During the past several decades, the indications for spinal arthrodesis have expanded, with a dramatic increase in the rate of cervical spine fusion in the United States during the past decade.1 However, as more of these procedures are performed over time, there have been concerns regarding the potential for these patients to develop changes at levels adjacent to the index procedure. During this time, fusion technologies have dramatically advanced and indications for cervical arthrodesis have been expanded. Given the early reported success rates of spinal arthrodesis, the implications of eliminating spinal motion on adjacent segments were largely ignored and questions remain whether the development of adjacent segment pathology (ASP) is iatrogenic in nature or part of natural history.
When discussing ASP, it is important to differentiate between radiographical ASP (RASP), which is radiographical evidence of degeneration at the levels adjacent to a previous fusion and clinical ASP (CASP), which is the development of clinically relevant symptoms (i.e., radiculopathy and/or myelopathy) that correlate with radiographical evidence of degeneration that is adjacent to a previous fusion.2
Although several review articles have been published summarizing risk factors associated with lumbar CASP,3–7 we did not identify any systematic reviews summarizing the risks of or risk factors for CASP after fusion in the cervical spine. Therefore, we sought to elucidate factors that may play a role in CASP development after spinal fusion in the cervical spine. Specifically, we seek to address the following key questions: (1) What is the estimated risk of CASP after cervical fusion for degenerative disease? (2) Among patients undergoing cervical fusion, are there patient, disease, surgical, or radiographical factors associated with an increased risk of CASP?
MATERIALS AND METHODS
We conducted a systematic search in PubMed and the Cochrane Library for literature published between January 1990 and March 15, 2012. The search results were limited to human studies published in the English language. Reference lists of key articles were also systematically checked to identify additional eligible articles. We included studies evaluating adult patients who had cervical spinal surgery due to degenerative disease (spondylosis, spondylolisthesis, radiculopathy and/or myelopathy, deformity, kyphosis, ASP) or revision surgery (Table 1). We included all studies evaluating risk factors of CASP (whether or not the patient received surgery) or risk factors for reoperation due to ASP in a cervical population. We were interested in the following prognostic categories: patient factors such as age, sex, body mass index, osteoporosis, and occupation; disease factors such as spondylosis with or without radiculopathy or myelopathy, and deformity; surgical factors such as length of fusion, last instrumented level selected, interbody versus no interbody graft, anterior versus posterior approach; and radiographical factors such as pre- and postoperative thoracic and lumbar curves, lordosis, disc degeneration, and sagittal and coronal balance. The primary outcome for this review is CASP; however, we also included studies that reported on the secondary outcome of RASP. Exclusion criteria included pediatric patients, and patients with infection, tumor, or trauma; studies that did not report CASP or RASP as an outcome, but reported outcomes such as range of motion, kinematic measures, disc height, lordosis/angle changes at adjacent levels, n < 10; and animal, cadaver, and biomechanical studies. Full text of potential articles meeting the inclusion criteria were reviewed by 2 independent investigators (J.R.D., E.B.) to obtain the final collection of included studies (Figure 1).
From the included articles, the following data were extracted: study design and study purpose, patient demographics, inclusion and exclusion criteria, follow-up duration and the rate of follow-up for each treatment group, risk factor analyzed, definition of CASP or RASP, and risk of and potential risk factors for CASP or RASP (see Supplemental Digital Material, Supplemental Digital Content 1, available at http://links.lww.com/BRS/A704).
Where the data were available, we reported incidence or prevalence of CASP. For the incidence, we recorded, when provided, either the annual incidence rate or the cumulative incidence of CASP. The annual incidence rate was defined as the proportion of patients who had been disease free at the start of a given year and had subsequent development of CASP during that year. The cumulative incidence (%) of CASP was defined as the proportion of patients who had been ASP free at the time of the index fusion, had subsequent development of new CASP at final follow-up, and had CASP from which one cannot recover (e.g., when CASP is defined as symptoms requiring reoperation). Prevalence was defined in 1 of the 2 ways: (1) as the proportion of patients who had been ASP free at the time of the index fusion, had subsequent development of new CASP at the final follow-up, and had CASP from which one can recover before the follow-up evaluation (e.g., when CASP was defined as pain); (2) as the proportion of patients with RASP at follow-up from among all patients in the study, some of whom had RASP at the time of the index procedure. We pooled risks weighting the pooled estimate by the sample size and calculated the 95% confidence interval (CI). For risk factor analysis, we report effect sizes from multivariate analysis (i.e., adjusted effect size estimates) and/or of significance based on adjustment for confounders when provided by the authors. In studies that did not use multivariate analysis, crude risk ratios (RRs) and 95% CI were calculated to provide an estimate of effect size. All calculations were performed using Stata 9.0 (Statistical Software, release 9, College Station, TX).8 RRs, prevalence ratios, or hazard ratios (HRs) whose CI includes the value of 1 are not statistically significant. Values above 1 suggest increased risk and values below 1 suggest decreased risk for the factor.
Study Quality and Overall Strength of Body of Literature
Level-of-evidence ratings were assigned to each article independently by 2 reviewers (J.R.D., E.B.) using criteria set by the Journal of Bone & Joint Surgery, American Volume,9 for prognostic studies and modified to delineate criteria associated with methodological quality and described elsewhere10 (see supplemental digital material, Supplemental Digital Content 1, available at http://links.lww.com/BRS/A704 for individual study ratings). The overall body of evidence with respect to each clinical question was determined on the basis of precepts outlined by the Grades of Recommendation Assessment, Development, and Evaluation working group11 and recommendations made by the Agency for Healthcare Research and Quality.12 Risk of bias was evaluated during the individual study evaluation as described earlier. This system that derives strength of evidence grade for each outcome or clinical question of “high,” “moderate,” “low,” or “insufficient” is described in further detail in the methods article of this Focus Issue.
Consensus statements were made through a modified Delphi approach by applying the Grades of Recommendation Assessment, Development, and Evaluation/Agency for Healthcare Research and Quality criteria that imparts a deliberate separation between the strength of the evidence (i.e., high, moderate, low, or insufficient) from the strength of the recommendation. When appropriate, recommendations or statements “for” or “against” were given “strong” or “weak” designations based on the quality of the evidence, the balance of benefits/harms, and values and patient preferences. In some instances, costs may have been considered. A more thorough description of this process can be found in the methods article of this focus issue.
We identified 5 studies (4 retrospective cohorts, 1 database study) from our search strategy that met the inclusion criteria (Figure 1). Our initial search produced 176 possible studies for review. We excluded 159 after abstract review, the majority of which were biomechanical studies or studies of effectiveness and did not evaluate risk factors. Among the 17 full-text articles, 12 were excluded after review. A list of excluded articles can be obtained in the supplemental information (see Supplemental Digital Material, Supplemental Digital Content 1, available at http://links.lww.com/BRS/A704).
The primary indications for cervical fusion across the 4 retrospective cohort study populations were cervical spondylosis and disc herniation (Table 2).13–16 Mean patient ages ranged from 50.2 to 56.1 years and men comprised 48% to 81% of the study populations. Mean follow-up times ranged from 5.1 to 9.8 years across 3 studies; 1 study did not provide a mean follow-up period but indicated that patients were observed for a maximum of 21 years after the operation.13 Inclusion/exclusion criteria varied across the studies. The definition of CASP was similar across all 4 studies and was defined as the presence of new radiculopathy or myelopathy referable to an adjacent-level motion segment, compatible with radiographical changes. One of these studies also reported on subsequent operation due to CASP.16 Risk factors for the development of cervical CASP investigated across these 4 studies include: sex (1 study), age (2 studies), number of levels fused (3 studies), level of fusion (3 studies), and various radiographical factors (2 studies).
The fifth study was an inpatient database study (medical claims data from Taiwan's National Health Insurance program) designed to calculate the incidence of secondary fusion surgery after anterior cervical discectomy and fusion (ACDF) for cervical disc disease.17 A total of 19,385 patients (58% male) were included with a mean age of 50 years and a mean follow-up time of 10 years (Table 2). Patients were required to have at least 1 year of follow-up and were excluded if they had undergone multiple ACDF operations within 3 months. Risk factors for subsequent operation due to CASP reported by this study include: age, sex, comorbidities, and socioeconomical factors.
What Is the Estimated Risk of CASP After Cervical Fusion for Degenerative Disease?
Annual incidence rate of CASP was reported by 1 of the retrospective cohort studies with a rate of 2.9% per year (95% CI, 1.6%–4.2%).13 At 5 and 10 years, the corresponding prevalence of CASP was 11.7% (95% CI, 8.5%–14.8%) and 19.2% (95% CI, 15.4%–23.0%), respectively. In a second cohort study, the cumulative incidence of CASP was 17.0% and the prevalence was 11% at 5 years, 16% at 10 years, and 33% at 17 years.14 In the final 2 retrospective cohorts, the prevalence of CASP was reported as 11.8% at a mean 5.1-year follow-up and 38.1% at a mean 9.8-year follow-up (Figure 2).15,16
The large inpatient database study reported an annual incidence of 0.76% for secondary fusion operations after ACDF.17 The 10-year risk for a second fusion surgery in this population was 5.6%. Furthermore, the 10-year risk for a third fusion operation among those who had had a secondary operation was 9.6%.
Are There Identifiable Risk Factors for the Development of Symptomatic Cervical CASP?
Only 1 study reported on sex as a risk factor for CASP. Although women were at a slightly greater risk for developing cervical CASP, the difference was not statistically significant: 18.4% versus 16.2% (RR, 1.1; 95% CI, 0.5–2.6; P = 0.769)14 (Table 3).
Two studies investigated the role of age in the development of CASP and reported conflicting results. In 1 study, older age was highly correlated with CASP; the mean age of those in the CASP group was 64.5 years compared with only 41.5 years in the group without CASP (r2 = 0.994).13 In the second study, no statistically significant difference was determined between the mean ages of those who did and did not develop CASP (46.3 ± 6.2 yr vs. 50.1 ± 10.1 yr, respectively; P = 0.146)14 (Table 4).
Number of Levels Fused
Three studies evaluated whether the number of levels fused was a risk factor for CASP, with all the 3 reporting a greater risk with fewer number of levels fused, but only 1 reporting a statistically significant difference. Two studies compared single-level with multilevel fusion and reported risks of 17.6% versus 12.1% (RR, 1.5; 95% CI, 0.9–2.3; P = 0.12)13 and 18.2% versus 15.2% (RR, 1.2; 95% CI, 0.5–2.8; P = 0.68),14 respectively. In the third study, an almost 11-fold greater risk of CASP was noted in patients who underwent fusion of 3 or fewer levels compared with those who underwent fusion of 4 or more levels: 21.2% versus 2.0% (RR, 10.6; 95% CI, 1.42–78.9; P = 0.004)16 (Table 3).
Levels of Fusion
Three studies determined the level of fusion to be a significant risk factor for the development of CASP. In 1 study, compared with fusing either the top (C2–C3) or the bottom (C7–T1) of the cervical spine, the risk of developing CASP was almost 5 times greater when C5–C6 or C6–C7 were fused (13.3% vs. 2.8%; RR, 4.7; 95% CI, 2.2–10.0; P < 0.001) and 3 times greater when C3–C4 or C4–C5 were fused (8.7% vs. 2.8%; RR, 3.1; 95% CI, 1.4–6.7; P = 0.003).13 Similarly, another study reported a greater risk of CASP when either C5–C6 or C6–C7 and C3–C4 or C4–C5 were fused compared with C2–C3 or C7–T1; 11.1% and 11.9%, respectively, versus 0% (P = 0.027 and 0.019).14 The third study reported that patients with fusions excluding levels C5–C6 and/or C6–C7 (i.e., leaving them as an adjacent level) were at nearly 5 times the risk of developing CASP as those whose fusions included those levels: 25.8% versus 5.6% (RR, 4.6; 95% CI, 1.5–14.1; P = 0.007)16 (Table 3).
A variety of preoperative radiographical parameters were explored as possible risk factors for CASP. One study reported that the presence of disc protrusion (magnetic resonance imaging), indentation of dura mater (myelography), or a low-density area (T2-weighted magnetic resonance imaging) on preoperative imaging corresponded to a 2 to 3.5 times greater risk of developing CASP compared with absence of these findings, respectively14: 46.2% versus 13.1% (RR, 3.5; 95% CI, 1.6–7.6; P = 0.003), 38.9% versus 12.8% (RR, 3.0; 95% CI, 1.4–6.7; P = 0.007), and 30.0% versus 14.1% (RR, 2.1; 95% CI, 0.92–4.9; P = 0.087) (Table 3). The same study reported only the means of various preoperative radiographical measurements (alignment of the cervical spine, range-of-motion of the cervical spine and at the upper and lower adjacent levels, and the anteroposterior diameter of the spinal canal) between those with and without CASP and determined no significant differences in any factor between the 2 groups (Table 4). Another study also evaluated the anteroposterior diameter of the spinal canal between those with and without CASP and reported a statistically significant difference, with a smaller mean diameter in those with CASP15: 13 ± 0.6 mm versus 14 ± 0.3 mm (P = 0.04) (Table 4).
Are there identifiable risk factors for subsequent operation due to the development of CASP (Table 5)
One inpatient database study determined that younger age and male sex were significant risk factors for a secondary ACDF operation due to CASP.17 In patients aged 15 to 39 years and 40 to 59 years, the risk of a secondary ACDF operation was almost 1.5 times greater than those aged 60 years or older: adjusted HR = 1.45 (95% CI, 1.10–1.93; P = 0.009) and adjusted HR = 1.41 (95% CI, 1.13–1.75; P = 0.002), respectively. For men, the adjusted HR was 1.27 (95% CI, 1.07–1.52; P = 0.008) compared with women. Comorbidities, including diabetes mellitus, hypertension, cerebrovascular disease, and heart disease, as well as socioeconomical factors (analyzed by looking at insurance amount as a proxy for income and urbanization levels) were not determined to be significant risk factors for secondary ACDF operations due to CASP. Of note, heart disease and cerebrovascular disease, despite statistical insignificance, yielded relatively large adjusted HRs, which may warrant further clinical investigation.
One retrospective cohort study reported that patients with fusions excluding levels C5–C6 and C6–C7 were at a greater risk of a subsequent operation due to CASP compared with those who had fusions that included those levels16: 9.7% versus 0%; P = 0.026 (RR could not be calculated for this risk factor).
The overall strength of evidence estimating the absolute risk of CASP after cervical fusion is “low”; that is, we have low confidence in the absolute estimate and further research may change the estimate. With respect to risk factors, the overall strength of evidence is “moderate” that fusing adjacent to, but not including, the C5–C6 and/or C6–C7 disc spaces increases the risk of CASP after cervical fusion (we have moderate confidence that the evidence reflects the true effect). The overall strength of evidence is “low” that multiple levels of fusion reduce the risk of CASP, and “insufficient” that sex, age, or preoperative radiographical factors affect risk (the evidence does not permit a conclusion). The overall strength of evidence that men and younger age at the time of the index fusion increases the risk of “subsequent operation” due to CASP in patients undergoing cervical fusion is “moderate” (Table 6).
Despite there being many published studies defining the incidence of CASP as well as potential risk factors for the development of CASP in the cervical spine, this is the first attempt at a systematic review. The 5 studies that met our inclusion criteria included 4 retrospective cohort studies and 1 inpatient database study. Fortunately, the definition of CASP remained consistent through the 4 retrospective cohort studies but the 1 inpatient database study used reoperation as an endpoint and the definition of CASP was not quite as consistent as the others. Unfortunately, each of the studies measured different variables to define potential risk factors with the exception of the levels fused during the index procedure.
In an attempt to address our key question 1, which is to estimate the risk of CASP after cervical surgery, we determined that the prevalence of CASP ranged from 11% to 12% at 5 years and from 16% to 38% at 10 years. Two of the studies by Hilibrand et al13 and Ishihara et al14 reported a rate of 16% and 19.2%, respectively, with Komura et al16 reporting a rate of 38.1% at 10 years. Ishihara et al14 reported a 17-year rate of 33%. Hilibrand et al13 calculated an incidence rate of CASP of 2.9% per year. Of the 55 patients who developed CASP in this study, 46 were observed for at least 2 years. Of those 46 patients, 13 were treated nonoperatively and 33 required a reoperation. As discussed in the article by Hilibrand et al,13 this rate is very similar to the natural history of cervical spondylosis. In a study by Henderson et al,20 they observed 846 consecutively treated patients undergoing posterior laminoforaminotomy without fusion and reported a 5.2% rate of radicular symptoms at a second ipsilateral primary level after their index procedure at an average of 2.8-year follow-up (1.9% mean annual incidence). All these patients required a reoperation.
In an attempt to address our key question 2, which is to define the risk factors for developing CASP, we attempted to categorize risk factors based on: (1) patient factors, (2) surgical factors, and (3) radiographical factors. Because Wu et al17 used reoperation secondary to CASP as their endpoint, we categorized the findings into 2 separate tables (Tables 3 and 5). Patient factors that may contribute to the development of CASP include age more than 60 years, whereas sex does not seem to play a role. Surgical factors that may contribute to developing CASP include fusing adjacent to the C5–C6 and/or C6–C7 levels as well as fusions involving 3 or less segments when compared with 4 or more segments. The most consistent finding across multiple studies was fusing adjacent to but not including the C5–C6 and/or C6–C7 segments. Radiographical factors that may contribute to developing CASP include a pre-existing disc herniation and/or dural compression as well as having a smaller mean anteroposterior diameter spinal canal of 13 mm versus 14 mm.
When reviewing the factors that may predispose patients to developing CASP after cervical spinal surgery, it is important to note that several factors stand out and remain consistent throughout the literature. If the development of CASP was secondary to a pure iatrogenic effect of fusion causing increased stress on the adjacent and supra-adjacent levels, then the effects would likely occur at levels consistent throughout the cervical spine.
What has been noted in this systematic review is that the C5–C6 and C6–C7 levels portray the greatest risk of CASP, and these levels are the most likely to degenerate as part of natural history. Again, Henderson et al20 reported that the C5–C6 and/or C6–C7 levels made up 823 of 846 (97%) of their primary patients requiring a posterior laminoforaminotomy.20 In addition, if the C5–C6 and C6–C7 levels are included in the fusion, then the risk of CASP decreases significantly. Including these levels seems to be a more important prognostic factor than the number of levels fused. Also noted in this systematic review was that the risk of developing CASP is higher if 3 or fewer levels are fused versus 4 or more levels. If the development of CASP were purely a mechanical mechanism, then one would tend to believe that the more levels fused the higher impact that would have on the adjacent discs. More likely, the patients who undergo a fusion of 4 or more levels likely include the C5–C6 and C6–C7 disc spaces.
CASP remains a controversial topic despite multiple attempts of elucidating an iatrogenic effect of cervical spinal arthrodesis versus the natural history of spinal degeneration. The development of CASP is multifactorial, and spine surgeons must balance the biomechanical effects of performing a cervical fusion with the biology of cervical degeneration when counseling patients. With that said, there does seem to be a consistent rate of the development of degeneration in the spine after arthrodesis that ranges from 1.6% to 4.2%, which may be similar to the natural history of cervical degeneration. Performing an arthrodesis adjacent to but not including the C5–C6 and/or C6–C7 disc spaces seems to consistently increase the risk of developing CASP, and it seems as though these levels should be included in an arthrodesis construct if disc degeneration is pre-existing at 1 or both of these levels before the index procedure.
- The risk of developing new symptoms secondary to adjacent segment pathology causing radiculopathy and/or myelopathy after cervical fusion surgery ranges from a cumulative rate of 1.6–4.2% per year.
- Strength of Statement: Strong
- The risk of developing adjacent level symptoms may be increased if disc protrusion, disc degeneration or cord effacement is present at C5-6 and/or C6-7 and if those levels are adjacent to the planned surgical level.
- Strength of Statement: Strong
- CASP is estimated to occur between 1.6% and 4.2% per year after cervical arthrodesis.
- Reoperation rate for CASP is estimated to be 0.8% per year.
- Other factors that may predispose to the development of CASP include the following:
- Excluding the C5–C6 and/or C6–C7 levels at the time of the index surgery
- Pre-existing disc protrusion causing cord effacement
- Fusion constructs of 3 or fewer levels
- Age less than 60 years
The authors thank Ms. Nancy Holmes, RN, and Chi Lam, MS, for their administrative assistance.
The authors B.D.L., A.H., J.R.D., and D.S.B. contributed to the study in concept, interpretation, manuscript preparation, and manuscript revision; and EB: data analysis and interpretation, manuscript preparation, and manuscript revision.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.spinejournal.org).
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