal cord signs and symptoms was significantly higher among the patients with cervical cord plaques; interestingly the patients with both cervical discopathy and cervical plaques had more spinal cord signs than the patients with only cervical cord plaques (P < 0.05).

There wasn’t any significant correlation between presences of spinal cord signs and symptoms in two groups.

In our study group, 346 patients (64.6%) had remitting-relapsing MS, and 190 patients (35.4%) had progressive MS.

73 patients (38%) with progressive MS had cervical plaques and discopathy in the same site (group one) while only 21.5% of the patients with remitting relapsing MS were in group one, the difference was statistically significant. (P value < 0.05)

Spinal cord signs were significantly higher among the patients with progressive MS. (P value < 0.05)

4. Discussion

MS is an autoimmune chronic inflammatory disease. Pro-inflammatory cytokines play a significant role in the pathogenesis of the disease. In this study we showed that there are some correlations between the site of cervical cord plaques and discopathy especially disk herniation. This correlation may be due to the inflammatory basis for both discopathy process and MS plaque formation.

It has been demonstrated that Interleukin-17 (IL-17), interferon-γ (IFNγ) and tumor necrosis factor alpha (TNFα) are effective cytokines in degenerated and herniated intervertebral disk tissues[15], [16], [17], and [18]. It has also been shown that these cytokines are effective in the pathogenesis of MS.

There are several studies that have shown interleukin (IL)-17 is involved in the pathogenic mechanisms of MS [19] .Similarly Gabr MA et al. in 2011 showed that this cytokine expression in human intervertebral disk cells. [15] They showed that IL-17 is a cytokine which is elevated, along with IFNγ and TNFα, in degenerated and herniated intervertebral disk tissues. Intervertebral disk cells respond with a catabolic phenotype to IL-17 and co-stimulants IFNγ and TNFα. These cells also express surface ligands which have consequent potential to recruit additional lymphocytes and immune cells to the Intervertebral disk microenvironment. So they concluded that (IL)-17 has important regulatory role in the pathogenesis of disk herniation.

On the other hand, in CNS, IL-17 blocks proliferation of neural stem cells, resulting in significantly reduced numbers of astrocytes and oligodendrocyte precursor cells. Thus, in addition to its proinflammatory role in the immune system, IL-17 may also play a direct role in blocking remyelination and neural repair. [20]

Interferon-γ (IFNγ),similar to IL-17, involves in the pathogenesis of MS, although interferon-β (IFNβ) is used for treatment of MS patients; it was shown that administration of exogenous IFNγ aggravates the symptoms of MS [21]

Moreover it was shown that that IFNγ is involved in the pathogenesis of intervertebral disk herniation too. [18]

Tumor necrosis factor (TNF) is a multifunctional cytokine; it is one of the key mediators of inflammation and innate immunity. The association between MS and TNF-α gene polymorphisms has been demonstrated in several studies[22] and [23]. Rossi S et al. in their study showed that TNF-α was higher in CSF of progressive MS subjects, and caused excitotoxic neuronal death in vitro. [24]

Interestingly it was shown that this cytokine is contributed in disk herniation too.

Nucleus pulposus, on disk herniation, in the epidural space induces spinal nerve damage both with mechanical and chemical mechanism. Nucleus pulposus has been shown to be capable of producing TNF-α. TNF-α may play key roles in the Nucleus pulposus -induced chemical damage. [25]

MMP-3 (matrix metalloproteinases-3), comprise a family which are a group of over 20 zinc-dependent enzymes that catalyze the degradation of protein components of the extracellular matrix. MMP-3 was shown to be effective in the pathogenesis of both disk herniation and MS. It was demonstrated that MMP-3 are capable of disrupting the blood-brain barrier (BBB), mediating the destruction of extracellular matrix and myelin components. Circulatory MMP-3 levels are significantly correlated with disease activity in relapsing-remitting MS. MMPs are shown to be relevant to the ongoing development and disappearance of areas of demyelination in the white matter of the CNS of MS patients.[26] and [27].

Genevay S et al. showed the effect of MMP-3 in human disk herniation. [28] Additionally it was shown that gene of MMP-3 has been associated with intervertebral disk degeneration in human. [29]

Similarities in the inflammatory basis of these two pathogeneses are considerable. On the other hand, it is possible to consider that disk herniation may cause inflammation in the neighbouring cord, which aggravates the plaque formation at this site.

Moreover Inflammation at the site of cord plaques may be a predisposing factor for disk herniation in the intervertebral disk beside it.

The other possible mechanism is the vascular compression effect of a herniated disk. This compression effect may cause hypoperfusion and mild local ischemia. In the severe cases there are reports of spinal cord infarcts following to a herniated disk. [30]

Moreover, patients with MS also have global cerebral hypoperfusion in imaging studies; there are some examples which suggest this finding too. Epidemiological studies suggest that patients with MS have a higher risk for ischaemic stroke comparing with normal population. This may be due to endothelial dysfunction secondary to inflammatory disease and also increased plasma homocysteine concentrations. [31] The global decrease in perfusion in normal-appearing white matter and grey matter in MS may not be only secondary to axonal degeneration but also a result of reduced axonal activity, reduced astrocyte energy metabolism, and also perhaps increased blood concentrations of endothelin-1. Chronic cerebrospinal venous insufficiency (CCSVI) theory is the other view. [32] Some studies suggest association between hypoperfusion and T1-hypointense lesions. [33]

Accordingly, it is possible to consider that a discopathy with compressive effects on the vessels may cause hypoperfusion and ischemia. This hypoperfusion may be the other predisposing factor for plaque formation in such patients.

Besides these facts it is shown that, Oxidative stress is a crucial factor in MS pathogenesis by ameliorating leukocyte migration, contributing to oligodendrocyte damage and axonal injury. [34] Oxidative stress thought to promote tissue damage in MS too. [35]

Moreover, in animal model McMichael MA et al. showed that intervertebral disk disease are in a state of oxidative stress and antioxidants may be preemptive treatments. [36]

These two conditions both aggravated with oxidative stress and this may suggest similar improving factors.

Based on the above mentioned pathogenesis and considering the data of the current study, it is possible to consider a relation between cervical discopathy and cervical MS plaque. In summary, discopathy may predispose MS patients to cervical plaque. Accordingly, Prevention and treatment of cervical discopathy may cause improvement in the cervical plaques of the MS patients. Further investigations with a larger number of patients are required to investigate the validity of our findings and are strongly recommended. As far as we know, this is the first paper describing the potential association between discopathy and MS.

Acknowledgement

The authors would like to thank Mr. John Cyrus who provided us editorial assistance.

We also thank Dr. H. Jafari, Radiologist, for reviewing cervical MRIs.

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Footnotes

a Associate Professor of Neurology

b Resident of Neurology Student research committee

c Assistant Professor of Neurology Department of Neurology

d Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, United States

e Research Centre for Health Sciences, Department of Epidemiology, Shiraz University of Medical Sciences Shiraz, Iran

lowast Corresponding author. Resident of Neurology Department of Neurology Nemazi Hospital Student research committee Shiraz University of Medical Sciences Shiraz, Iran. Tel.: +98 9177133608.