Joseph M. Mankin and Franck Forterre
Introduction
Glucocorticoids have been used in cases of intervertebral disc disease managed both medically and surgically since the 1960s and have been shrouded in controversy for at least the past 15 years. While clinical improvement can be seen in certain cases, the use of steroids is not without risk and potential detriment to the patient. Most physicians and veterinarians today prescribe steroids in this setting, not because of an understanding of the evidence surrounding their use, but largely because the practice has been so common over a long period of time [1]. In this chapter, we will address the reasons steroids can be useful, the controversy surrounding them, and their effects in our patients.
Pathophysiology
One of the effects of acute spinal cord injury (SCI) is reduction in blood flow to the neural tissue. As reperfusion occurs, highly reactive free radicals are liberated. These free radicals cause damage to the plasma membrane of cells by the process of lipid peroxidation. This phenomenon is key in irreversible tissue loss following spinal cord trauma and ischemia [2].
The potentially beneficial mechanism of action of glucocorticoids in SCI is inhibition of this lipid peroxidation as well as hydrolysis, processes that lead to damage of both neuronal and microvascular membranes [3]. This inhibition is postulated to be due to the steroids’ high lipid solubility and ability to intercalate into artificial membranes between the hydrophobic polyunsaturated fatty acids of the membrane phospholipids and limit the chain reaction of lipid peroxidation throughout the phospholipid bilayer [4–6]. This is the so-called “membrane stabilization” phenomenon that steroids are known for. In addition to the primary action of glucocorticoids at physiologic doses, some formulations, such as methylprednisolone sodium succinate (MPSS) and lazeroids (21-aminosteroids), can exert a number of other actions on the spinal cord when given at suprapharmacologic doses, including maintenance of tissue blood flow, maintenance of aerobic energy metabolism, improved reversal of intracellular calcium accumulation, reduction of neurofilament degradation, and enhanced neuronal excitability and synaptic transmission [3, 5, 7].
Another effect of methylprednisolone is inhibition of phospholipase A2 formation, inhibiting arachidonic acid release as well as prostaglandin F2α and thromboxane A2, which can produce anti-inflammatory effects. Dexamethasone has historically been used frequently for SCI, based on the fact that it is such a potent glucocorticoid and has a high anti-inflammatory potency. However, as an inhibitor of lipid peroxidation it is only slightly more potent than methylprednisolone, as well as having fewer antioxidant properties [5, 6]. Due to these findings, both animal and human studies have focused on methylprednisolone for SCI in the past two decades.
In cases of chronic spinal cord compression, both blood flow and oxygen levels can be better maintained without intervention due to the slow, progressive nature of the process. The most common pathology in these cases is predominantly demyelination and axonal swelling, with white matter edema occurring later. Glucocorticoids are effective against this vasogenic edema, accounting for the clinical response seen in chronic cases [8].
Justification of steroid use based on human literature
Initial studies
Starting in 1979, three National Acute Spinal Cord Injury Studies (NASCIS) were conducted to determine the efficacy of MPSS as a treatment modality for acute SCI. The first study compared a standard dose of MPSS to high-dose MPSS, with sensory and motor assessments being performed at admission, 6 weeks, 6 months, and 1 year after injury. The results showed no significant difference between the two groups [2, 7].
The second study compared groups receiving high-dose MPSS, a placebo, or an opioid antagonist (Naloxone). Once again, sensory and motor assessments were conducted at admission, 6 weeks, 6 months, and 1 year after injury. Results showed improved sensory function at 6 months, but no significant difference at 1 year. There was no difference in motor score between treatment groups at any time point. However, with post hoc stratification of patients by time to treatment, patients receiving steroids within 8 h had a statistically significant improvement in motor score at 6 months and 1 year [9].
The third NASCIS was performed on those patients receiving therapy within 8 h, and the groups consisted of MPSS bolus with 24 h infusion, MPSS bolus with 48 h infusion, and MPSS bolus followed by Tirilazad, a lazeroid drug that has similar lipid peroxidation effects without the glucocorticoid activity. There was no significant difference in motor score between treatment groups at any time point. Using post hoc analysis, patients treated with 48 h infusion of MPSS starting between 3 and 8 h of injury had higher motor scores at 6 weeks and 6 months, but not at 1 year [10].
Follow-up studies and reassessment
Since the results of NASCIS trials have been published, there has been significant controversy over the results. There have been many criticisms of the studies including the study design, determination of timing of therapy, and the statistical analysis performed. The use of post hoc analysis of subgroups raises the possibility that the statistically significant results were random events. The fact that only right-sided motor scores were reported, while bilateral sensory scores were reported, has raised questions. The statistics performed were only done on one-third of the patients enrolled due to exclusion criteria, which reduced the power of the study. In addition, there was not a standard medical or surgical treatment regimen for patients in the study.
The higher motor and sensory scores for patients receiving methylprednisolone do not necessarily correlate with significant, life-altering improvement as the functional scores remained the same. In addition, those differences in recovery were only seen in those patients with complete SCI (i.e., loss of both motor function and sensation).
Several other studies have been performed, but none could reproduce the findings from the initial studies. However, there has been evidence that those treated with methylprednisolone have an increased risk of complications including pneumonia, sepsis, and death due to respiratory complications [11–14].
The controversy surrounding the results has brought into question the use of steroids as standard of care. In fact, many hospitals no longer use steroids in cases of spinal trauma.
