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. 2020 Nov 18;12(5):829–839. doi: 10.1177/2192568220966328

High-Intensity Zones on MRI of the Cervical Spine in Patients: Epidemiology and Association With Pain and Disability

Austin Q Nguyen 1, Garrett K Harada 1, Kayla L Leverich 1, Krishn Khanna 1, Philip K Louie 1, Bryce A Basques 1, Youping Tao 1, Fabio Galbusera 1,2, Frank Niemeyer 1,3, Hans-Joachim Wilke 1,3, Howard S An 1, Dino Samartzis 1,✉
PMCID: PMC9344501  PMID: 33203250

Abstract

Study Design:

Retrospective cohort study.

Objectives:

This study aimed to address the prevalence, distribution, and clinical significance of cervical high-intensity zones (HIZs) on magnetic resonance imaging (MRI) with respect to pain and other patient-reported outcomes in the setting of patients that will undergo an anterior cervical discectomy and fusion (ACDF) procedure.

Methods:

A retrospective cohort study of ACDF patients surgically treated at a single center from 2008 to 2015. Based on preoperative MRI, HIZ subtypes were identified as either traditional T2-hyperintense, T1-hypointense (“single-HIZs”), or combined T1- and T2-hyperintense (“dual-HIZs”), and their level-specific prevalence was assessed. Preoperative symptoms, patient-reported outcomes, and disc degeneration pathology were assessed in relation to HIZs and HIZ subtypes.

Results:

Of 861 patients, 58 demonstrated evidence of HIZs in the cervical spine (6.7%). Single-HIZs and dual-HIZs comprised 63.8% and 36.2% of the overall HIZs, respectively. HIZs found outside of the planned fusion segment reported better preoperative Neck Disability Index (NDI; P = .049) and Visual Analogue Scale (VAS) Arm (P = .014) scores relative to patients without HIZs. Furthermore, patients with single-HIZs found inside the planned fusion segment had worse VAS Neck (P = .045) and VAS Arm (P = .010) scores. In general, dual-HIZ patients showed no significant differences across all clinical outcomes.

Conclusions:

This is the first study to evaluate the clinical significance of HIZs in the cervical spine, noting level-specific and clinical outcome–specific variations. Single-HIZs were associated with significantly more pain when located inside the fusion segment, while dual-HIZs showed no associations with patient-reported outcomes. The presence of single-HIZs may correlate with concurrent spinal pathologies and should be more closely evaluated.

Keywords: high-intensity zones, HIZ, disc, MRI, neck pain, cervical, degenerative, disease, low back pain

Introduction

Various magnetic resonance imaging (MRI) phenotypes of the spine have been associated with clinical symptoms and outcomes.1-4 High-intensity zones (HIZs) are a specific spinal imaging phenotype that may have implications on the development of discogenic pain.5-10 HIZs have been largely studied in the lumbar spine and have been traditionally characterized as focal T2-weighted hyperintensities in the posterior annulus of the intervertebral disc on MRI. 11 Aprill and Bogduk 12 originally described this phenomenon in 1992, where identification of an HIZ had an 86% positive predictive value for a painful annulus disruption. Subsequent histological studies of HIZs in the lumbar spine appear to support this hypothesis, having identified vascularized granulation tissue in the outer region of the annulus fibrosus, suggestive of a healing response to annular disruption.8,13-15

In a recent systematic review, Teraguchi et al 4 assessed associations between low back pain and lumbar HIZs, noting no conclusive relationship could be inferred due to small sample sizes, heterogeneous populations, and unclear imaging methodology. This suggests the relationship between HIZs and patient symptomatology may not be as concrete as proposed by Aprill and Bogduk, 12 but rather, may represent an understudied entity with unclear clinical value.16-18 Furthermore, outside of the thoracolumbar spine, little is known about HIZs, with a gross paucity of studies having specifically examined the cervical intervertebral segments. In practice, HIZs are frequently identified in the cervical spine, and it is unclear if these imaging findings may lead to similar associations with axial neck pain and/or patient-reported outcomes before and after surgery.

As other studies have reported HIZs in asymptomatic cohorts, some investigators have begun to question whether different subtypes of HIZs exist.4,19-21 For example, a recent study examined lumbar HIZs on both T1- and T2-weighted MRI, noting 2 distinct HIZ phenotypes: a traditional T2-intense and T1-hypointense “single-HIZ” and another T1- and T2-intense “dual-HIZ.”8,22 They further reported a significant difference in the patients’ pain response associated with each subtype, noting that dual-HIZs were generally less symptomatic, and may represent calcified or ossified tissues in contrast to the annular disruption that is observed in the conventional single-HIZ. In addition, a population-based cohort study by Teraguchi et al 23 evaluated the lumbar spine MRIs of 1214 volunteer subjects. Of these individuals, 59% had HIZ and 41% did not. The study noted that specific patterns of HIZ were more associated with the development and severity of low back pain than others. However, whether similar HIZ patterns exist in the cervical spine remains unknown.

According to recent Global Burden of Disease studies, neck pain is considered one of the world’s most disabling conditions.24,25 Patients seeking medical consultation for cervical spine–related ailments is not uncommon and can have detrimental socioeconomic consequences to many stakeholders. Therefore, understanding pain generators is critical. With respect to HIZs located in the cervical spine, their manifestation and clinical relevance remains largely unknown. As such, the main purpose of this study was to characterize the prevalence and distribution of HIZs on MRI in the cervical spine in patients with degenerative cervical conditions indicated for an anterior cervical discectomy and fusion (ACDF) and to assess the nature of dual-HIZs and how they may clinically manifest in comparison to the traditional single-HIZ.

Methods

This was a retrospective cohort study of all patients indicated and surgically treated for an ACDF at a single academic institution from 2008 to 2015. Patients were deemed eligible for study if preoperative T1- and T2-weighted MRI studies of the cervical spine were obtainable, and proper visualization of HIZs could be made. Patients were excluded if they were undergoing surgery for the treatment of a tumor, trauma, or infection, and/or if the patient was under 18 years of age at the time of operation.

Patients’ medical records were reviewed for demographics including age, body mass index (BMI), sex, smoking history, and ageless Charlson Comorbidity Index (CCI). The CCI is a well-validated metric that estimates 10-year mortality risk based upon a list of baseline medical comorbidities. 26 Baseline clinical and operative characteristics such as preoperative symptomatology (radiculopathy, myelopathy, myeloradiculopathy, neck pain, arm pain, sensory deficits, and weakness) duration of preoperative symptoms (months) and number of fused vertebral levels were collected.

Both T1- and T2-weighted MRI studies of the cervical spine were assessed for presence of HIZs throughout C2-T1, with documentation of the overall number, intervertebral disc level, location (anterior or posterior) within the disc, and location of HIZs in relation to the planned operative levels. Single-HIZs were identified as conventional T2-weighted signal intensities while dual-HIZ subtypes were identified as combined T1- and T2-weighted hyperintensity findings (Figure 1). HIZ subtype and location stratifications were subsequently assessed for association with baseline symptomatology and preoperative patient-reported outcomes (Neck Disability Index [NDI], Visual Analog Scale [VAS] Neck, VAS Arm).

Figure 1.

Figure 1.

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T1- and T2-weighted images of single- and dual-HIZ subtypes. (a, a*) T1-weighted image (left) without evidence of a HIZ, and corresponding T2-weighted image (right) with a single-HIZ in the posterior annulus of C5-C6 (arrow). (b, b*) T1-weighted image (left) showing the distinct morphology and intensity of a dual-HIZ in the anterior annulus of C6-C7 (arrow), with corresponding T2-weighted image (right) depicting a similar lesion (arrow).

A secondary analysis was performed to determine association of HIZs and their subtypes with concurrence of other disc pathologies (disc degeneration, disc space narrowing, disc displacement) overall and at the same cervical vertebral levels. Degenerative discs were identified as Pfirrmann Grade V hypointense black discs on T2-weighted MRI. 27 This designation was used to promote inter- and intraobserver reliability, so as to prevent ambiguity when presented with partially degenerated disc imaging findings. Disc space narrowing was defined as a 30% decrease in disc height relative to adjacent healthy disc spaces. Last, disc displacement was measured if protrusion of disc material was observed either anteriorly or posteriorly at a given intervertebral level. Three readers independently assessed all images, and after a short training period, intra- and interobserver reliability was deemed to be good to excellent (intraclass coefficient constant [ICC] > 0.80). ICC cutoffs were established as ≤0.50 for poor reliability, 0.51 to ≤0.74 for moderate, 0.75 to 0.89 for good, and ≥0.90 for excellent. 28

Statistical Analysis

The collected data was analyzed using the statistical software STATA version 15.1 (StataCorp). Continuous baseline variables are reported as mean ± standard deviation (SD). Baseline patient demographics and operative characteristics were compared using 2-way t tests and χ2 analysis for continuous and categorical outcome variables, respectively. Multivariate logistic regression was used to determine the association of preoperative cervical HIZs with baseline patient symptomatology and degenerative disc pathology. Multivariate linear regression was used to assess the relationship with patient-reported outcomes. Statistical models were built by incorporating all baseline demographic and operative characteristics in addition to the HIZ variable to be examined. Beta coefficients, odds ratios (ORs), and corresponding 95% confidence intervals (CIs) were also assessed for each covariate within multivariate linear and logistic regression. A P value of <.05 was used to determine statistical significance.

Results

A total of 861 patients indicated for an ACDF for degenerative pathology with a preoperative cervical MRI were identified from 2008 to 2015. The incidence of patients with HIZs within this surgical cohort was 6.7% (58/861). There were no demographic differences observed between either cohort (Table 1).

Table 1.

Baseline Patient Demographic and Operative Characteristics.

HIZ No HIZ P value
#/Mean %/(SD) #/Mean %/(SD)
Overall total 58 6.86 803 93.14
Demographics
 Age 52.47 (12.15) 52.50 (11.29) .980
 BMI 28.70 (6.23) 29.13 (6.19) .624
 Female sex 24 41.4 382 47.99 .330
 Current smoker 5 9.62 104 15.25 .271
 CCI 1.18 (1.81) 0.92 (1.48) .235
Operative
 Duration of preoperative symptoms (months) 27.15 (40.35) 22.22 (36.55) .338
 Number of vertebral levels fused 1.90 (0.88) 1.90 (0.75) .972
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Abbreviations: HIZ, high-intensity zone; BMI, body mass index; CCI, Charlson Comorbidity Index.

Within the 861 patients, 58 patients had HIZs. When stratifying by HIZ subtype, the incidence of single-HIZs and dual-HIZs was 63.8% and 36.2%, respectively. Patients with dual-HIZs were significantly older, with a mean age of 57.1 ± 11.8 years when compared to single-HIZ patients, with a mean age of 49.9 ± 11.7 years (P = .029). No other demographic differences were observed between HIZ subtypes (Table 2).

Table 2.

Baseline Patient Demographic and Operative Characteristics.

Single-HIZ Dual-HIZ P value
#/Mean %/(SD) #/Mean %/(SD)
Overall total 37 63.79 21 36.21
Demographics
 Age 49.86 (11.71) 57.05 (11.82) .029
 BMI 28.23 (6.64) 29.57 (5.45) .468
 Female sex 16 43.24 8 38.1 .702
 Current smoker 4 11.76 1 5.56 .47
 CCI 1.09 (1.91) 1.33 (1.68) .659
Operative
 Duration of preoperative symptoms (months) 23.01 (21.90) 34.60 (61.14) .308
 Number of vertebral levels fused 1.90 (0.88) 1.89 (0.90) .967
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Abbreviations: HIZ, high-intensity zone; BMI, body mass index; CCI, Charlson Comorbidity Index.

Bolded values indicate statistical significance with p < 0.05.

In regard to specific location, most HIZs were seen in the posterior annulus (45/58; 78.0%) and outside the operative segment (34/58; 58.6%). The greatest number of overall HIZ observations was seen at C4-C5 (16/58; 27.6%), and C6-C7 (16/58; 27.6%), followed by C5-C6 (13/58; 22.4%). The fewest HIZs were observed at C2-C3 (2/58; 3.45%) and C7-T1 (1/58; 1.7%). Dual-HIZs were more frequently found in the anterior annulus (9/21 = 42.9%) when compared to single-HIZs (4/37 = 10.8%). Conversely, single-HIZs were more frequently observed in the posterior annulus (33/37 = 89.2%) than dual-HIZs (12/21; 57.1%). A similar distribution was observed between single- and dual-HIZ cohorts along the length of the cervical spine, with the greatest number observed between C3-C7 (single-HIZ: 35/37, 94.6%; dual-HIZ: 20/21; 95.2%; Table 3). The distribution of HIZs by cervical vertebral level are illustrated graphically in Figure 2.

Table 3.

Distribution and Location of High-Intensity Zones.

HIZ Single-HIZ Dual-HIZ P valuea
# % # % # %
Disc location
 Anterior 13 22.41 4 10.81 9 42.86 .005
 Posterior 45 77.59 33 89.19 12 57.14 .005
Relation to operative level(s)
 Inside operative level(s) 24 41.37 15 40.54 9 42.86 .863
 Outside operative level(s) 34 58.62 22 59.46 12 57.14 .863
Cervical vertebral level
 C2-C3 2 3.45 1 2.70 1 4.76 .680
 C3-C4 10 17.24 5 13.51 5 23.80 .318
 C4-C5 16 27.59 10 27.03 6 28.57 .899
 C5-C6 13 22.41 9 24.32 4 19.05 .643
 C6-C7 16 27.59 11 29.73 5 23.80 .628
 C7-T1 1 1.72 1 2.70 0 0.00 .447
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Abbreviation: HIZ, high-intensity zone.

a Calculation of P values was performed using χ2 test. Bolded values indicate statistical significance at P < .05.

Figure 2.

Figure 2.

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Distribution of high-intensity zones (HIZs) by cervical intervertebral level. X-axis = Count data for number of HIZs observed per level; Y-axis = Cervical intervertebral level.

Evaluating preoperative symptomatology and patient-reported outcomes, HIZs were generally associated with better outcomes when found outside of the planned fusion segment. Specifically, patients reported better preoperative NDI (P = .049; Coeff. = −11.63; 95% CI: −23.2 to 0.04) and VAS Arm (P = .014; Coeff = −2.56; 95% CI: −4.60 to −0.53) scores relative to patients without HIZs. However, when stratified by HIZ subtype, patients with single-HIZs within the fusion segment were found to have significantly worse VAS Neck (P = .045; Coeff. = 3.34; 95% CI: 0.07 to 6.60) and VAS Arm (P = .010; Coeff. = 4.90; 95% CI: 1.20 to 8.60) scores compared to patients without HIZs. Interestingly, dual-HIZ patients did not demonstrate any significant differences relative to patients without HIZs across all patient-reported outcomes. There was no association with preoperative symptoms with HIZs or HIZ subtypes (Table 4).

Table 4.

Multivariate Analyses of High-Intensity Zones With Preoperative Symptoms and Patient-Reported Outcomes.a

No stratification Anterior Posterior Inside fusion segment Outside fusion segment
Beta/OR 95% CI P value Beta/OR 95% CI P value Beta/OR 95% CI P value Beta/OR 95% CI P value Beta/OR 95% CI P value
HIZ
Preoperative symptom
 Radiculopathy 1.26 0.25-6.40 .784 0.52 0.08-3.4 .488 — — — 0.73 0.13-4.30 .729 — — —
 Myelopathy 1.23 0.43-3.50 .695 2.11 0.47-9.5 .327 0.77 0.17-3.50 .738 0.79 0.15-4.00 .773 1.77 0.48-6.60 .394
 Myeloradiculopathy 1.32 0.58-3.00 .507 1.20 0.25-5.8 .816 1.31 0.52-3.30 .570 1.18 0.37-3.80 .777 1.41 0.47-4.20 .539
 Neck pain 0.96 0.28-3.40 .951 0.94 0.11-7.8 .957 1.03 0.23-4.60 .972 0.70 0.15-3.30 .658 1.44 0.18-11.0 .731
 Arm pain 0.74 0.35-1.60 .424 0.38 0.11-1.3 .113 1.08 0.42-2.80 .866 0.47 0.19-1.20 .118 1.40 0.40-4.90 .601
 Sensory deficits 0.86 0.44-1.70 .672 0.69 0.20-2.4 .551 0.96 0.44-2.10 .928 0.65 0.26-1.60 .344 1.16 0.42-3.20 .773
 Weakness 0.97 0.52-1.80 .928 0.53 0.16-1.8 .316 1.11 0.55-2.20 .778 0.89 0.38-2.10 .795 1.05 0.45-2.50 .905
Patient-reported outcomes
 NDI −7.63 −17.0 to 1.40 .096 −11.0 −27 to 4.7 .168 −5.99 16.0 to 4.40 .256 −2.85 −17.0 to 11.0 .68 −11.63 −23.0 to 0.04 .049
 VAS Neck 0.03 −1.40 to 1.40 .962 −1.63 −4.00 to 0.70 .169 1.01 −0.58 to 2.60 .211 0.31 −1.9 to 2.50 .78 −0.27 −2.00 to 1.50 .755
 VAS Arm −0.61 −2.20 to 1.00 .463 −0.71 −3.30 to 1.90 .593 −0.18 −2.10 to 1.70 .857 2.13 −0.36 to 4.60 .09 −2.56 −4.60 to −0.53 .014
Single-HIZ
Preoperative symptom
 Radiculopathy 1.00 — — 1.00 — — 1.00 — — 1.00 — — 1.00 — —
 Myelopathy 1.18 0.26-5.40 .834 7.76 0.60-100.0 .116 0.64 0.08-5.00 .668 1.00 — — 2.42 0.49-12.0 .279
 Myeloradiculopathy 1.58 0.59-4.20 .360 0.76 0.05-12.0 .846 1.72 0.61-4.90 .302 1.25 0.28-5.60 .765 1.90 0.52-6.90 .330
 Neck Pain 0.75 0.16-3.50 .717 1.00 — — 0.65 0.14-3.00 .582 0.66 0.08-5.60 .701 0.80 0.10-6.70 .840
 Arm Pain 1.09 0.39-3.10 .871 0.54 .043-6.80 .632 1.22 0.40-3.80 .726 0.58 0.16-2.00 .387 3.05 0.38-24.0 .292
 Sensory deficits 0.84 0.36-2.00 .701 0.19 .016-2.20 .178 1.05 0.40-2.70 .927 0.60 0.19-1.90 .378 1.22 0.33-4.50 .770
 Weakness 1.30 0.60-2.80 .510 0.60 .053-6.80 .679 1.42 0.62-3.20 .404 0.87 0.29-2.60 .795 1.95 0.64-6.0 .243
Patient-reported outcomes
 NDI −4.38 −17.0 to 8.40 .501 −24.67 −62.0 to 13.0 .198 −1.82 −15.0 to 12.0 .791 8.86 −10.0 to 28.0 .363 −14.95 −32.0 to 2.00 .084
 VAS Neck −0.16 −2.20 to 1.90 .873 −4.43 −10.0 to 1.10 .117 0.47 −1.70 to 2.60 .668 3.34 0.07 to 6.60 .045 −2.23 −4.70 to 0.26 .079
 VAS Arm 0.62 −1.90 to 3.10 .623 −4.86 −11.0 to 1.50 .130 1.57 −1.10 to 4.20 .245 4.90 1.20-8.60 .010 −2.57 −5.80 to 0.60 .111
Dual-HIZ
Preoperative symptom
 Radiculopathy 0.75 0.13-4.30 .742 0.49 .073-3.30 .462 — — — 0.46 0.07-3.20 .435 — — —
 Myelopathy 1.29 0.32-5.30 .721 1.32 0.22-8.00 .764 0.99 0.11-8.80 .993 1.39 0.22-8.70 .723 1.13 0.13-10.0 .912
 Myeloradiculopathy 0.88 0.22-3.50 .856 1.54 0.24-10.0 .649 0.49 0.06-4.20 .516 1.06 0.18-6.40 .951 0.69 0.08-6.10 .742
 Neck pain 1.38 0.17-11.0 .760 0.72 0.08-6.30 .765 — — — 0.72 0.08-6.40 .770 — — —
 Arm pain 0.48 0.17-1.40 .172 0.33 0.08-1.30 .120 0.87 0.17-4.50 .869 0.38 0.09-1.60 .180 0.63 0.12-3.30 .582
 Sensory deficits 0.87 0.30-2.50 .796 1.17 0.24-5.90 .845 0.78 0.20-3.10 .725 0.72 0.17-3.00 .655 1.08 0.22-5.30 .924
 Weakness 0.58 0.21-1.60 .296 0.51 0.12-2.10 .354 0.54 0.13-2.20 .391 0.92 0.24-3.60 .904 0.34 0.07-1.70 .189
Patient-reported outcomes
 NDI −11.00 −23.0 to 1.20 .078 −8.15 −25.0 to 9.10 .351 −11.93 −28.0 to 3.70 .134 −14.78 −34.0 to 4.60 .134 −8.93 −25.0 to 6.70 .261
 VAS Neck 0.12 −1.70 to 1.90 .899 −1.06 −3.60 to 1.50 .415 1.60 −0.70 to 3.90 .173 −2.04 −4.90 to 0.83 .163 1.40 −0.90 to 3.70 .231
 VAS Arm −1.47 −3.5 to 0.60 .163 0.14 −2.70 to 3.0 .923 −1.86 −4.50 to 0.80 .170 0.06 −3.20 to 3.30 .971 −2.48 −5.10 to 0.15 .064
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Abbreviations: HIZ, high-intensity zone; OR, odds ratio; CI, confidence interval; NDI, Neck Disability Index; VAS, Visual Analogue Scale.

aBeta-coefficents, Odds ratio and p-values were calculated using multivariate linear and logistic regression models controlling for patient demographics. Bolded values indicate statistical significance with p < 0.05.

When assessing relationships between HIZs and other disc pathologies, anterior HIZs and HIZs inside the area of fusion were significantly associated with lower odds of disc displacement (P = .019; OR = 0.03; 95% CI: <0.01 to 0.54) and disc degeneration (P = .049; OR: 0.31; 95% CI: 0.10 to 0.99). However, when stratified further by cervical vertebral level, HIZs were found to be associated with increased odds of disc displacement at C3-C4 (P = .002; OR = 2.93; 95% CI: 1.50 to 5.70). Comparably, anterior annulus HIZs at C6-C7 was still significantly associated with lower odds of disc degeneration (at C6-C7; P = .036; OR: 0.27; 95% CI: 0.08 to 0.92). When stratified by subtype, single-HIZs were similarly associated with lower odds of disc displacement when found in the anterior annulus (P = .011; OR: <0.01; 95% CI: <0.01 to 0.30) or within the planned fusion segment (P = .026; OR: 0.04; 95% CI: <0.01 to 0.68). Again, the relationship between single-HIZs and disc displacement reversed when considering cervical vertebral level at C3-C4 (P = .019; OR = 2.65; 95% CI: 1.18 to 6.00), while odds of disc degeneration remained decreased at C7-T1 (P = .017; OR = 0.34; 95% CI: 0.14 to 0.82). Dual-HIZs were not significantly associated with any other disc phenotype, unless stratified by vertebral level. Specifically, dual-HIZs had lower odds of disc degeneration at C4-C5 within the fusion segment (P = .011; OR = 0.16; 95% CI: 0.037 to 0.65), greater odds of disc space narrowing at C3-C4 outside of the fusion segment (P = .031; OR = 7.28; 95% CI: 1.20 to 44.00), and greater odds of disc displacement at C3-C4 (P = .024; OR = 3.67; 95% CI: 1.20 to 11.00; Table 5).

Table 5.

Multivariate Analyses of High-Intensity Zones With Concurrence of Disc Pathology at Identical Intervertebral Level.a

No stratification Anterior Posterior Inside fusion segment Outside fusion segment
Beta/OR 95% CI P value Beta/OR 95% CI P value Beta/OR 95% CI P value Beta/OR 95% CI P value Beta/OR 95% CI P value
HIZ
Overall disc phenotype
 Disc degeneration 0.57 0.28-1.20 .128 0.22 0.04-1.10 .065 0.85 0.39-1.90 .681 0.31 0.10-1.00 .049 0.93 0.37-2.40 .886
 Disc space narrowing 1.17 0.61-2.30 .634 0.72 0.20-2.60 .607 1.31 0.63-2.70 .468 1.09 0.44-2.70 .850 1.3 0.51-3.10 .621
 Disc displacement 0.11 0.01-1.60 .108 0.03 <0.01-0.50 .019 — — — 0.05 <0.01-1.00 .050 — — —
Disc degeneration by cervical vertebral level
 C2-C3 0.87 0.42-1.80 .699 0.66 0.17-2.50 .545 1.00 0.43-2.30 .995 0.79 0.29-2.10 .645 0.93 0.33-2.60 .893
 C3-C4 0.92 0.44-1.90 .820 0.44 0.13-1.60 .204 1.24 0.52-3.00 .630 2.01 0.57-7.10 .280 0.51 0.21-1.30 .155
 C4-C5 0.67 0.34-1.30 .239 0.48 0.14-1.70 .252 0.78 0.36-1.70 .533 0.46 0.18-1.10 .093 0.98 0.37-2.70 .976
 C5-C6 1.17 0.52-2.70 .708 0.93 0.19-4.50 .925 1.29 0.51-3.30 .588 2.63 0.59-12.0 .206 0.68 0.25-1.80 .446
 C6-C7 0.74 0.37-1.50 .407 0.27 0.08-0.90 .036 1.11 0.47-2.60 .807 1.01 0.35-2.90 .992 0.56 0.22-1.40 .225
 C7-T1 0.61 0.32-1.20 .137 0.70 0.20-2.40 .577 0.60 0.29-1.30 .182 0.55 0.22-1.40 .214 0.65 0.27-1.60 .342
Disc space narrowing by cervical vertebral level
 C2-C3 — — — — — — — — — — — — — — —
 C3-C4 0.84 0.18-3.80 .817 — — — 1.43 0.30-6.80 .652 — — — 2.47 0.50-12.0 .268
 C4-C5 1.65 0.66-4.20 .287 2.10 0.46-9.60 .341 1.43 0.46-4.50 .536 1.03 0.27-4.00 .965 2.66 0.80-8.90 .112
 C5-C6 1.13 0.57-2.20 .725 1.35 0.37-5.00 .647 1.03 0.47-2.20 .939 0.84 0.33-2.20 .715 1.53 0.60-3.90 .375
 C6-C7 0.82 0.39-1.70 .590 0.33 0.07-1.70 .182 1.05 0.47-2.40 .905 0.86 0.33-2.30 .753 0.76 0.26-2.20 .617
 C7-T1 1.61 0.51-5.00 .415 2.52 0.49-13.0 0.271 1.09 0.23-5.10 .915 3.28 0.94-11.0 .062 — — —
Disc displacement by cervical vertebral level
 C2-C3 0.52 0.12-2.30 .385 0.74 0.09-6.20 .783 0.41 0.05-3.20 .390 0.97 0.21-4.50 .971 — — —
 C3-C4 2.93 1.50-5.70 .002 6.08 1.30-29.0 .025 2.52 1.20-5.30 .014 1.04 0.42-2.60 .933 10.1 3.20-31.0 .000
 C4-C5 1.63 0.82-3.30 .166 1.01 0.28-3.70 .988 1.76 0.81-3.80 .156 1.02 0.41-2.60 .968 2.63 0.97-7.20 .058
 C5-C6 2.71 0.62-12.0 .187 1.49 0.17-13.0 .717 2.00 0.45-8.90 .362 2.09 0.26-17.0 .486 3.28 0.42-26.0 .260
 C6-C7 1.20 0.53-2.70 .669 2.09 0.26-17.0 .489 1.09 0.45-2.70 .851 0.96 0.30-3.00 .938 1.42 0.46-4.40 .543
 C7-T1 1.25 0.52-3.00 .616 1.43 0.34-6.00 .629 1.08 0.37-3.20 .884 2.13 0.73-6.30 .168 0.52 0.10-2.60 .432
Single-HIZ
Overall disc phenotype
 Disc degeneration 0.55 0.21-1.40 .223 — — — 0.65 0.24-1.70 .391 0.32 0.07-1.60 .158 0.84 0.24-2.90 .777
 Disc space narrowing 1.33 0.58-3.00 .502 — — — 1.13 0.48-2.70 .781 1.94 0.59-6.30 .273 0.94 0.29-3.00 .913
 Disc displacement 0.07 0.005-1.10 .060 <0.01 <.01-0.30 .011 — — — 0.038 <0.01-0.68 .026 — — —
Disc degeneration by cervical vertebral level
 C2-C3 0.95 0.38-2.40 .908 — — — 0.82 0.33-2.10 .678 2.12 0.45-10.0 .341 0.52 0.16-1.60 .261
 C3-C4 0.82 0.34-2.00 .660 0.61 0.05-7.34 .696 0.85 0.34-2.20 .734 4.70 0.59-37.3 .143 0.30 0.10-0.90 .034
 C4-C5 0.81 0.34-1.90 .620 — — — 0.68 0.28-1.60 .388 0.95 0.28-3.20 .935 0.71 0.22-2.30 .558
 C5-C6 1.01 0.39-2.60 .980 — — — 0.92 0.35-2.40 .871 3.86 0.48-31.0 .203 0.47 0.15-1.50 .203
 C6-C7 0.62 0.27-1.40 .260 — — — 0.94 0.37-2.40 .888 1.24 0.33-4.70 .753 0.34 0.11-1.0 .059
 C7-T1 0.34 0.14-0.82 .017 0.34 0.03-4.17 .400 0.34 0.13-0.86 .023 0.54 0.16-1.80 .301 0.20 0.05-0.80 .020
Disc space narrowing by cervical vertebral level
 C2-C3 — — — — — — — — — — — — — — —
 C3-C4 — — — — — — — — — — — — — — —
 C4-C5 1.79 0.54-5.90 .337 13.30 0.97-182.68 .053 1.00 0.21-4.70 .996 1.53 0.29-8.0 .613 2.15 0.42-11.0 .358
 C5-C6 1.00 0.42-2.40 .993 — — — 0.75 0.29-2.00 .566 1.17 0.36-3.80 .796 0.85 0.24-3.10 .800
 C6-C7 0.58 0.21-1.60 .294 — — — 0.72 0.26-2.10 .545 0.92 0.27-3.20 .900 0.24 0.03-1.90 .173
 C7-T1 2.82 0.72-11.0 .135 11.10 0.74-167.60 .082 1.95 0.40-9.70 .412 6.99 1.50-33.0 .014 — — —
Disc displacement by cervical vertebral level
 C2-C3 0.54 0.07-4.30 .557 — — — 0.66 0.08-5.30 .697 1.14 0.13-9.80 .901 — — —
 C3-C4 2.65 1.20-6.0 .019 3.34 0.28-39.96 .340 2.61 1.10-6.10 .028 0.67 0.20-2.30 .527 14.31 3.0-68.0 .001
 C4-C5 2.04 0.84-5.0 .115 — — — 1.83 0.74-4.50 .190 1.12 0.35-3.60 .852 3.89 1.0-15.0 .049
 C5-C6 3.14 0.41-24.0 .273 — — — 3.05 0.39-23.70 .287 1.07 0.13-8.90 .951 — — —
 C6-C7 0.82 0.33-2.10 .674 — — — 0.72 0.28-1.80 .486 0.81 0.21-3.10 .761 0.82 0.24-2.80 .750
 C7-T1 1.04 0.29-3.80 .954 — — — 1.21 0.33-4.50 .777 1.36 0.27-7.0 .710 0.69 0.09-5.70 .733
Dual-HIZ
Overall disc phenotype
 Disc degeneration 0.61 0.21-1.80 .366 0.28 0.05-1.50 .143 1.43 0.38-5.30 .598 0.31 0.06-1.68 .172 1.04 0.26-4.10 .955
 Disc space narrowing 0.97 0.35-2.70 .956 0.36 0.08-1.70 .204 1.87 0.45-7.80 .389 0.46 0.11-2.00 .297 1.99 0.45-8.80 .364
 Disc displacement — — — — — — — — — — — — — — —
Disc degeneration by cervical vertebral level
 C2-C3 0.75 0.23-2.40 .622 0.40 0.10-1.70 .216 2.06 0.25-17.0 .506 0.25 0.06-1.00 .053 — — —
 C3-C4 1.15 0.32-4.20 .832 0.40 0.09-1.70 .209 — — — 0.77 0.15-4.00 .759 1.85 0.22-15.0 .569
 C4-C5 0.50 0.17-1.40 .192 0.25 0.06-1.00 .052 1.20 0.23-6.10 .827 0.16 0.04-0.65 .011 2.23 0.27-18.0 .457
 C5-C6 1.59 0.35-7.30 .553 0.67 0.13-3.50 .635 — — — 1.52 0.18-13.0 .701 1.65 0.19-14.0 .649
 C6-C7 1.13 0.31-4.20 .856 0.65 0.12-3.40 .605 2.39 0.28-20.0 .425 0.71 0.13-3.90 .694 1.90 0.23-16.0 .555
 C7-T1 1.51 0.49-4.60 .473 0.92 0.21-4.10 .915 2.79 0.52-15.0 0.234 0.58 0.13-2.50 .469 5.14 0.61-43.0 .132
Disc space narrowing by cervical vertebral level
 C2-C3 — — — — — — — — — — — — — — —
 C3-C4 1.72 0.34-8.60 .511 — — — 4.55 0.79-26.0 .089 — — — 7.28 1.20-44.0 .031
 C4-C5 1.47 0.37-5.80 .585 0.71 0.07-7.00 .771 2.26 0.42-12.0 .343 0.62 0.07-5.80 .671 3.23 0.56-18.0 .188
 C5-C6 1.34 0.48-3.80 .578 0.72 0.15-3.50 .684 1.94 0.50-7.60 .342 0.50 0.11-2.30 .379 3.56 0.78-16.0 .101
 C6-C7 1.25 0.44-3.50 .675 0.54 0.10-3.00 .475 2.09 0.55-8.00 .279 0.79 0.18-3.50 .753 1.98 0.47-8.30 .350
 C7-T1 0.70 0.08-5.80 .740 1.39 0.15-13.0 .770 — — — 1.21 0.13-11.0 .863 — — —
Disc displacement by cervical vertebral level
 C2-C3 0.52 0.06-4.20 .535 1.07 0.12-9.60 .954 — — — 0.87 0.10-7.60 .900 — — —
 C3-C4 3.67 1.20-11.0 .024 8.74 1.00-75.0 .047 2.43 0.60-9.80 .212 2.08 0.44-9.80 .354 6.22 1.20-32.0 .030
 C4-C5 1.17 0.40-3.40 .776 0.62 0.14-2.70 .515 1.59 0.37-6.80 .529 0.89 0.19-4.10 .876 1.52 0.35-6.60 .576
 C5-C6 2.18 0.27-18.0 .469 1.39 0.16-13.0 .766 0.88 0.10-7.90 .906 — — — 1.11 0.12-10.0 .929
 C6-C7 3.78 0.48-30.0 .205 1.40 0.17-12.0 .758 — — — 1.45 0.17-13.0 .736 — — —
 C7-T1 1.49 0.45-4.90 .515 1.97 0.42-9.20 .387 0.88 0.15-5.30 .891 3.22 0.73-14.0 .123 0.38 0.035-4.10 .423
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Abbreviations: HIZ, high-intensity zone; OR, odds ratio; CI, confidence interval.

aBeta-coefficents, Odds ratio and p-values were calculated using multivariate linear and logistic regression models controlling for patient demographics. Bolded values indicate statistical significance with p < 0.05.

Discussion

Previous studies have examined the association of lumbar HIZs and low back pain, but similar investigations have largely evaded application in the cervical spine.4,6,9 Thus, we sought to characterize HIZs in the cervical spine and determine their association with preoperative symptoms and clinical outcomes. In this study, we have demonstrated a unique and significant association between cervical HIZ subtypes and subjective reports of neck and arm pain. Specifically, the traditional imaging definition of the HIZ (single-HIZs) when located inside the area of planned fusion was associated with self-reported pain symptoms, though dual-HIZs bore no relationship with subjective outcomes before surgery. This finding provides evidence that when located inside the area of fusion, HIZs may somehow contribute to symptoms of pain. Furthermore, both HIZ subtypes demonstrated patterns of association with other disc imaging findings different than previously reported in the lumbar literature. As such, this study provides new evidence on the possible significance of HIZs and suggests that associated clinical manifestations may largely relate to the subtype and location within the cervical spine.

The findings of the present study discussing HIZ subtypes and patient symptomatology may explain why the relationship between HIZs and pain is inconclusive. In a systematic review by Teraguchi et al, 4 they noted the clinical relevance of HIZs in the lumbar spine was inconclusive, largely due to small sample size, heterogeneous study populations, and lack of standardized imaging protocols. However, the studies they reviewed did not discuss the presence or significance of HIZ subtypes. Shan et al 22 originally introduced this concept in their examination of HIZs in the lumbar spine, and remains the only other study to perform such an analysis. Similarly, in their study, they found a difference in pain response between the 2 HIZ subtypes, noting a greater pain response in those with single-HIZs. Given this, the single-HIZ appears to resemble the clinical and imaging features of the traditional HIZ and suggests the dual-HIZ is likely a different phenomenon. To this point, histological analysis performed by Shan et al 22 demonstrated significantly higher calcium content within the dual-HIZ lesion, suggesting the single-HIZ phenotype may be a different age-related entity. 29 As such, previous studies examining HIZs may be confounded by the presence of 2 distinct HIZ phenotypes, and a description of the true clinical presentation of those with HIZs remains unknown. In a recently submitted population-based cohort study evaluating 496 HIZs in the lumbar spine, it was reported that certain patterns of HIZ phenotypes in the lumbar spine are more associated with the development and severity of low back pain than others. This provides further evidence for the clinical use of HIZs in the lumbar spine and the importance of interpreting phenotype patterns. 23 Future investigations should aim to understand varying HIZ patterns and the pathogenesis of single- and dual-HIZs to evaluate how differing HIZ phenotypes may manifest in the spine.

Given these phenotypic differences, further consideration was given to reported associations of HIZs with other disc pathologies. Previous studies suggest lumbar HIZs are highly associated with disc degeneration.6,8,20,22,30 The current study analyzed the relationship between cervical HIZs (as well as HIZ subtypes) and other disc pathologies, stratified by concurrence at the same intervertebral level, and by incidence overall from C2-C7. Unexpectedly, cervical HIZs were significantly associated with lower odds of concurrent disc degeneration and disc displacement. However, when stratified by subtype and location within the intervertebral disc, single-HIZs showed similarly lower odds of disc displacement, while dual-HIZs were unrelated to all other disc phenotypes. While possibly underpowered to detect findings related to the latter, both subtypes trended toward lower odds of concurrent degenerative disc pathology. Moreover, it may also be that the dual-HIZ has a distinct pathogenesis, such that the calcific nature of the lesion may lead to a different risk profile for other degenerative phenotypes.

In the lumbar spine, Wang and Hu 9 performed an analysis on the risk factors for HIZs, suggesting that these phenomena are part of the natural history of intervertebral disc degeneration. However, they concluded that the association of HIZs with disc degeneration was confounded by associations with older age. Other studies have found the incidence of HIZs in the lumbar spine was greater with higher rates of disc degeneration.8,10,31 Similar considerations for confounding may also be present in our study, as the population under study was comprised entirely of a surgical cohort awaiting treatment with ACDF. These patients, by default, had a significant level of baseline degenerative findings at other cervical vertebral levels, such that the observed associations may be attributable to other underlying pathologies. Irrespective, these results suggest the potential of cervical HIZs as possible biomarkers for pain and disability, emphasizing the need for further exploration.

Despite providing new evidence surrounding HIZs in the cervical spine, this study has notable limitations. As with all retrospective studies, selection bias may be prevalent, and could have affected the outcomes observed. Similarly, as this study was performed on a degenerative spine cohort at a single academic institution, there may be concerns regarding external validity. Furthermore, patients obtained MRIs from various outside facilities; thus, we could not control for specific differences in MRI techniques/protocols/parameters. In examination of our surgical cohort of ACDF patients, this study is limited as it does not cover all cervical spine pathologies but focuses on a group of patients with a diagnosis that ACDF was indicated to treat. Future studies will aim to address HIZ phenotypes in asymptomatic populations. Additionally, this study was limited by its small sample size and the relatively low incidence of HIZs, which both may contribute to an underpowered analysis. Last, given the number of independent tests utilized in this study, concerns for false positive findings may be prevalent. However, given the lack of previous studies on cervical spine HIZs, and consequently, an unclear historical effect size, corrections for multiple comparisons were omitted to prevent masking of potential associative relationships. Overall, this study aimed to address these shortcomings by performing its analysis on prospectively acquired data, and exploring variations of HIZs in great detail, performing a rigorous assessment of different phenotypes, HIZ location, and association with other degenerative cervical spine pathologies. In addition, this is, to our knowledge, the first study to systematically address HIZs of the cervical spine in a relatively large cohort of cervical spine patients. Findings from this study are meant to raise awareness of the HIZ phenotype that may be further addressed in multicenter projects whose larger sample size may allow further exploration of these imaging findings and their clinical relevance.

Conclusions

This is the first study to evaluate the epidemiology and clinical significance of HIZs in the cervical spine in patients, noting level-specific and clinical outcome–specific variations. In accordance with previous reports on the association of lumbar HIZs with clinical outcomes, HIZs in the cervical spine were also found to be associated with symptoms of pain. However, these results were largely attributable to the single-HIZ, a subtype consistent with the traditional imaging definition. Interestingly, the single-HIZ was associated with increased preoperative pain symptoms when observed inside the planned area of fusion suggesting the presence of single HIZs may correlate with concurrent spinal pathologies and therefore should be more closely evaluated. Furthermore, these findings highlight the need to perform a comprehensive T1- and T2-weighted MRI analysis of HIZs in the cervical spine. In contrast to lumbar spine literature showing at times significant association of HIZs with disc degeneration pathology, the results of the current study showed lower odds of disc degeneration (ie, black disc) in association with cervical HIZs. This provides credence to explore the pathophysiological spatial development of HIZs in the context of disc changes which may vary between cervical and lumbar regions. Given these findings, it is important to consider the different ways that imaging pathology may manifest in different regions of the spine and further assessments of HIZs should utilize a holistic MRI approach. This may provide a better assessment of the clinical significance of HIZs within the cervical and lumbar spine. However, prospective and longitudinal studies are needed to further validate our findings and to further explore the HIZ phenotype in conservatively managed as well as nonpatient groups.

Footnotes

Ethical Approval: Institutional review board approval was obtained by the RUSH University Ethics Committee. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (RUSH Institutional Review Board + IRB Number 18033101-IRB01) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

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