Reconsidering high intensity zones: its role in intervertebral disk degeneration and low back pain

Many degenerative classifications of the lumbar spine have been devised to try and illustrate the degenerative process and provide insight on the symptomatic intervertebral disk (IVD). High intensity zones (HIZs), originally defined as a bright white signal in the posterior annulus fibrosus (AF) on T2 weighted (T2W) MRI are thought to be pathognomonic of a symptomatic IVD [1] (Fig. 1). However, literature regarding HIZ and its predictive value as the cause of discogenic LBP remains controversial.

Studies have found HIZ to be related to LBP [2‐4]. Contrarily, other studies have observed HIZ in asymptomatic patients and found non-significant relationships between HIZ and LBP, leading researchers to question the significance of HIZ as a marker for LBP [5, 6]. To explain this Bogduk postulated that low intensity zones are asymptomatic fissures that need to be activated to form symptomatic HIZs. Subsequently, Liu et al. observed that symptomatic HIZs were significantly associated with a signal intensity of \(\ge\) 50% of the cerebrospinal fluid (CSF) [3]. Many authors have suggested that HIZ is a part of the disk degeneration process, finding significant associations between HIZ and degenerative changes, whilst others have not [1, 4‐7].

To date, discography is still regarded as the gold standard for diagnosing LBP, however, it is highly invasive. Recent advances in literature regarding the pathogenesis of HIZ and using T1 weighted (T1W) MNRI scans have provided insight into the clinical significance of HIZ as a diagnostic indicator for LBP. Studies have observed HIZs exist circumferentially around the IVD, adding to the original definition that HIZs are posterior radial tears [1, 7]. HIZ has been proposed by authors to be fluid-filled zones in the AF resulting from inflammatory oedema [8]. Gadolinium DTPA-MR imaging has demonstrated enhanced signal intensity surrounding HIZs, positing HIZ’s association with extradural inflammation [9]. Histological studies have also backed up the presence of granulation tissue and resulting oedema [8]. Additionally, cadaveric studies have found that HIZs were generated by mucoid fluids containing fat [10]. Therefore, a single-subject multimodal approach was necessary to produce a more detailed definition of different HIZ phenotypes which can provide a higher clinical significance.

The studies mentioned previously have a variety of limitations, including inconsistency in the field strength of MR, no uniform consensus on the true definition of HIZ, and selection basis. As a result, the prevalence of HIZ and its relationship with LBP and lumbar degenerative parameters is still heavily debated. No studies to date have evaluated the relationship between HIZ and degenerative parameters observed on X-ray as potential risk factors. Hence, we performed a retrospective cohort study to assess the prevalence of HIZ in the lumbar spine, establish the independent relationships between IVDs with HIZs and lumbar X-ray and MRI degenerative parameters and identify the association between patients with HIZs and LBP.

To our knowledge, this is the first cohort study that reports the independent relationship between recumbent MRI-based HIZ, gravity-loaded standing x-rays, degenerative MRI parameters and clinical variables via a logistical regression. The prevalence of HIZ reported in studies has varied greatly. Our results showed that the prevalence of HIZs in this consecutively selected population was approximately 41.9%, with 11.0% of IVDs affected. Posterior HIZ was most common at the lower lumbar levels of L5/S1 (21/25) followed by L4/L5 (12/18), replicating many previous published results [2, 5, 6]. Dissimilar to other papers, we found 36% of the total HIZ to be anterior, with the most occurring at L3/L4 followed by L2/L3. This supports the postulation that upper lumbar (L1-L4) IVD degeneration has a developmental origin whilst lower lumbar (L4-S1) abnormalities are associated with aging and BMI [18]. However, this study cannot validate previous results as previous studies did not perform pan-disk analysis and did not have a uniform definition for HIZ.

This study was the first to introduce sagittal alignment measurements on X-ray. However, none were significantly associated with HIZ which demonstrates that HIZ is possibly a local disk based segmental issue with no associations to sagittal imbalance. The logistic regression model showed that the odds of developing HIZ was 6.4 and 3.0 times higher in disks with disk bulge/protrusion and disk degeneration, respectively. Increasing IVD angle was also found to increase the risk of developing HIZs. When confounding for factors, foraminal stenosis was found to be non-significant. These results support the view that degenerative findings can be a precursor to HIZ. The pathophysiological basis behind these associations can be attributed to the altered biomechanics of a degenerative disk. Many cadaveric studies have found reduced stiffness and increased range of motion in disks with HIZ. Instability in the disk results in increased fluid movement through the annular tear into the outer annulus causing disk degeneration and bulging/protrusion and consequently the formation of a HIZ [19]. Many articles have found a significant correlation between disk degeneration and foraminal width and foraminal area [20], which explains why the model has found that foraminal stenosis, independently, is not a risk factor for HIZ. Some caution is needed when interpreting these results as some technical assumptions may have been violated by the model. The measurements for each individual IVD were conducted independently, however, they were taken from the same patient (L1-S1) violating the independence of observation assumption [21]. This technical violation is very common in our field and many studies have found region specific differences within the lumbar spine to exist. As a result, the error due to correlated outcomes is minimized.

The clinical significance of HIZ is still heavily debated by researchers. The proportion of the population in industrial countries that have experienced LBP is at 84%. Approximately 85% percent of these cases are classified as non-specific LBP [22]. In our study, the percentage of patients with LBP in the HIZ group was higher at 72% compared to the control (46%) and the odds of having LBP were 3.1 times higher in the HIZ group compared to the control. This finding is due to the use of a qualitative definition for HIZ which allowed us to omit low intense zones [3]. It also underscores the fact LBP is only correlated to HIZs when large amounts of oedema and/or fatty infiltration occur because of inflammation or there is a large herniating process of the NP. This is supported by findings of mucoid fluids and inflammatory tissue in cadaveric and histology studies [8, 9, 23]. As a result, our results suggest that HIZ may be used independently in routine MRI and clinical assessments of patients with LBP, other degenerative parameters should be used in conjunction to formulate a diagnosis. Ultimately, HIZ may help in decreasing the number of non-specific LBP diagnoses.

Although there was higher prevalence of endplate changes in disks with HIZ compared to disks without (8% vs. 7.5%), this was not significant. Endplate changes represent severe toxic inflammatory responses in the vertebrae causing bone-oedema, re-vascularization, fatty infiltration, and subsequent repair which are all observed differently on MRI [24]. Therefore, future prospective pathohistological studies coupling T1W and T2W MRI are critical. It will allow us to further study the pathological connections between HIZ and lumbar degenerative parameters to see the progression of HIZ and determine if HIZ is a result of degeneration, if degeneration is a result of HIZ, or if HIZ and degeneration are both indications of nucleus pulposus material herniating into the annulus fibrosus meaning that there exists no functional difference between them.

The results of our studies were impacted by certain limitations. The first is that it is a retrospective cohort study that did not analyze patients’ clinical and radiological trends over time. Certain demographic information such as body mass index and socioeconomic status was not recorded. The population only included patients referred for MRI imaging, therefore the prevalence of HIZ in patients who do not present to a clinical or is not imaged is difficult to assess. The mean age was high in both the case and control groups, signifying the need for further studies that only look at certain age ranges. The nature (i.e., VAS) and duration of pain as well as disability scores were not recorded. Classification of patients into groups with and without pain based on the referral letters is imperfect and may be susceptible to classification error. This would bias the reported odds ratio towards 1 and mean the true underlying association between HIZ and pain may be somewhat stronger than observed here (Electronic Supplementary Material 1: ESM_1).

HIZ was found in 41.9% of patients. At all affected levels there was a significant association between HIZ and nucleus degeneration, disk bulge/protrusion, and foraminal stenosis on MRI and IVD angle on X-ray. The likelihood of having HIZ was 6.4 times and 3 times higher in IVDs with disk bulge/protrusion and nucleus degeneration, respectively. There was also an increased likelihood of HIZ in disks with increasing IVD angle. The odds of having LBP in patients with HIZ were 3.061 times higher than the control. According to the findings, HIZ is likely a clinically useful diagnostic parameter. However, creating a standardized definition for HIZ is essential for identifying problematic patients and minimizing harm from unnecessary management of non-specific LBP.