Mark Troxel, DVM, DACVIM (Neurology)
Massachusetts Veterinary Referral Hospital, Woburn, MA
Acute spinal cord injury (SCI) secondary to external trauma or intervertebral disk disease is a common cause of paresis and ataxia in people and dogs. The annual incidence of SCI in dogs is unknown. In human medicine, there are approximately 12,000 new spinal cord injuries annually. Beyond prevention of injury, surgical decompression, and repair of fractures/luxations, there are few treatments available to treat the spinal cord itself. This article discusses the pros and cons of Solu-Medrol and reviews the veterinary and human medical literature.
Spinal cord pathology
Understanding the pathophysiology of SCI is important to developing effective treatments. Primary cell death occurs at the time of injury and is due to a combination of direct biomechanical forces to the vertebral column and the subsequent compression applied to the spinal cord. The goal of surgical intervention in these cases is to prevent further spinal cord injury and to reestablish vertebral stability. However, surgery does not prevent secondary injury, a cascade of biochemical reactions that begins to occur in the spinal cord within minutes of primary injury and can progress over weeks. Secondary injury is due to a variety of factors, including hypoxia, ischemia, lipid peroxidation, free radical production, release of excitotoxic molecules, prostaglandin production, ionic shifts, neutral protease activation, and programmed cell death. These chemical reactions lead to the death of additional neurons and glial cells that survived the initial primary injury. Prevention of secondary spinal cord injury is the focus of intense ongoing pharmaceutical research. This article will examine several studies that lead to the widespread use of methylprednisolone sodium succinate (MPSS), the controversy surrounding the data, and the advantages and disadvantages to using MPSS in both human and veterinary medicine.
National acute spinal cord injury studies (NASCIS)
These three studies constitute the primary reason that MPSS is used in traumatic SCI in humans with extrapolation to veterinary medicine.
NASCIS I (1979)
This study compared a standard dose of MPSS (100 mg) to a megadose (1000 mg) given IV once daily for 10 days. There was no difference between treatment groups at all time points for both sensory and motor assessments.
NASCIS II (1990)
The NASCIS II study examined 487 patients who arrived to the hospital within 12 hours of injury and were given a megadose of MPSS (30 mg/kg IV bolus followed by 5.4 mg/kg/hr for 24 hours), naloxone, or a placebo. Motor function was evaluated by testing the power in 14 muscle groups and given a graded score from 0 to 5 (total score range 0-70). Sensory function was evaluated by pinprick & tactile sensation in 29 dermatomes and given a graded score of 1-3 (total score range 29-87).
Post hoc statistical manipulation was performed and the patients were divided into those in which treatment was initiated within eight hours of injury and those in which treatment was started later. The authors reported that patients who received MPSS had a better outcome at six months compared to placebo, but this effect disappeared by one year. They also reported that patients receiving MPSS within eight hours of injury had a statistically significant improvement in motor scores at both six months and one year.
Numerous criticisms have been made regarding this study, only some of which will be highlighted here. First, the time point for statistical analysis was changed from 12 hours to 8 hours without logical explanation. This suggests that the authors tested the effects at various times and found the best effect at the eight hour time point and reported data based on this post hoc statistical manipulation. This compromises the scientific value of the data. Next, only 62 placebo patients and 65 MPSS patients were analyzed meaning that 70% of all the patients that were enrolled were excluded from data analysis! Additionally, there was no consideration given to whether aggressive medical management or surgical intervention may have had an effect on patient outcome. Finally, functional recovery was not tested, so it is unclear if the modest improvements in motor scores lead to improved function.
Two unusual results were reported in this study that suggests that the conclusions may be based on statistical artifacts. First, patients who received a placebo within eight hours of injury had a worse outcome than patients who received a placebo more than eight hours after SCI. Second, the placebo group of patients presenting with incomplete SCI after eight hours from injury had an almost identical outcome to those patients who were treated with MPSS within eight hours. Regardless of whether or not a patient received MPSS or a placebo, one would expect that patients treated within eight hours of injury would have a better outcome than patients who received treatment after eight hours simply because aggressive treatment was begun earlier. These two points suggest that the placebo had the same effect as MPSS!
NASCIS III (1997)
This study included 499 patients who presented to the hospital within eight hours of SCI. The patients were randomized into three groups:
- MPSS 30mg/kg IV bolus followed by 5.4 mg/kg/hr for 23 hours
- MPSS 30 mg/kg IV bolus followed by 5.4 mg/kg/hr for 47 hours
- MPSS 30 mg/kg IV bolus followed by Tirilizad 2.5 mg/kg q6hr for 48 hours.
Sensory & motor scores were obtained as for the NASCIS II trial, but this study also evaluated the patient’s functional recovery using the Functional Independence Measure (FIM), which includes “self care, sphincter control, mobility, locomotion, communication, and social cognition.” At the six month follow-up there was no significant difference between groups. At this point, the authors performed a statistical bait & switch by dividing patients into those that received MPSS within three hours versus those that received it 3-8 hours after SCI. Following this, the authors identified a statistically significant difference in motor scores at six weeks and six months in patients who received 48 hours of MPSS compared to those that received 24 hours, but this was less apparent at one year (P=0.053). Based on these results, the authors concluded that patients seen within three hours should receive 24 hours of MPSS while patients seen between 3-8 hours should receive 48 hours of MPSS.
Again, this study has several major limitations. First, there was no placebo group, presumably because they were included in the NASCIS II trial. Second, more patients with an initial normal motor score were randomized into the 24-hour MPSS group, thus skewing the results toward improved benefit. Third, the authors conclude that MPSS should be administered based on modest improvement in motor scores, but the FIM was similar for all groups, which is perhaps most important outcome measure for SCI patients. Fourth, the three hour time limit appears arbitrary and it is not clear how this time frame was chosen. Post hoc manipulation of this time point alters the scientific value of the data. As with the NASCIS II trial, the effect of standardized medical or surgical care on the outcome was not analyzed. Finally, there was no minimum motor impairment criterion for patient inclusion, and, as a result, patients with normal motor function were admitted into the study, thus skewing the results.
Other clinical studies testing MPSS treatment
To date, numerous other studies and meta-analyses of data across multiple studies have been unable to reproduce the results obtained in the NASCIS trials. Admittedly, most are either retrospective or smaller prospective studies with less statistical power. A recent PUBMED search for methylprednisolone and spinal cord injury yielded 47 results, none of which supported the use of MPSS with the exception of articles written by the original NASCIS authors.
Complications associated with the use of MPSS
There appears to be little controversy regarding potential harmful side effects. The most worrisome study was the CRASH trial in people in which MPSS was randomly given to 10,008 patients with traumatic brain injury (TBI) at doses similar to the NASCIS III 48-hour protocol. The study was terminated prior to reaching the target population of 20,000 patients because interim analyses showed the relative risk of death to be 1.18 for MPSS patients compared to controls (P=0.00001). This suggests that 1 in 30 patients with TBI that are treated with 48-hour MPSS will die because of the drug itself! Thus, the current recommendation is to NEVER give steroids to human or veterinary patients with head trauma. Returning to the SCI trials, a small prospective cohort study by Qian and others showed that high-dose MPSS may cause an acute, rapid myopathy in SCI patients. They suggested that some of the improvement in motor scores may be due to natural recovery from the myopathy rather than protection afforded by MPSS. A veterinary retrospective study by Boag and others compared the incidence of clinically-evident post-operative complications in Dachshunds that were treated surgically for disc extrusion. They found that dogs who were given MPSS (± another corticosteroid) had a significantly higher total hospital charge, increased use of GI protectants, and increased incidence of diarrhea than dogs who received any other steroid.
Clinical studies in veterinary medicine
To date, there are no prospective, double-blind, placebo-controlled studies examining the use of MPSS in veterinary patients. Although there are many experimental studies detailing the benefits of MPSS in animals, the method in which SCI is induced is artificial and may not accurately reflect the consequences of naturally occurring disease. A retrospective study performed by Davis & Brown to determine prognostic indicators for time to ambulation after surgical decompression demonstrated that “there was no difference in time to ambulation between dogs who were treated with any glucocorticoid protocol and dogs not treated with glucocorticoids (P=0.98).” In fact, a study by Bush, et. al. (2004), showed that 100% of 51 nonambulatory dogs weighing less than 15 kg body weight with intact pain sensation that DID NOT receive MPSS and were treated with hemilaminectomy recovered the ability to walk. A very small study by Coates and others failed to demonstrate a protective effect of MPSS in dogs with experimental SCI. However, only four dogs were given MPSS and the data would only be reliable if the experimental model was extremely reproducible. Finally, an abstract by Simmering and Vomering in Veterinary Surgery described a beneficial effect of using MPSS in dogs undergoing surgery. However, there were no controls included, and the importance of their findings is unknown.
Why do physicians use MPSS in acute SCI?
Two surveys provide interesting insight into why physicians use MPSS for acute SCI. The first study found that steroids were routinely administered by 98% of all trauma centers in Colorado, but approximately 50% of the medical directors were either uncertain about, or did not believe, the data supporting the use of steroids. In another study of 60 spinal surgeons, only 17% replied that they administer MPSS solely because they found it to be beneficial. In fact, 70% of the surgeons prescribed it due to fears of litigation (35%) or due to peer pressure (35%). The remaining surgeons (13%) said they prescribed it for all of the above reasons.
Should veterinarians use MPSS in acute SCI?
Parallels are often drawn between human and veterinary medicine with regard to treatment outcome for many diseases. However, spinal cord injury is one area of medicine in which the outcomes we expect are far different from our physician counterparts. In human medicine, self-sufficiency (e.g., being able to eat without assistance, urinary & anal sphincter control) is considered adequate functional recovery. Since dogs and cats are not self-sufficient, our patients have to be able to walk and eliminate voluntarily. Otherwise, euthanasia often is the ultimate outcome.
At this time, there are no conclusive data showing a CLEAR and REPEATABLE improvement in functional outcome following administration of MPSS in humans. There also is NO scientific proof that MPSS leads to a significant and consistent improvement in functional recovery in veterinary patients with naturally occurring disease. As a result, use of MPSS in veterinary patients remains controversial. However, stay tuned, as there is a multi-institutional, double-blind, placebo-controlled study currently underway being lead by Dr. Natasha Olby at North Carolina State University. This prospective clinical trial will compare MPSS, Polyethylene glycol (PEG), and saline placebo as adjunctive medical therapies to surgical decompression in dogs with acute intervertebral disc herniations.