Synovial Cyst as a Marker for Lumbar Instability: A Systematic Review and Meta-Analysis

Original Article

Synovial Cyst as a Marker for Lumbar Instability: A Systematic Review and Meta-Analysis Seba Ramhmdani1,2, Wataru Ishida2, Alexander Perdomo-Pantoja2, Timothy F. Witham2, Sheng-Fu L. Lo2, Ali Bydon1,2

BACKGROUND: The pathogenesis of synovial cysts is largely unknown; however, they have been increasingly thought of as markers of spinal facet instability and typically associated with degenerative spondylosis. We specifically investigated the incidence of concomitant synovial cysts with underlying degenerative spondylolisthesis.

require additional fusion surgery. The results from the present review lend credence to the argument that synovial cyst herniation might be a manifestation of an unstable spinal level.

METHODS: A literature search was performed using 4 online databases to assess the association between lumbar synovial cysts and degenerative spinal pathological features. Meta-analyses were performed on the prevalence rates of coexisting degenerative spinal pathological entities and treatment modalities. A random effects model was used to calculate the mean and 95% confidence intervals.

INTRODUCTION

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RESULTS: A total of 17 studies encompassing 824 cases met the inclusion criteria. The pooled prevalence rates of concurrent spondylolisthesis, facet arthropathy, and degenerative disc disease at the same level of the synovial cysts were 42.5% (range, 39.0%e46.1%), 89.3% (range, 79.0%e94.8%), and 48.8% (range, 43.8%e53.9%), respectively. Among these, patients with coexisting spondylolisthesis were more likely to undergo spinal fusion surgery (vs. laminectomy alone) and reoperation than were patients without spondylolisthesis with a pooled odds ratio of 11.5 (95% confidence interval, 4.5e29.1; P < 0.0001) and 2.0 (95% confidence interval, 0.9e4.2; P [ 0.088), respectively.

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CONCLUSIONS: Patients with a combination of synovial cysts and degenerative spondylolisthesis are more likely to undergo spinal fusion surgery than laminectomy alone compared with patients with synovial cysts and no preoperative spondylolisthesis. Furthermore, patients with synovial cysts and spondylolisthesis are more likely to

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Key words Degenerative disc disease - Facet arthropathy - Lumbar spondylosis - Spondylolisthesis - Synovial cyst -

From the 1Spinal Column Biomechanics and Surgical Outcomes Laboratory and 2Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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ynovial cysts are benign extradural lesions characterized by a synovium epithelium lining that contains clear or xanthochromic fluid.1 They exist as a herniation from the degenerative intervertebral facet joint capsule, most commonly in the lower lumbar spine, at the L4-L5 level.2 A synovial cyst that extends into the spinal canal can result in intractable back pain, radiculopathy, neurogenic claudication, and/or cauda equina syndrome.3 Although nonoperative management and spontaneous regression of synovial cysts have been previously reported,4 surgical excision remains the mainstay of treatment in the presence of unremitting symptoms or neurological deficits.3,5 Synovial cysts typically extend posterolaterally to the thecal sac, requiring hemilaminectomy or laminectomy for complete cyst excision. Some cases of synovial cysts will be accompanied by spondylolisthesis and require stabilization to surgically address the underlying instability. The pathogenesis of synovial cysts is largely unclear. Predominantly a disease of the elderly, synovial cysts can present simultaneously with other degenerative spinal pathological entities, most commonly facet joint osteoarthritis and, to a lesser degree, degenerative disc disease and degenerative spondylolisthesis.6,7 Segmental instability of the facet joints has been suggested to be an important factor in the etiology of synovial cysts.8 Furthermore, synovial cysts themselves have been considered markers of spinal instability because they disrupt a key component of the motion unit, the facet joints.9 To better understand the significance of this interchangeable association between lumbar synovial cysts and degenerative spinal diseases,

To whom correspondence should be addressed: Ali Bydon, M.D. [E-mail: [email protected]] Seba Ramhmdani and Wataru Ishida contributed equally to the present report. Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.10.228 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.

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specifically spondylolisthesis, we reviewed the reported data and discuss the findings of these reports. METHODS Literature Review A literature review was performed in compliance with the Preferred Reporting Items for Systematic Reviews and MetaAnalyses guidelines to identify all the studies describing the clinical characteristics of patients presenting with symptomatic lumbar synovial cysts. The purpose was to determine a relationship between the presence of synovial cysts and other degenerative spinal disorders, including spondylolisthesis, facet arthropathy, degenerative disc disease, and degenerative scoliosis. Our specific question focused on the incidence of synovial cysts at the same level of degenerative spondylolisthesis and whether the presence of the synovial cyst affected the treatment plan or clinical outcomes. We used 4 databases (MEDLINE, EMBASE, Scopus, and Web of Science) to identify relevant reports from 1970 to

Figure 1. Flow diagram depicting the literature review, search strategy, and selection process using the

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August 2018. The literature search strategy is summarized in Figure 1. To achieve maximum sensitivity, we searched the following terms through the PubMed portal: synovial cyst[MeSH Terms] OR synovial cyst[Title] OR ganglion cyst[MeSH Terms] OR ganglion cyst[Title] OR juxtafacet cyst[MeSH Terms] OR juxtafacet cyst[Title] AND lumbar. We limited our search to studies reported in the English language and focusing on human subjects. Other databases were systematically searched using the same criteria. A total of 411 citations were found, and abstracts summaries of the reports were screened by 2 independent reviewers, followed by whole article review for related studies. The references of these publications were also manually searched to retrieve more studies. Inclusion/Exclusion Criteria and Data Collection For all relevant studies, we documented the patient characteristics, symptom duration, spinal levels synovial cysts, spinal level and grade of spondylolisthesis, treatment modalities, surgery types performed, and patients’ clinical outcomes. We also recorded the

Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

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rate of reported facet joint arthropathy and degenerative disc disease. The presence of degenerative spinal conditions was determined from the radiographic images. We excluded those reports that had not described the patient characteristics, radiological findings, treatment methods, and/or outcomes (n ¼ 47). We also excluded those reports with a heterogeneous population (n ¼ 28).10-13 Finally, we excluded case series and reports with <5 patients reported (n ¼ 3), which yielded 17 reports.1,3,5,8,14-26 The quality of each study was evaluated using the National Heart, Lung, and Blood Institute Study Quality Assessment Tools.27 The data were extracted from the studies’ texts, tables, and figures. The final results were reviewed by 1 of us (A.B.). Statistical Analysis Statistical analyses were performed using Comprehensive MetaAnalysis Software, version 3 (Biostat, Edgewood, New Jersey, USA). Initially, a meta-analysis of the data from the 17 reports was performed to estimate the overall pooled rates of the concomitant spine diseases (i.e., spondylolisthesis, facet arthropathy, disc degenerative disease) associated with synovial cysts, with the 95% confidence intervals. A fixed effect model was used for this portion of the meta-analysis. Additionally, to investigate the correlation between the preoperative diagnosis of spondylolisthesis and the decision to perform spinal fusion procedures instead of decompression alone, we calculated the pooled odds ratio and 95% confidence intervals, assuming a random effect.

The heterogeneity was calculated using the I2 statistics.28 I2 values <25% were considered to indicate low heterogeneity, 25%e75%, moderate heterogeneity, and >75%, severe heterogeneity.28 Finally, the presence of a publication bias was assessed by drawing funnel plots for each outcome of interest. The classic fail-safe N test was conducted, and P values were obtained.29 The effect size was calculated using logit event rates [¼log(prevalence/ (1  prevalence))] for the disease prevalence comparison and a log odds ratio was used to evaluate the relationship between the presence of spondylolisthesis and fusion surgery. Additionally, Duval and Tweedie’s trim and fill test was performed to determine the number of potentially missing reports and the adjusted fusion rates.30 All reported P values were 2-sided, and P < 0.05 was considered to indicate statistical significance in all analyses. RESULTS The literature review yielded 17 studies encompassing 824 cases of synovial cysts (Figure 1).1,3,5,8,14-26 As summarized in Table 1, all the studies were retrospective case series with a clinical evidence level of IV. Using the National Institutes of Health’s Study Quality Assessment Tools, the study qualities of the 17 studies were rated as follows: 8 were “good” quality,3,5,14,19-21,25,26 8 were “fair” quality,1,8,15-18,22,23 and 1 “poor” quality.24 The number of patients included in each study varied widely from 8 to 194. Of the 824 patients, 346 (42.0%) were found to have concurrent

Table 1. Summary of Baseline Characteristics of 17 Included Studies Study Design

Investigator

Study Quality

Clinical Evidence

Patients (n)

Preoperative Spondylolisthesis

FA

DDD

Lyons et al.,20 2000

RCS

Good

IV

194

97 (66.0)

NR

89 (60.5)

Xu et al.,3 2010

RCS

Good

IV

167

53 (32.9)

NR

14 (8.4)

RCS

Good

IV

80

35 (43.8)

NR

NR

Métellus et al., 2006

RCS

Good

IV

77

37 (48.1)

77 (100.0)

57 (74.0)

Sabo et al.,8 1996

RCS

Fair

IV

56

15 (26.7)

56 (100.0)

7 (12.5)

25

Epstein,

2004 19

5

Weiner et al., 2007

RCS

Good

IV

46

23 (50.0)

NR

23 (50.0)

Khan et al.,21 2005

RCS

Good

IV

39

32 (82.1)

NR

22 (56.4)

Deinsberger et al.,26 2006

RCS

Good

IV

31

14 (45.2)

31 (100.0)

NR NR

16

Sehati et al., 2006

RCS

Fair

IV

19

2 (10.5)

NR

Trummer et al.,14 2001

RCS

Good

IV

19

6 (31.6)

NR

Tillich et al., 2001

RCS

Fair

IV

18

6 (33.3)

18 (100.0)

18 (100.0)

Sandhu et al.,17 2004

RCS

Fair

IV

17

8 (47.1)

NR

NR

RCS

Fair

IV

16

9 (56.3)

NR

NR

Ganau et al., 2013

RCS

Fair

IV

15

2 (13.3)

15 (100.0)

NR

Jankowski et al.,22 2012

RCS

Fair

IV

11

1 (9.1)

6 (54.5)

NR

15

James et al.,

23

2012

1

18

3 (15.8)

Oertel et al., 2017

RCS

Fair

IV

11

4 (36.4)

10 (90.9)

NR

Indar et al.,24 2004

RCS

Poor

IV

8

2 (25.0)

NR

NR

Data presented as n (%). FA, facet arthropathy; DDD, degenerative disc disease; RCS, retrospective case series; NR, not reported.

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Figure 2. Meta-analysis of the prevalence of concurrent spondylolisthesis at the same level as the synovial cysts.

spondylolisthesis preoperatively. A combination of spondylolisthesis and synovial cysts was most frequently found at the L4-L5 level (72.3%), followed by L3-L4 (13.7%) and L5-S1 (12.2%). In addition, 8 cases of synovial cysts were reported at L2-L3 and 1 at L1-L2. Patient Characteristics The average age ranged from 49 to 82 years (median, 65). Of the 824 patients, 433 were women (53%) and 391 were men (47%). The symptom duration before treatment varied widely from 3 to 48 months (median, 12). The most common symptoms were radiculopathy in 77.6% of cases (625 of 824), back pain in 75.3% (426

of 565), neurological deficit (including paresthesia, weakness, and cauda equina syndrome) in 55.9% of cases (451 of 807), and neurogenic claudication in 35.4% of cases (273 of 771). Prevalence of Degenerative Spinal Diseases Concomitant with Synovial Cysts The overall pooled prevalence rates of the concurrent spine diseases associated with synovial cysts, spondylolisthesis, facet joint arthropathy, and degenerative disc disease were as follows: 42.5% (range, 39.0%e46.1%; I2 ¼ 71.8; Figure 2), 89.3% (range, 79.0%e94.8%; I2 ¼ 72.5; Figure 3), and 48.8% (range, 43.8%e53.9%; I2 ¼ 89.0; Figure 4).

Figure 3. Meta-analysis of the prevalence of concurrent facet arthropathy.

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Figure 4. Meta-analysis of the prevalence of concurrent degenerative disc disease.

Treatment Modalities For comparison purposes, the 824 patients were divided into 2 groups: 478 patients (58.0%) had presented with lumbar synovial cysts without preoperative spondylolisthesis (group A) and 346 patients (42.0%) had presented with a combination of synovial cysts and preoperative spondylolisthesis (group B). Conventional laminectomy was performed in 445 patients (93.1%) in group A and 230 patients (66.5%) in group B. Decompression with fusion was performed in 33 patients (6.9%) in group A and 116 patients (33.5%) in group B (Table 2). In the meta-analysis, the use of these 2 procedures differed significantly between the 2 groups. The odds ratio of group B receiving spinal fusion surgery compared with group A was 11.5 (95% confidence interval, 4.5e29.1; P < 0.0001; I2 ¼ 26.8; Figure 5).

prevalence of spondylolisthesis, facet joint arthropathy, and degenerative disc disease) and the rate of performing fusion surgery on patients with preoperative spondylolisthesis revealed no suggested publication biases (P < 0.001 for each). Duval and Tweedie’s trim and fill tests demonstrated that 4 studies could have been missed, which would have increased the pooled prevalence of spondylolisthesis from 42.5% to 43.7% (Figure 7A), 2 missing studies, which would have reduced the pooled prevalence of facet arthropathy from 89.2% to 86.1% (Figure 7B), and 3 missing articles, which would have increased the odds ratio of patients with spondylolisthesis receiving fusion procedures versus those without from 11.5 to 17.1 (Figure 7D).

Surgical Outcomes The average follow-up period ranged from 10.5 to 116.4 months (median, 21). In group A, new-onset instability necessitating reoperation was reported in 7 patients (1.7%).8,20,25 In group B, 15 patients (4.4%) underwent a second operation, either decompression alone or decompression plus fusion because of worsening spondylolisthesis (n ¼ 11) or adjacent level disease (n ¼ 4). Moreover, postoperative radiographic worsening of spondylolisthesis after decompressive laminectomy alone for synovial cyst resection was found in 23 patients (6.7%), with grade 2 spondylolisthesis in 2 patients. The odds ratio of group B undergoing a second operation after initial surgery compared with group A was 2.0 (95% confidence interval, 0.9e4.2; P ¼ 0.088; I2 ¼ 8.2; Figure 6).

Synovial cysts, also known as juxtafacet cysts or ganglion cysts, are commonly found in the articular regions of the facet joints and, less frequently within the ligamentum flavum and interspinous ligaments.8,31 Both synovial cysts and ganglion cysts have similar clinical presentations, radiographic features, and treatment indications and only differ histopathologically.32 Synovial cysts are lined with synovial epithelium, which is connected to the capsule and commonly consists of granulation tissue.32,33 In contrast, ganglion cysts develop from the periarticular connective tissues that undergo a myxoid degeneration and generally have no connection with the synovium.33 The underlying pathophysiology of the synovial cysts, although still unclear, appears to be related to degenerative changes in the facet joints consistent with repetitive microtrauma.3,34 This process leads to a gradual thinning of the joint capsule and subsequent rupture of its wall through the structural weakness. Local inflammation and mesenchymal cell proliferation with activation of proinflammatory mediators (i.e., cytokines, chemokines,

Publication Bias The funnel plots of each outcome of interest are shown in Figure 7. The classic fail-safe N test for each variable (the

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Table 2. Summary of the Treatment Options and Surgical Outcomes Laminectomy Only

Investigator

Laminectomy Plus Fusion

Fusion in Group A (No Preoperative Spondylolisthesis)

Fusion in Group B (With Preoperative Spondylolisthesis)

Follow-Up (Months)

Lyons et al.,20 2000

176 (90.7)

18 (9.3)

0 (0.0)

18 (18.6)

26

3

Xu et al., 2010

90 (53.9)

74 (44.3)

32 (28.1)

42 (79.2)

16

Epstein,25 2004

80 (100.0)

0 (0.0)

0 (0.0)

0 (0.0)

13

77 (100.0)

0 (0.0)

0 (0.0)

0 (0.0)

45

19

Métellus et al., 2006 8

Sabo et al., 1996

48 (85.7)

7 (12.5)

1 (2.4)

6 (40.0)

NR

Weiner et al.,5 2007

46 (100.0)

23 (50.0)

0 (0.0)

23 (100.0)

116.4

Khan et al.,21 2005

13 (33.3)

26 (66.7)

0 (0.0)

26 (81.3)

26

Deinsberger et al.,26 2006

31 (100.0)

0 (0.0)

0 (0.0)

0 (0.0)

21

19 (100.0)

0 (0.0)

0 (0.0)

0 (0.0)

16

19 (100.0)

0 (0.0)

0 (0.0)

0 (0.0)

22.7

18 (100.0)

0 (0.0)

0 (0.0)

0 (0.0)

NR

17 (100.0)

0 (0.0)

NR

NR

13

16 (100.0)

0 (0.0)

NR

NR

18

15 (100.0)

0 (0.0)

0 (0.0)

0 (0.0)

28

1 (100.0)

16

Sehati et al., 2006 Trummer et al.,

14

2001

Tillich et al.,15 2001 Sandhu et al.,

17

2004

James et al.,23 2012 1

Ganau et al., 2013 22

Jankowski et al., 2012

11 (100.0)

1 (9.1)

0 (0.0)

Oertel et al.,18 2017

11 (100.0)

0 (0.0)

NR

NR

10.5

12

Indar et al.,24 2004

8 (100.0)

0 (0.0)

0 (0.0)

0 (0.0)

23.7

Data presented as n (%). NR, not reported.

growth factors) follow. Eventually, a synovial cyst will form and fill with a serous fluid or will calcifies.34 Some factors are thought to accelerate this process, including older age, physical trauma, rheumatoid arthritis, and any other osteoarthritic disease that affects the facet joints.12,15 The frequent association of degenerative joint diseases and synovial cysts might further support this theory.15 Our literature review, which demonstrated that synovial cysts are likely to present with facet joint osteoarthritis, with a pooled prevalence rate of 89.3%, is in accordance with the findings from Doyle and Merrilees,6 who reported a 100% prevalenc6e of facet joint osteoarthritis at the same level of synovial cysts found on 303 magnetic resonance imaging scans of the lumbar spine. More importantly, Doyle and Merrilees6 found a significant increase in the incidence and severity of both facet joint arthritis and degenerative spondylolisthesis in patients with synovial cysts compared with those without. Associated and/or concurrent spondylolisthesis with synovial cyst herniation was reported in 43% and 45% of cases in previous reports,7,26,35 and the pooled prevalence rate was 42.5% in our meta-analysis. This association was first described in a case report by Reust et al.36 in 1988. Nevertheless, the relationship between the presence of synovial cysts and degenerative spondylolisthesis is uncertain in terms of which entity leads to the other.9 The facet joints are a major component of spinal motion segment and, therefore, are subject

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to degenerative changes as a result of the aging process, physical activity, repetitive mechanical stress, and other factors. An unstable motion segment can occur in the setting of weakened facet joints, which will, ultimately, lead to anterior slippage of the superior vertebrae. Moreover, the presence of synovial cysts might accelerate the ongoing degenerative process of the facet joint, leading to mechanical compensation failure and the development of spondylolisthesis. Facet joint arthropathy is linked to translatory instability, leading to anterior displacement of the lumbar spine motion segment.37 In line with this hypothesis, most reported cases of synovial cyst with spondylolisthesis have been noted to occur at the most mobile segment of the spine, L4-L5.38 This finding was replicated in our study, with 72% of cases reported at the L4-L5 level. Further strengthening this theory is that most patients had coexisting facet joint arthropathy and were aged >50 years, with a slight female sex predominance. In the absence of neurological findings, synovial cysts can be treated conservatively with anti-inflammatory medications, analgesic agents, physical therapy, computed tomography-guided cyst aspiration, and epidural steroid injections.10,13,39 However, surgical resection is considered to be the mainstay treatment of symptomatic juxtafacet cysts with greater effectiveness than nonoperative modalities.3,13,40 In a recent meta-analysis, Shuang et al.41 reviewed 29 reported studies to investigate the clinical outcomes of patients with synovial cysts treated nonoperatively.

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Figure 5. Meta-analysis of the odds ratio of patients with spondylolisthesis undergoing fusion procedures compared with those without.

They found that 38.7% of the patients who had undergone percutaneous synovial cyst procedures experienced treatment failure and, ultimately, required a surgical intervention.

Fusion can be considered when instability is suspected, either clinically (back pain) or radiographically (widened facet joints gap, increased fluids within the facet joints, and spondylolisthesis). In a series of 194 patients reported by Lyons et al.,20

Figure 6. Meta-analysis of the odds ratio of patients with spondylolisthesis undergoing second surgeries compared with those without.

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Figure 7. Funnel plots for each primary outcome of interest: the prevalence of (A) spondylolisthesis, (B) facet joint arthropathy, and (C) degenerative disc disease. (D) The odds ratio for patients with spondylolisthesis receiving fusion procedures compared with those without. White plots and

18 had required spinal fusion at the first surgery and 4 had required a second operation with stabilization because of postoperative spondylolisthesis at the 6-month follow-up examination. In the series reported by Epstein,25 of 80 patients with lumbar synovial cysts who had undergone surgical decompression without fusion initially, 11 showed new-onset or worsening spondylolisthesis, 8 of whom required fusion surgery. Our meta-analysis showed that patients presenting with a combination of a synovial cyst and spondylolisthesis were more likely to undergo fusion surgery initially (odds ratio, 11.5; P < 0.0001) and subsequent reoperation (odds ratio, 2.0; P ¼ 0.088) because of lumbar instability. However, the limited data available are insufficient to compare the 2 groups of patients in terms of the reported clinical outcomes. However, it is important to highlight that 6 cohort studies in the present review, with a total number of 554 cases and an average of 1 year of follow-up, found no statistically significant differences in the patient-reported outcomes according to a preoperative diagnosis of spondylolisthesis.3,5,19-21,26

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rhomboid represent each study included and the observed pooled value, respectively; black dots and rhomboid represent studies that might have been missed and the adjusted pooled value, respectively.

Study Limitations Finally, one must acknowledge that with all meta-analysis studies, the patient populations were subject to heterogeneity in patient characteristics and surgical outcomes. Although we primarily minimized this bias during the initial screening process by excluding studies that reported differing presenting symptoms, disease etiologies, and comorbidities, the heterogeneities of the primary outcomes such as the prevalence rates of spondylolisthesis, facet arthropathy, and degenerative disc disease in the present meta-analysis were moderately high, with I2 values of 71.8, 72.5, and 89.0, respectively (Figures 2e4). This result might potentially suggest that the diagnostic criteria for these concurrent lumbar pathologic entities varied across the 17 studies, and other underlying mechanisms could have been involved in the pathophysiology of synovial cysts. Nonetheless, we demonstrated minimal heterogeneity in the patients’ treatment outcomes, because the I2 values of the association between preoperative spondylolisthesis and the use of fusion procedures (Figure 5) and between preoperative spondylolisthesis and the

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reoperation rate (Figure 6) were 26.2 and 8.2, respectively. The publication bias in the present meta-analysis was minimal, as shown by the fail-safe N test, further supporting the results of our study. These findings strengthen the generalizability and clinical relevance of the present review. The Duval and Tweedie trim and fill test results suggested that the true prevalence of concurrent spondylolisthesis and facet arthropathy might have been slightly greater (43.7%) and lower (86.1%), respectively, than the pooled rates we have reported (42.5% and 89.2%; Figure 7A and B) and that the odds ratio of group B receiving fusion procedures compared with group A might have been greater than the pooled odds ratio described (increase from 11. 5 to 17.1; Figure 7D), which could further support our findings. Finally, the 17 included studies were all retrospective case series with a clinical level of evidence of IV, which could have potentially biased the results of the meta-analyses. Nonetheless, our meta-analysis represents the first and largest review focusing on the presence of degenerative spondylolisthesis

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concurrent with synovial cysts and reporting on the surgical outcomes of this unique and rare entity. CONCLUSIONS Synovial cysts are associated with other degenerative diseases of the spine, most commonly facet joint arthropathy, spondylolisthesis, and degenerative disc disease. From our review of the reported data, patients with a combination of synovial cysts and degenerative spondylolisthesis are more likely to undergo spinal fusion versus laminectomy alone compared with patients with synovial cysts and no preoperative spondylolisthesis. Furthermore, patients with synovial cysts and spondylolisthesis are more likely to require an additional fusion procedure. The present review represents evidence of the destabilizing effect of synovial cyst herniation on the facet joints. It is reasonable to consider synovial cysts in certain cases as markers of instability.

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Conflict of interest statement: T.W. is a recipient of a research grant from the Gordon and Marilyn Macklin Foundation and Eli Lilly Company. S.L. is a recipient of a research grant from the AO Foundation and the Chordoma Foundation. The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 7 September 2018; accepted 29 October 2018 Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.10.228 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.

WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.10.228