The Early Evolution of Spinal Cord Lesions on MR Imaging following Traumatic Spinal Cord Injury

Methods

Results

The time interval between injury and MR imaging (time to MR imaging) ranged from 2.5 to 66.25 hours, with a mean time of 18.8 ± 14.9 hours. These findings and other demographic/clinical data are summarized in Table 2.

All 48 subjects were found to have spinal cord edema at MR imaging (Table 3). To examine the relationship of time to MR imaging to spinal cord edema length, we performed multiple regression analysis. This analysis demonstrated a correlation between increased time to MR imaging and increased cord edema length (R² = 32%, F_3,44 = 6.9, P = .002; Table 4). The magnitude of the effect of time to MR imaging on edema length is large, in that the regression coefficient for time to MR imaging is 0.108 (95% confidence interval [CI], 0.04–0.176). Stated differently, during the acute timeframe in this severely injured cohort, spinal cord edema length is calculated to increase by an average of 0.108 U of length per hour; given that there are 3 U per vertebral level, this rate corresponds to a 1-vertebral-level increase in edema for every additional 1.2 days between injury and MR imaging.

Because the size of spinal cord lesions is known to be affected by a number of clinical factors such as age,^9,17 other available clinical factors were included in the regression analysis described previously to control for their potentially confounding effects. This analysis confirmed a significant effect of age on spinal cord edema. The regression coefficient for age is −0.065 (P = .008, 95% CI, −0.019 to −0.111). Thus, in this cohort, an additional 10 years of patient age corresponds to a decrease in spinal cord edema of 0.65 U, or approximately one fifth (21.7%) of a vertebral level. The effect of sex on cord edema was not significant in the final analysis, but there remained a trend (P = .06; regression coefficient, 2.5; 95% CI, 0.1–4.9) toward significance, with women exhibiting greater overall lengths of spinal cord edema. However, the number of women included in the study was comparatively small (9 of 48 patients).

Intramedullary spinal cord hemorrhage was demonstrated in 67% of patients. In contrast to the results for edema length, a relationship between time to MR imaging and spinal cord hemorrhage was not demonstrated by multiple regression analysis (P = .825). In the exploratory analysis, there was a trend toward decreased hemorrhage with increasing age (P = .13). Other studies have reported a significant effect of age on hemorrhage length.^9,17

In 5 of the patients, a short-interval follow-up MR image was available (Table 1). All of these patients had undergone a follow-up study within 5 days, with an average time between MR imaging studies of 2.3 days. In the intervening time, 2 patients underwent open surgical reduction, 2 patients underwent closed reduction, and 1 patient had no intervention. As described in “Methods,” the reasons given for follow-up MR imaging were variable, but in no case was there an ascension of the neurologic level of injury. An example of a follow-up scan is shown in Fig 1.

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Fig 1.

Short-interval follow-up cervical MR imaging of a 67-year-old male ASIA A patient with SCI. T2-weighted FSE images were obtained from an initial MR imaging examination performed 9.5 hours after injury (A and C), as well as from a follow-up postreduction examination performed 55 hours after the first MR imaging (B and D). Demonstrated on the sagittal images (A and B) is a large increase in T2-hyperintense spinal cord edema (arrows demonstrate cranial-most extent), whereas representative axial images from the C5/C6 interspace (C and D) confirm the absence of cord edema at that level on the initial study, with the development of cord edema (arrow) on the second study.

In all 5 patients, an increase in cord edema was observed between the 2 MR imaging examinations, which was statistically significant (t = −6.5, P = .003). The average increase in cord edema between studies was 4.4 U. Given 3 U per level, the average rate of increase was 1 vertebral level every 1.6 days. Thus, the results parallel the increase in edema predicted from the prior correlation of time to imaging with edema length. The magnitude of the increase was less than that calculated in the multiple regression analysis (ie, less than 1 vertebral level per 1.2 days). However, this diminished rate is not surprising, given that the multiple regression analysis was restricted to studies performed within 72 hours of injury, whereas in some of the follow-up patients, the second MR imaging examination was performed outside of the 72 hour timeframe. Animal data¹³ have shown that increases in edema eventually plateau.

Discussion

MR imaging is rapidly performed in patients presenting with spinal trauma and a concomitant neurologic deficit because of its unparalleled ability to depict spinal cord hemorrhage and edema. Although most patients with SCI are imaged early after injury, no study to date has examined the relationship between time to imaging and lesion extent on MR imaging in the acute setting. Likewise, prior studies relating neurologic status to MR imaging findings have not accounted for the potential effects of time to MR imaging, despite the fact that animal studies clearly show that early SCI lesions are dynamic.^13,14 Because most patients are imaged early, an understanding of the early evolution of SCI lesions would be important in the initial diagnosis of SCI, both for the accurate determination of functional prognosis and for the performance of clinical research, particularly with regard to studies designed to test novel therapies that use MR imaging findings as selection criteria or as surrogate outcome measures.

Animal studies have correlated the histopathology of acute SCI with MR imaging findings. Weirich et al¹³ studied rats at time points ranging from 2 hours to 1 week postinjury. The study describes an initial very early pattern (t = 2 hours) of scattered focal gray matter hemorrhages, which rapidly evolve to diffuse hemorrhage throughout the white and gray matter, maximum at 12 hours. The acute spinal cord hemorrhage had specific signal-intensity characteristics, even at the earliest time point (t = 2 hours) appearing T2 hypointense. In contrast, T2-hyperintense signal intensity correlated to areas of edema formation, white matter myelin degeneration surrounding the hemorrhage, and necrotic and inflammatory changes. Although it was not quantified, the investigators reported that surrounding white matter edema became most severe by 48–72 hours after injury in lower severity contusions, with little additional change in sections obtained at 72 and 96 hours. Most interesting, in more severe contusions, the necrotic and infiltrative changes continued to progress in sections obtained at 72 and 96 hours, suggesting that the time course of lesion evolution is dependent on injury severity.

For a serial in vivo assessment of the evolution of cord signal-intensity changes, MR imaging has also been used to repeatedly scan the same animal. Bilgen et al¹⁴ studied hemorrhage in the very early phase (9–400 minutes postcontusion) in rats and reported that the volume of hemorrhage increased linearly with time at a rate of approximately 0.15% per minute, relative to the initial volume. In the same study, edema was observed at the gray matter/white matter junction as early as 12 minutes postinjury but was initially “scattered and focal,” making quantification difficult at early time points. Edema was readily apparent in both the gray matter and white matter compartments within 3 hours. Taken together, these animal studies suggest that hemorrhage, represented by T2 hypointensity, expands rapidly in the very early phase but plateaus comparatively early. Edema initially appears patchy but gradually becomes more extensive and confluent as the secondary injury cascade continues, expanding for a greater length of time than hemorrhage.

The results of the present study parallel prior animal studies. Using multiple regression analysis in a cohort of clinically complete spinal cord injuries (ASIA A), we found a significant correlation between time to MR imaging and the magnitude of spinal cord edema. The correlation was then confirmed in a subset of patients for whom short-term follow-up imaging was available. By contrast, no significant correlation was found between time to MR imaging and hemorrhage length. However, the detection of changes might have been limited by the small number of patients imaged within the very early phase (<6 hours), when changes in hematoma size would most likely be observed. Only 4 patients in this study were imaged within the first 6 hours after injury. Expansion of hematoma size with increased time to MR imaging might have been discernable if a larger number of patients were imaged immediately after injury. It is also possible that emergent MPS administration, which all study subjects received, may have played a role in limiting hemorrhage in the acute phase.^17–20

The finding of dynamic cord edema on MR imaging has implications for its correlation with clinical neurologic status. Although an inverse relationship between the severity of the neurologic deficit and edema length has been reported, the relationship is less robust than is the association with hemorrhage.^7–10 Additionally, the association of spinal cord edema location with the neurologic level of injury remains imprecise. However, the few available studies that have specifically differentiated between acute and subacute timeframes in their inclusion criteria did not factor the time interval from injury to MR imaging into their data analysis.^7,9 However, on the basis of the current evidence, one can speculate that if time to MR imaging was taken into account, spinal cord edema would exhibit an improved association with neurologic level of injury, grade of functional motor and/or sensory impairment, and prognosis. Such associations, if demonstrated, would be of significant interest, in light of the fact that in many patients with lower grade SCI, edema is the only cord pathology seen on MR imaging (ie, no macroscopically detectable hemorrhage is present).

Besides time to MR imaging, other factors have an effect on edema length. Patient age was found to have an inverse correlation to cord edema length. Prior studies have also demonstrated a significant correlation between increased patient age and decreased spinal cord edema¹⁷ and hemorrhage.^9,17 A correlation of female sex with increased edema was suggested in the exploratory analysis, though the trend did not reach statistical significance (P = .06) in the final analysis. Recent articles on the sex effects on clinical and neurologic outcomes after SCI suggested no difference²¹ or slight differences²² between sexes. However, it remains possible that for a given neurologic deficit, women may exhibit comparatively more edema than men, perhaps on the basis of injury pattern or hormonal/neurovascular differences. Given that only 9 of the 48 patients in the study were women, this suggestion would obviously require further investigation.

Consistent with the results of animal studies,^13,14 we did not observe the presence of T2 hyperintense oxyhemoglobin even in the patients imaged most rapidly after injury (n = 4 patients imaged at <6 hours, the earliest imaged at t = 2.5 hours). Bilgen et al¹⁴ studied animals 9–400 minutes postinjury and reported that hemorrhage appears hypointense on T2-weighted images, even at the earliest times. Thus, the rate at which hematoma signal-intensity characteristics evolve in the spinal cord appears to differ significantly from that of parenchymal hemorrhage in the brain, which is classically characterized by a predictable and evolving MR imaging signal-intensity pattern for hours and days that corresponds to the progression of oxyhemoglobin to deoxyhemoglobin to methemoglobin.²³ Caution is, therefore, indicated when applying observations in the brain to SCI hemorrhage. We observed that the predominant species of hemorrhage during the very early phase of SCI is deoxyhemoglobin rather than oxyhemoglobin, most likely due to the local hypoxic state of the injured segment.

There are limitations to the study. Although large-magnitude statistically significant increases in cord edema were predicted by using retrospective multiple regression analysis and directly confirmed in a small number of patients with short-interval follow-up imaging, the study was retrospective. Future prospective studies using a large number of subjects and serial imaging are needed to confirm retrospective findings and improve modeling of the behavior of spinal cord lesions postinjury. Because lesion size in experimental studies¹³ has been shown to depend on injury severity, an attempt was made to normalize injury severity by including only ASIA A patients. However, injury severity within this group will still vary. Additionally, because only patients with clinically complete cervical injuries were studied, it is unclear if patients with lower grades of injury severity also exhibit changes in spinal cord edema with time. As reviewed previously, there are data from animal work¹³ that suggest that the timing of MR imaging signal-intensity changes varies with injury severity.

MR imaging in the setting of traumatic SCI currently provides an invaluable and rapid assessment of cord pathology, augments the clinical examination (particularly in patients who cannot fully comply with a neurologic examination), and helps predict prognosis for functional recovery. Here we demonstrate that spinal cord edema increases significantly during the early time period after injury, whereas intramedullary hemorrhage is comparatively static. Because most patients are imaged rapidly after injury, understanding how cord lesions evolve during the early phase should assist in efforts to refine the correlation of neurologic findings with those on MR imaging, as well as to help better guide the use of MR imaging in clinical trials to assess novel therapies.