Background
Degenerative cervical myelopathy (DCM) is an overarching term used to describe the most common forms of non-traumatic cervical spinal cord myelopathy (including cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament). DCM, which increases in prevalence with aging, is caused by degenerative or congenital changes to the discs and soft tissues of the cervical spine, which leads to chronic compression of the spinal cord [
1]. Importantly, increased recruitment and excessive activation of different immune cells (activated microglia/macrophages, T cells and neutrophils), accompanied by the production of inflammatory cytokines in the spinal cord, have been shown to contribute to the progression of DCM [
2,
3].
DCM is associated with significant neurological dysfunction, including gait impairment, loss of manual dexterity, and pain [
1]. The current treatment, particularly with moderate to severe impairment [
4], consists of surgical decompression [
5]. However, approximately 4% of patients who undergo decompression develop perioperative neurological complications, including worsening of myelopathy and delayed C5 palsy [
5]. Moreover, while most patients show neurological recovery with decompressive surgery, approximately 20% of patients fail to show neurological improvement, with a minority exhibiting continued neurological decline. Additionally, our DCM mouse model has demonstrated that post-decompression neurological decline is associated with the presence of an ischemia-reperfusion injury (IRI) and increased activation of the immune system [
6,
7]. Thus, neuroprotective or neuroregenerative strategies, which complement surgical decompression and rehabilitation approaches, would enhance the management of patients with DCM.
In the present study, we hypothesized that reducing neuroinflammation following decompression for DCM would attenuate perioperative neurological decline and promote enhanced neural recovery. To examine this hypothesis, we used a mouse model of DCM that is associated with severe neuroinflammation [
7]. This model is intended to mimic patients who present with chronically progressive DCM. The anti-inflammatory treatment selected for this study was methylprednisolone (MP), which has long-standing use in clinical practice as an anti-inflammatory and neuroprotective treatment for traumatic spinal cord injury (SCI) [
8]. Patients with cervical SCI and low baseline severity of injury have been shown to benefit the most from MP treatment [
9]; however, the use of MP for SCI has been questioned by some clinicians due to heterogeneous findings reported in the literature [
10]. In animal models of SCI, MP has also been shown to preserve neurons and limit axonal dieback, as well as reduce microglia/macrophages and cytokine levels immediately following injury [
11]. In addition to its use in SCI, the use of perioperative corticosteroids as a complementary approach to decompressive surgery has been shown to reduce pain as well as the duration of postoperative hospitalization in patients with lumbar and cervical radiculopathy due to degenerative conditions [
12,
13]. Given this background, we sought to examine the repurposing of MP as a potential neuroprotective treatment for DCM as a complement to surgical decompression.
In the present study, we examined the effectiveness of MP treatment to reduce inflammation following decompression in a mouse model of DCM at the C5-C6 level. We observed perioperative MP treatment accelerated locomotor recovery by preserving the number of neurons, while modest effects on inflammation were observed. There was also a reduction in the incidence of perioperative motor complications (defined as reduced ankle movement and plantar stepping, forepaw palsy, and upper/lower limb stiffness and/or weakness) following MP treatment. Importantly, no harmful side effects (including increased incidence of wound infection and death) or changes in the peripheral white blood cell composition were observed after MP treatment.
Discussion
In this study, we showed that perioperative MP treatment following decompressive surgery for DCM accelerates locomotor recovery through enhanced neuronal preservation and reductions in inflammation, without compromising the composition of peripheral immune cells populations. Traumatic SCI has been shown to elicit systemic and parenchymal activation of the immune response that can contribute to organ dysfunction and post-injury complications [
29] [
25]. However, it is not known whether DCM, the most common form of non-traumatic SCI, has similar immune system activation. Therefore, we addressed the effectiveness of a combinatorial treatment paradigm to target delayed DCM decompression surgery. Previously, our lab has shown successful repurposing of the sodium-glutamate blocker Riluzole, an FDA-approved drug for the treatment of amyotrophic lateral sclerosis, in mitigating ischemia-reperfusion injury in an experimental animal model of DCM [
6]. This work was the foundation for the CSM-PROTECT clinical trial aimed at evaluating the efficacy of Riluzole in combination with decompression [
30]. However, considering significant inflammation associated with delayed decompression, this study (for the first time) assessed the potential combinatorial use of the anti-inflammatory drug MP. Overall, MP treatment sped locomotor recovery and enhanced neuronal preservation, without compromising peripheral white blood cell composition.
Major surgical procedures can lead to alterations to the hemodynamic, endocrine, and immune functions of the body. Specifically, this leads to an initial activation of the peripheral immune system along with enhanced blood flow to muscle, liver, and ischemic organs [
22]. These changes are followed by a phase of depressed immune function and recovery [
31]. It is important to understand the duration of these phases following surgical decompression in order to determine the optimal time window and route (e.g., systemic or local) of administration for potential peri- and/or postoperative treatments that will enhance the effectiveness of decompression. In our DCM mouse model, excessive activation of the inflammatory response in the spinal cord has been associated with long-lasting symptoms and poor functional outcomes after decompression [
7]. Interestingly, at 5 weeks after decompression in the present study, the number of white blood cells from the adaptive and innate immune system was significantly decreased. Although the systemic changes associated with decompression are different compared with other central nervous system (CNS) injury models, such as SCI, stroke, or multiple sclerosis (MS) [
32‐
36]; a decreased number of T cell subsets has been reported as part of the normal response after major surgeries in patients [
37]. In the context of traumatic SCI, mixed results associated with MP usage have led to significant controversy. When administered within the first 8 h after traumatic SCI, MP has been reported to improve neurological outcomes and short term motor scores [
9,
38,
39]. However, aggregate evidence from different studies suggests a lack of effect in long-term motor recovery [
39]. Despite evidence suggesting that steroids compromise the composition of the peripheral immune system in non-injured as well as injured conditions [
24,
40‐
42], which raises concerns of possible negative side effects, the current guidelines for the management of acute SCI recommends MP treatment within the first 8 h of injury [
8].
We have previously shown that there is an increased inflammatory response following delayed decompression for DCM, which can reduce the beneficial effects of surgical decompression [
6,
7]. In the present study, MP administration resulted in, overall, small effects on the production of inflammatory cytokines, recruitment of Iba1
+ cells and astrogliosis within the spinal cord. Albeit modest, these changes could lead to a more permissive environment that will allow neuronal preservation and an improved rate of functional recovery. This was reflected by an increased number of neurons in the MP-treated group, as compared to saline-treated animals. Similarly, in experimental models of traumatic SCI and ischemic optic neuropathy, MP treatment has been shown to preserve the number of neurons from apoptosis [
43] and to reduce inflammation early after injury [
11,
44]. Such regimens have been shown to accelerate the recovery of blood barrier integrity, reduce tissue damage, and attenuate recruitment of macrophages into the injured tissue [
11,
44,
45]. MP may also be directly acting over neurons and their networks, potentially attenuating axonal excitability loss through the 5-HT
1A receptor [
46]. These receptors are key players of the locomotor network in vertebrates responsible for a regular locomotor pattern, whose function that can be inhibited by the production of nitric oxide [
47]. Similarly, patients receiving corticosteroids for lumbar decompression or cervical radiculopathy have been shown to experience a shorter duration of postoperative hospitalization and pain [
12] [
13]. In our model, MP effects on the inflammatory response were modest and did not translate to long-term gait improvement. This could be partially explained by the short half life of MP [
48] or the frequency of MP delivery. Future studies will need to address whether a repeated low-dose MP injection protocol will be able to induce long-term gait improvements and assess the effects of such a protocol on the peripheral immune response.
Our study has certain limitations that should be acknowledged. Firstly, although mouse models are commonly used in research, the composition of peripheral white blood cells between humans and mice is different. Human white blood cells are enriched in granulocytes and monocytes, whereas mouse white blood cells are rich in B and T cells [
49]. Therefore, the inflammatory response following surgical decompression for DCM may differ between mice and humans. Secondly, DCM patients may have other co-morbidities, including cardiovascular disease and diabetes, which are not present in our animal model. Thus, the potential clinical translation of this work to DCM patients will need to control for other potential side effects of steroids.
Importantly, the incidence of motor complications was reduced after decompression with MP treatment. Given that 1 out of 3 (34.9%) [
50] patients undergoing decompression for DCM can develop postoperative complications, which are not only neurological in nature, the use of complementary treatments for decompression, such as MP, that can reduce this incidence rate are encouraged.