Lamina Slope Angle Is A Risk Factor for Ligamentum Flavum Hypertrophy in Patients with Lumbar Degenerative Disease: A Retrospective Study

Xiaosheng Yu (  johnsonyxs@hotmail.com ) Shanghai Jiao Tong University School of Medicine A liated Renji Hospital Junduo Zhao Shanghai Jiao Tong University School of Medicine Fan Feng Shanghai Jiao Tong University School of Medicine A liated Renji Hospital Yingchao Han Shanghai Jiao Tong University School of Medicine A liated Renji Hospital Guibin Zhong Shanghai Jiao Tong University School of Medicine A liated Renji Hospital Zude Liu Shanghai Jiao Tong University School of Medicine A liated Renji Hospital Jianwei Chen (  jwchenbone@126.com )


Introduction
Low back pain (LBP) is highly prevalent across the world, affects all ages, and is a the most common reason for patients living with disability [1][2][3][4] . A previous epidemiological investigation showed that the mean point prevalence was 18.3% 5 . LBP is common in people aged 60-65 years which cause by lumbar degenerative disease and can become more serious with age as the accumulation of mechanical stress damage increases 6 . Lumbar degeneration arises from a range of pathoanatomical alterations caused by mechanical stress, including lumbar disc degeneration(LDD), facet joint osteoarthritis(FJOA), hypertrophic ligamentum avum(HLF), and paravertebral muscle atrophy. 7 The spine bears the weight of our body under gravity. The functional spine unit (FSU) is a basic building block of the spine and is used to investigate the physical properties and functional biomechanics of the spine 8 . The FSU is composed of two adjacent vertebrae, the intervertebral disc, the facet joints, and the spinal ligaments. Many researchers have investigated the relative relationships between the components of the FSU as these can be measured or calculated easily. P rrmann et al. developed a formal classi cation scheme for discs in 2001 and allowed us to quantify and compare the degeneration of lumbar discs 9 . From then on, an increasing number of researchers and clinicians have investigated the relationship between lumbar disc degenerative grade and the degeneration of other FSU structures [10][11][12][13][14] .
In 2017, Kalichman et al. described three signs of muscle degeneration on imaging: decreased muscle size, decreased radiographic density, and the increased deposition of fat 15 . Sun et al. further reported that disc degeneration was positively correlated with the atrophy of the multi dus muscles at the L3-L4 disc level and emphasized strengthening the paraspinal muscle helps to prevent muscle atrophy and slowed down the progression of lumbar spinal degeneration 11 .
The laminar slope angle(LSA) was rst proposed by Xu in 1999and de ned as the intersection angle of the plane of the lamina and the horizontal plane of the vertebral body 16 , thus representing the tilt of each lamina. This angle did represent an anatomical index that re ected the relative tilt of the lamina and was rst used to provide a preference for spinal surgeons to place sublaminar instruments. Qin's work con rmed that the LSA was associated with the ossi cation of the ligamentum avum in thoracic segments but there was no research about the relationship between LSA and lumbar structure 17 . Thus, we hypothesize that the extent of the LSA may affect the vertebral anatomical structure and give rise to LDD, HLF, multi dus muscle atrophy and fatty in ltration. These changes could lead to degenerative lumbar disease.

Study participants
We retrospected a total of 687 patients, of all ages, who came to the inpatient department of spinal surgery at Renji hospital and were scheduled for lumbar surgeries between January and December 2017. We divided these patients into ve groups according to age: below 35 years, between 36 and 45 years, between 46 and 55 years, between 56 and 65 years, and above 66 years. Then, we randomly selected 20-30 samples(a ratio of 6:1) from each group and mixed them up to create a nal sample group. A total of 122 patients remained in the analysis (Fig. 1). We registered the age and sex of all 122 patients, who all underwent magnetic resonance imaging(MRI) and computerized tomography(CT) scans of the lumbar spine prior to surgery. The inclusion criteria were: (1) no history of spinal surgery; (2) no recent history of severe lumbar trauma; (3) no abnormal radiological ndings, such as vertebral fractures, space occupying lesions of the lumbar spine, or apparent spinal deformities (e.g., scoliosis); and (4) no history of systemic diseases (rheumatic diseases of the spine or carcinoma).
The study protocol was approved by the ethics committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University. Informed consent was were obtained from each patient prior to the imaging examination.

Magnetic Resonance Imaging Protocol
As reported previously by Yu 10 , all T2-weighted images were acquired using the same 3.0 T imaging system (Magnetom; Siemens, Erlanger, Germany) with a repetition time of 3220 ms and an echo time of 120 ms. Slice thickness was 4 mm. The acquisition matrix was 512 × 512 and the eld of view was 310 mm. We then obtained and evaluated Original Digital Imaging and Communications in Medicine les from transverse oblique MRI images parallel to the superior end plate of L4 and L5.

Computed Tomography Protocol
Preoperative patients who were eligible for CT underwent imaging with an 8-slice multidetector CT scanner (Lightspeed Ultra; GE, Milwaukee, Wisconsin). Each patient underwent unenhanced lumbar CT performed with a sequential scan protocol with slice collimation of 8 × 2.5 mm (120 kVp, 320/400 mA for 0.220 lb body weight) during a single end-inspiratory breath hold (typical duration, 18 s). For the lumbar scan, 256 contiguous 2.5 mm slices of the lumbar region were acquired, covering a 150 mm area above the level of S1. The evaluation of CT scans was performed with blinding to clinical and personal data.

Disc Degeneration Assessment
Disc degeneration assessment used the disc degeneration grade described by P rrmann in 2001 9 . Observers analyzed the L4-L5 lumbar intervertebral disc from each patient on T2-weight sagittal MRI images using Picture Archiving and Communication Systems (PACS), version 11.4 (Carestream health, Shanghai, China)( Fig. 2) with P rrmann's original article to con rm the grade at the time of evaluation. Independently, more than half of the selected grade was recorded. If there was a dispute, then images were reevaluated until more than half of the observers agreed.

Laminar Slope Angle Measurements
Laminar slope angle was measured with PACS. We reconstructed pre-operation CT in three dimensions and proofread the central axis in parallel with the direction of the spinous process on the axis CT image and with the postural tilt of the spine on the coronal image. We then chose the sagittal images at the level of the tip of the unilateral facet joints (Fig. 3). Evaluators analyzed the selected sagittal CT images using our rede ned method similar to Bai-ling's on lateral radiographs 18 We drew two separate lines connecting the tip of the superior facet with the base of the inferior facet and connecting the midpoints of the anterior and posterior vertebral cortices; we then measured the intersecting angle between the two lines. We selected L4 and L5 axis position on sagittal CT images, measured the corresponding LSA, and calculated the absolute value of the difference between the two adjacent segments of LSA ( Fig. 2)

Muscle Measurements And Analysis
Muscle measurements and analysis were carried out with PACS and Image J software, version 1.42q (National Institutes of Health, Bethesda, Maryland) following the method described in our previous article 10 . We selected the axial slice at the level of the L5 vertebral body upper endplate to calculate L4-5 muscle cross section area(CSA) (Fig. 2). Intramuscular fatty in ltration was obtained with a widely Page 4/13 accepted muscle-fat index, which represents the ratio of mean signal intensity in a region of lean muscle tissue relative to the signal intensity in a homogeneous region of fat (Fig. 2).

Thickness Of The Ligamentum Flavum
The thickness of the ligamentum avum was measured on axis T2-weight MRI images with PACS. We located the spinal level of the L4-5 intervertebral spaces on sagittal T2-weight MRI images and selected the axial slice at the level of the L5 vertebral body upper endplate. 13,19−21 We then drew two parallel lines along the direction of the ligamentum avum and chose the maximum distance between the dural side and the dorsal side. The maximum thickness of the LF was measured on both the right and left sides (Fig. 2)

Reliability Tests
To avoid bias, two radiologists and two surgeons were blinded to the study design; consequently, when measuring the parameters, they all ignored the laminar slope angle. To ensure the objectivity of the results, all measurements were repeated by the radiologists and surgeons 2 weeks after the initial evaluation. The mean of the data was then used in the primary analysis.

Statistical Analysis
Statistical analyses were performed with SPSS software, version 24.0 (IBM, Armonk, New York). The association between age and measurement indexes were determined by the independent-samples T test. The association between laminar slope angle and other parameters were determined by Pearson correlation. Partial correlation was used to analyze the correlation of other remaining variables while controlling age variables. The reliability of the measured parameters was evaluated using intraclass correlation coe cients.
Signi cance was set at P < 0.05 and values represent mean ± standard error.

Results
A total of 122 patients were in our study including 66 men and 56 women (1.18:1). The mean age was 50.97 ± 14.78 years, ranging from 22 to 86 years. The descriptive anthropometric characteristics of the patients are shown in Table 1. The Cronbach's alpha was 0.67; thus, the quantity of all measurements had good credibility. The independent-samples T-test showed that males were younger than the females. Women also had a smaller multi dus and more serious fatty in ltration, but there was no signi cant difference in LSA and ligamentum avum when compared between the male and female group ( Table 2).

Correlation Analysis
Correlation analysis (Table 3)

Partial Correlation Analysis
After controlling for age, our results (Table 4)  There was no signi cant relationship between the LSA of L5 and any of these measurement indices. LSA did not affect degeneration of the lumbar disc.  Our study was the rst one to investigate the relationship between the laminar slope angle and lumbar degenerative disease. Through analysis we found that age was an important element which correlated to almost all of the measurement indices except for the difference value of the two segment LSA. The reduction in the CSA of the multi dus, the increased lumbar disc degeneration grade, and the area of fatty in ltration, with increasing age is consistent with existing research [23][24][25][26][27] . LSA was positively related to age, this can be explained by the osteoproliferation caused by FJOA. Age is known to be one of the risk factors of FJOA; the main group of patients with FJOA were those of advanced age. If FJOA occurs repeatedly, it could lead to osteoproliferation in the facet joints 28 .
Calculating the angle of the lamina slope, we drew one straight line connecting the tip of the superior facet and the base of inferior facet. As the facet joint protruded, the line lay atter (as shown in Fig. 4); consequently, LSA was larger. This is the opposite of vertebral body compression. Compression changes in the vertebrae tend to be concentrated in the anterior column which is from the three column theory, proposed by Dennis in 1983, and modi ed by Allen in 1984 29 . With a reduction in anterior vertebrae height, the horizontal plane of the vertebral body leans forwards and downwards; this results in the LSA becoming smaller (Fig. 4).
The muscle-fat index is a ratio of signal intensity, it become larger represents more fatty in ltration. Our results showed that age and LDD was positively related to fatty in ltration; this concurred with Dahlqvist's opinion, who reported that the paraspinal muscles were more susceptible to fatty in ltration and age-related change 30 , and also Sun's conclusion 11 in that we need more exercise to slow down the process of muscle disuse-atrophy and neurotic atrophy caused by LDD.
Meanwhile, to optimize our results we excluded the inference of age for partial correlation analysis. This analysis showed a credibly negative relationship between the LSA of L4 and thickness of ligamentum avum. The ligamentum avum, which is part of the posterior ligamentous complex, and maintains the stability of the posterior column of the spine 21 . This was located under the lamina and connected the adjacent two vertebrae. Our spine represents the axial bone which carries our upper body weight whenever it is stretched or remains still 31 . Thus, when the lumbar bears the upper body weight, gravity can be decomposed into tension along the lamina and vertical lamina tension (Fig. 5).
The tension along the lamina could be referred to as an acting force and according to Newton's third law, the internal tension of the LF would be the reacting force equal to, and working against it. The internal tension of LF can be described as F LF =G*Cosβ, where G represents the upper body gravity, α represents LSA and β∝α (Fig. 5). The angle sum of a triangle is 180. Thus, in a right triangle β∈[0,90°] and the Cosine graph was a descending curve. Using this equation, β was negatively related to Cosβ. G was a constant quantity for an individual; so, α was also negatively related to F LF . Therefore, the tension along the lamina was negatively correlated with LSA. Hayashi et al.
previously reported that LF, with concentrated mechanical stress, showed degeneration with disruption of the elastic bers and an increase in the cartilage matrix increase; this is similar to HLF from patients with lumbar spinal stenosis(LSS) 32 . When LSA was small, the mechanical stress is larger, and the corresponding LF was more likely to be hypertrophied. This explains why the thickness of the ligamentum avum has a strong negative relationship with the LSA of L4. As Jun highlighted that a high T1 slope might be a predisposing factor in degenerative cervical spondylolisthesis 33 , while other research stated that the sacral slope was of importance because a reduction in the sagittal balance of the spine could cause chronic low back pain in patients with degenerative lumbar scoliosis 34 . We inferred that small LSA lead to HLF which was one reason of LSS. Smaller LSA may be one predisposing factor of LSS.
There are several limitations in our research that should be taken into consideration. First, this was a study based in a single center; our conclusions therefore need to be veri ed in future multi-center studies. Second, we did not consider the effect of body mass index, which can affect fatty in ltration, the CSA of the multi dus muscle, and cause stress on the ligament avum. Osteoproliferation appeared to be associated with the LSA, our results did not consider the grade of osteoproliferation in the facet joints. Further research could explore the relationship between these factors.

Conclusion
LSA increases with age and therefore, provides a good index to re ect the morphological differences of the individual lumbar vertebrae.
When excluding the in uence of age, our results showed that LSA will not affect LDD, or the size and quality of the multi dus, but it will have a certain degree of in uence on the HLF. The smaller the LSA, the thicker the corresponding segment of ligamentum avum. It may increase the risk of hypertrophy of ligamentum avum in future.    The proofreading procedure for measuring the lamina slope angle on a sagittal image from three-dimensional computerized tomography.  α3 represents the LSA of L4, while α4 represents the LSA of L5. This photograph shows the force analysis for the ligamentum avum beneath the lamina. 'G' represents the gravity of our upper body, while 'FLF' represents the internal tension of LF.