Modic changes, possible causes and relation to low back pain

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Summary

In patients with low back pain (LBP) it is only possible to diagnose a small proportion, (approximately 20%), on a patho-anatomical basis. Therefore, the identification of relevant LBP subgroups, preferably on a patho-anatomical basis, is strongly needed.

Signal changes on MRI in the vertebral body marrow adjacent to the end plates also known as Modic changes (MC) are common in patients with LBP (18–58%) and is strongly associated with LBP. In asymptomatic persons the prevalence is 12–13%. MC are divided into three different types. Type 1 consists of fibro vascular tissue, type 2 is yellow fat, and type 3 is sclerotic bone. The temporal evolution of MC is uncertain, but the time span is years.

Subchondral bone marrow signal changes associated with pain can be observed in different specific infectious, degenerative and immunological diseases such as osseous infections, osteoarthritis, ankylosing spondylitis and spondylarthritis. In the vertebrae, MC is seen in relation to vertebral fractures, spondylodiscitis, disc herniation, severe disc degeneration, injections with chymopapain, and acute Schmorl’s impressions.

The aim of this paper is to propose two possible pathogenetic mechanisms causing Modic changes. These are:

A mechanical cause: Degeneration of the disc causes loss of soft nuclear material, reduced disc height and hydrostatic pressure, which increases the shear forces on the endplates and micro fractures may occur. The observed MC could represent oedema secondary to the fracture and subsequent inflammation, or a result of an inflammatory process from a toxic stimulus from the nucleus pulposus that seeps through the fractures.

A bacterial cause: Following a tear in the outer fibres of the annulus e.g. disc herniation, new capilarisation and inflammation develop around the extruded nuclear material. Through this tissue it is possible for anaerobic bacteria to enter the anaerobic disc and in this environment cause a slowly developing low virulent infection. The MC could be the visible signs of the inflammation and oedema surrounding this infection, because the anaerobic bacteria cannot thrive in the highly aerobic environment of the MC type 1.

Perspectives: One or both of the described mechanisms can – if proven – be of significant importance for this specific subgroup of patients with LBP. Hence, it would be possible to give a more precise and relevant diagnosis to 20–50% of patients with LBP and enable in the development of efficient treatments which might be antibiotics, special rehabilitation programmes, rest, stabilizing exercise, or surgical fixation, depending on the underlying cause for the MC.

Introduction

Diagnosing patients with low back pain (LBP) is a challenge for clinicians [1]. It is frequently stated that only a small proportion (approximately 20%) of patients with LBP can with reasonable certainty be diagnosed based on a patho-anatomical entity [1]. The most commonly used classification, “non-specific LBP” (80%), is not satisfactory neither for the patient suffering from LBP nor for the clinician due to lack of accuracy in diagnosis and treatment. Therefore, the identification and diagnosis of relevant subgroups of patients with LBP, preferably with a sound patho-anatomical basis, is strongly needed.

There is emerging evidence that signal changes in the vertebral body marrow adjacent to the end plates, also known as Modic changes (MC) are rather strongly associated with LBP, and we will in this paper argue that this should be considered a specific and relevant subgroup of LBP patients. Furthermore, we will outline two hypotheses on the possible causes of MC.

Signal changes in the vertebral body marrow adjacent to the end plates visualized by magnetic resonance imaging (MRI) was described by de Ross et al. [2] in 1987. These changes are according to Modic et al. [3], [4], visible as three different types. Type 1 is seen on T2-weighted MRI as areas of increased signal intensity and on T1-weighted MRI as low signal intensity extending from the vertebral endplates into the vertebral body. From histological studies of material harvested during surgery, MC type 1 have been described as disruption and fissuring of the endplate with regions of degeneration, regeneration, and vascular granulation tissue [3] (Fig. 1A,B). Type 2 is observed as increased signal intensity on both T1- and T2-weighted images. Biopsies revealed the MC type 2 to be disruption of the end plates with increased reactive bone and granulation tissue, and the hematopoetic elements in the vertebrae are replaced by abundant fat (yellow marrow) [3] (Fig. 1C,D). MC type 3 are presumably bone sclerosis and are visualized on MRI as decreased signal intensity on both T1- and T2-weighted images [4].

Kjaer et al. [5] observed in a sample of 412 persons aged 40 from the general population a strong association with LBP within the past year, particularly for MC type 1. The prevalence of pain within the last year in people with MC was 88% and in people with no pain 12%. In the study by Albert and Manniche [6] 166 patients with sciatica (92% from a lumbar disc herniation) were evaluated. They all had an MRI in the acute stage and at follow-up 14 months later. At follow-up, 60% of the patients with MC suffered from LBP, whereas in the group without MC only 20% had LBP, OR of 6.1 (2.9–13.1) (p < 0.0001). The prevalence of MC increased in the 14 months from 25% to 49%.

In the study by Albert and Manniche [6] lumbar pain was more frequent in people with MC type 1 compared to those with type 2, although not statistically significant. Also Toyone et al. [10] and Kjaer et al. [5] observed such a difference. Therefore, MC type 1 is possibly more associated with pain compared to type 2. The reason why MC type 1 are more painful could be that they reflect an earlier and more active stage of inflammation.

See Table 1.

Braithwaite [7] studied 58 patients with discogenic pain who were referred to a discography prior to fusion. Among them 48% of the patients had MC predominantly type 2. The study showed that MC is a highly specific indicator (specificity of 0.97) of a painful disc. But the sensitivity was low, meaning that patients can have LBP from other causes. MC have also been shown to be painful on discography in other studies [7], [11], [13] also with a low sensitivity but at very high specificity, though this relationship was not confirmed in the study by Sandhu et al. [14] and Kokkonen et al. [12].

So why does MC hurt? Ohtori [16] evacuated during surgery the endplates of 14 LBP patients with MC and 4 controls without MC. After preparation they discovered that in 12(86%) of the 14 patients with MC, as opposed to none of the controls, PGP 9.5 immunoreactive nerve fibres were located in the endplate cartilage. Also TNF immunoreactivity was discovered in the endplates of both patients and controls, but the number of these cytokines was significantly higher in patients with MC compared to the controls, and significantly higher in patients with MC type 1 than type 2. Regardless if the patient had MC or not, only few PGP 9.5 immunoreactive fibres were present in the vertebral bone marrow, and no TNF immunoreactivity was observed. The presence of these proinflammatory cytokines and SP-immunoreactive nerve fibres may explain why MC causes pain [16].

Because MC in most cases are observed in conjunction with a degenerated disc, Crock [17] proposed the concept of “internal disc disruption”. According to his theory, repeated trauma to the disc could result in the production of inflammatory substances in the nucleus pulposus. When these toxic chemicals diffuse through the vertebral endplate, it could result in a local inflammatory reaction resulting in back pain.

Mitra et al. [9] studied a sub-sample of 44 patients with Modic type 1 from a population of 670 patients conservatively treated for LBP and/or sciatica. It can be assumed that a considerable percentage of these patients with symptoms of sciatica suffered from a herniated disc. Over a period of 12–72 months, 37% converted fully to type 2, 15% converted partially to type 2, 40% into more extensive type 1 changes, and 8% showed no change. In the patients whose symptoms had improved, the type 1 changes had developed into type 2. In the patients reporting a worsening of their symptoms, the type 1 changes had progressed and become worse [9]. Modic et al. [3] studied the evoluation in MC in 16 patients with LBP without sciatica. Five out of six MC type 1 converted at least partially into type 2, while ten patients with type 2 remained unchanged after a period of 12–36 months [3]. Bayer et al. [61] observed 55 non-surgically treated patients over a mean period of time of 2 years. Of the MC type 1, 6% had reverted to normal, 18% of the MC type 2 had evolved either to normal or MC type 1.

In a study by Albert and Manniche [6] 166 conservatively treated patients with sciatica (predominately from a herniated disc), had an MRI at the acute stage and again 14 months later. The prevalence rate of MC type 1 increased from 9% at baseline to 29% at follow-up. The MC type 2 and type 3 changes remained stable. New MC type 1 were observed in 17% of the patients. Furthermore, 11% patients who exhibited type 1 or 2 changes at baseline developed new type 1 changes in the same vertebrae as the previous MC was observed. None of the patients with an intact disc developed MC [6]. Kushima et al. [59] observed 60 patients with a herniated disc. At baseline 23% had MC predominating type 2 changes. At 3 years follow-up, new MC had developed in 6% of the discs predominately type 1 or mixed type1 and 2, the majority being localized at the level of the previously herniated disc.

The relationship between herniated disc and MC is also supported by the fact that more men than women suffer from a herniated disc, and men have a higher prevalence of MC than women [8]. The largest proportion of MC was observed in the adjacent vertebrae of the L4 and L5 discs [6], [8], where 95% of the herniations occur [18].

Signal changes in the vertebral bone marrow have been observed as a finding in several diseases, among them in immunological diseases such as ankylosing spondylitis and Reiter’s disease [44], [45]. The changes in the bone marrow in these diseases are probably related to the auto-immune pathogenesis of the specific disease. Although the pain mechanism is not fully understood, signal changes in the bone marrow, most often described as oedema, are also associated with pain in a variety of joint and bone disorders such as osteoarthritis, degenerative facet joint disease and lumbar spondylolysis [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56].

  • 1.

    Signal changes in the vertebral body marrow adjacent to the end plates also known as Modic changes (MC) are strongly associated with LBP.

  • 2.

    MC type 1 are probably more painful than type 2.

  • 3.

    The prevalence of MC amongst patients with LBP is 18–58%, depending of the study population.

  • 4.

    MC first occurs as type 1. Type 1 can then evolve to type 2 or convert into normal. Type 2 usually converts to normal. The time span is years.

  • 5.

    Disc herniation, severe disc degeneration, injections with chymopapain, and acute Schmorl’s impression [29], seems capable of inducing MC.

  • 6.

    Discography is painful in the discs with adjacent MC. Discography has high specificity but low sensitivity.

Section snippets

Hypotheses

Signal changes in the bone marrow are observed in conjunction with several immunological diseases as well as joint and bone disorders but their relationship to pain and development of the diseases are unknown. However, signal changes in the vertebral endplate and vertebral bone marrow are on the other hand closely linked to LBP [5], [6], [7], [9], [13], [14]. Furthermore, disc herniation and severe disc degeneration disc are strong risk factor for developing MC (especially type 1). Two

Acknowledgement

We thank Alan Jordan, Ph.D. and Charlotte Leboeuf-Yde, Ph.D for valuable editorial assistance.

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