Clinical and Radiological Characteristics of Cervical Spondylotic Myelopathy in Young Adults: A Retrospective Case Series of Patients under Age 30.

Background and Objectives: Cervical spondylotic myelopathy (CSM) is a degenerative disease and occurs more frequently with age. In fact, the development of non-herniated CSM under age 30 is uncommon. Therefore, a retrospective case series was designed to clarify clinical and radiological characteristics of young adult patients with CSM under age 30. Materials and Methods: A total of seven patients, all men, with non-herniated, degenerative CSM under age 30 were retrieved from the medical records of 2598 hospitalized CSM patients (0.27%). Patient demographics and backgrounds were assessed. The sagittal alignment, congenital canal stenosis, dynamic canal stenosis, and vertebral slips in the cervical spine were radiographically evaluated. The presence of degenerative discs, intramedullary high-signal intensity lesions, and sagittal spinal cord compression on T2-weighted magnetic resonance images (MRIs) and axial spinal cord deformity on T1-weighted MRIs was identified. Results: All patients (100.0%) had relatively high daily sports activities and/or jobs requiring frequent neck extension. Cervical spine radiographs revealed the sagittal alignment as the "reverse-sigmoid" type in 57.1% of patients and "straight" type in 28.6%. All patients (100.0%) presented congenital cervical stenosis with the canal diameter ≤12 mm and/or Torg-Pavlov ratio <0.80. Furthermore, all patients (100.0%) developed dynamic stenosis with the canal diameter ≤12 mm and/or posterior vertebral slip ≥2 mm at the neurologically responsible segment in full-extension position. In MRI examination, all discs at the neurologically responsible level (100.0%) were degenerative. Intramedullary abnormal intensity lesions were detected in 85.7% of patients, which were all at the neurologically responsible disc level. Conclusions: Patients with non-herniated, degenerative CSM under age 30 are rare but more common in men with mild sagittal "reverse-sigmoid" or "straight" deformity and congenital canal stenosis. Relatively high daily activities, accumulating neck stress, can cause an early development of intervertebral disc degeneration and dynamic canal stenosis, leading to CSM in young adults.

Involvement of Autophagy in Rat Tail Static Compression-Induced Intervertebral Disc Degeneration and Notochordal Cell Disappearance.

The intervertebral disc is the largest avascular low-nutrient organ in the body. Thus, resident cells may utilize autophagy, a stress-response survival mechanism, by self-digesting and recycling damaged components. Our objective was to elucidate the involvement of autophagy in rat experimental disc degeneration. In vitro, the comparison between human and rat disc nucleus pulposus (NP) and annulus fibrosus (AF) cells found increased autophagic flux under serum deprivation rather in humans than in rats and in NP cells than in AF cells of rats (n = 6). In vivo, time-course Western blotting showed more distinct basal autophagy in rat tail disc NP tissues than in AF tissues; however, both decreased under sustained static compression (n = 24). Then, immunohistochemistry displayed abundant autophagy-related protein expression in large vacuolated disc NP notochordal cells of sham rats. Under temporary static compression (n = 18), multi-color immunofluorescence further identified rapidly decreased brachyury-positive notochordal cells with robust expression of autophagic microtubule-associated protein 1 light chain 3 (LC3) and transiently increased brachyury-negative non-notochordal cells with weaker LC3 expression. Notably, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic death was predominant in brachyury-negative non-notochordal cells. Based on the observed notochordal cell autophagy impairment and non-notochordal cell apoptosis induction under unphysiological mechanical loading, further investigation is warranted to clarify possible autophagy-induced protection against notochordal cell disappearance, the earliest sign of disc degeneration, through limiting apoptosis.

Quality of life and cost-utility of surgical treatment for patients with spinal metastases: prospective cohort study.

PURPOSE: Palliative surgery for patients with spinal metastasis provides good clinical outcomes. However, there have been few studies on quality of life (QOL) and cost-utility of this surgery. We aimed to elucidate QOL and cost-utility of surgical treatment for spinal metastasis. METHODS: We prospectively analyzed 47 patients with spinal metastasis from 2010 to 2014 who had a surgical indication. Thirty-one patients who desired surgery underwent spinal surgery (surgery group). Sixteen patients who did not want to undergo spinal surgery (non-surgery group). The EuroQol 5D (EQ-5D) and relevant costs were measured at one, three, six, and 12 months after study enrollment. Health state values were obtained by Japanese EQ-5D scoring and quality-adjusted life years (QALY) gained were calculated for each group. Cost-utility was expressed as the incremental cost-utility ratio (ICUR). RESULTS: Health state values improved from 0.036 at study enrollment to 0.448 at 12 months in the surgery group, but deteriorated from 0.056 to 0.019 in the non-surgery group, with a significant difference between groups (P < 0.05). The mean QALY gained at 12 months were 0.433 in the surgery group and 0.024 in the non-surgery group. The mean total cost per patient in the surgery group was $25,770 compared with $8615 in the non-surgery group. The ICUR using oneyear follow-up data was $42,003/QALY gained. CONCLUSIONS: Surgical treatment for spinal metastases is associated with significant improvement in health state value. In orthopaedic surgery, an ICUR less than $50,000/QALY gained is considered acceptable cost-effectiveness. Our results indicate that surgical treatment could be cost-effective.

Predictive Risk Factors of Cervical Spine Instabilities in Rheumatoid Arthritis: A Prospective Multicenter Over 10-Year Cohort Study.

STUDY DESIGN: A prospective multicenter cohort study for more than 10 years of outpatients with rheumatoid arthritis (RA). OBJECTIVE: To identify predictive risk factors of cervical spine instabilities, which may induce compression myelopathy in patients with RA. SUMMARY OF BACKGROUND DATA: Many reports described the natural course of cervical spine involvement in RA. Only a few studies, however, conducted comprehensive evaluation of its prognostic factors. METHODS: Cervical spine instability was radiographically defined as atlantoaxial subluxation with the atlantodental interval greater than 3 mm, vertical subluxation (VS) with the Ranawat value less than 13 mm, and subaxial subluxation with irreducible translation of 2 mm or higher. The "severe" category of instability was defined as atlantoaxial subluxation with the atlantodental interval of 10 mm or lower, vertical subluxation with the Ranawat value of 10 mm or higher, and subaxial subluxation with translation of 4 mm or higher or at multiple levels. Of 503 "definite" or "classical" patients with RA without baseline "severe" instability, 143 were prospectively followed throughout for more than 10 years. The Cox proportional hazards regression analysis was performed to determine predictors for the development of "severe" instabilities. To exclude biases from the low follow-up rate, similar assessments were performed in 223 patients followed for more than 5 years from baseline. RESULTS: The incidence of cervical spine instabilities and "severe" instabilities significantly increased during more than 10 years in both 143 and 223 cohorts (all P < 0.01). Multivariable Cox proportional hazards models found that baseline mutilating changes (hazard ratio [HR]=19.15, 95% confidence interval [95% CI] = 3.96-92.58, P < 0.01), corticosteroid administration (HR = 4.00, 95% CI = 1.76-9.11, P < 0.01), and previous joint surgery (HR = 1.99, 95% CI = 1.01-3.93, P = 0.048) correlated with the progression to "severe" instability in 143 cases and also in 223 cases (HR = 8.12, 95% CI = 2.22-29.64, P < 0.01; HR = 3.31, 95% CI = 1.68-6.53, P < 0.01; and HR = 2.07, 95% CI = 1.16-3.69, P = 0.014, respectively). CONCLUSION: Established mutilating changes, concomitant corticosteroid treatment, and previous joint surgery are relatively robust indicators for a poor prognosis of the cervical spine in patients with RA, based on the consistency in more than 10-year analysis of two different settings. LEVEL OF EVIDENCE: 3.

Prospective Cohort Study of Performance Status and Activities of Daily Living After Surgery for Spinal Metastasis.

STUDY DESIGN: A prospective cohort study of performance status (PS) and activities of daily living (ADL) in patients with spinal metastasis. OBJECTIVE: To identify the effect of spinal surgery on PS and ADL in patients with spinal metastasis. SUMMARY OF BACKGROUND DATA: Spinal metastasis causes severe neurological deficits, resulting in drastic loss of patients' PS and ADL. However, the effect of spine surgery on PS and ADL is not well known. MATERIALS AND METHODS: Seventy patients with spinal metastasis were enrolled in this study. Forty-six patients desired and underwent spine surgery ("surgery" group) and 24 patients did not desire surgery ("nonsurgery" group). Both groups received optimal treatments, including radiation, chemotherapy, and palliative care services. Evaluation was performed at 1, 3, and 6 months after study enrollment using the Eastern Cooperative Oncology Group PS, the Barthel index (BI) for ADL, and Frankel classification for neurological status. RESULTS: There was no significant difference in baseline PS, the BI, or Frankel classification between the groups. The surgery group showed significant improvement in PS, maintaining grade 2 or less throughout the duration of the study, as well as in ADL, exceeding 70 points of the BI, compared with the nonsurgery group (P<0.05). Significantly improved neurological condition was also observed in the surgery group over the following 6 months. More than 95% of patients who underwent surgery improved their PS, the BI, and neurological status. Furthermore, >80% of these patients maintained improvement in PS, the BI, and neurological status for at least 6 months. In contrast, PS, the BI, and neurological status of patients in the "nonsurgery" group deteriorated throughout the study period. CONCLUSIONS: Spine surgery improves PS, ADL, and neurological status in patients with spinal metastasis for a minimum 6 months. This indicates that these patients can acquire an independent daily life.

Expression of adiponectin receptors in human and rat intervertebral disc cells and changes in receptor expression during disc degeneration using a rat tail temporary static compression model.

BACKGROUND: Adipose tissue is a large endocrine organ known to secret adiponectin, which has anti-diabetic, anti-atherogenic, and anti-inflammatory properties. Adiponectin is widely involved in systemic disease, diabetes mellitus, and cardiac infraction. This study aimed to investigate the involvement of adiponectin in intervertebral disc (IVD) degeneration. METHODS: Adipose and IVD tissues were obtained from human patients undergoing surgery (n = 4) and from skeletally mature Sprague-Dawley rats (n = 21). Tissues were stained immunohistochemically for adiponectin and adiponectin receptors AdipoR1 and AdipoR2. Changes in adiponectin receptor expression with IVD degeneration severity were then investigated using a rat tail temporary compression model. Rat IVD tissues were stained immunohistochemically with AdipoR1 or AdipoR2, and immunopositive cell percentages were calculated. Rat nucleus pulposus (NP) and annulus fibrosus (AF) tissues were isolated separately and treated with recombinant adiponectin (Ad 0.1 or 1.0 µg/ml) and/or interleukin-1 beta (IL-1ß) (0.2 µg/ml) for 24 h. The four groups were as follows: control group (no treatment), IL-1ß group (IL-1ß-only treatment), IL-1ß+Ad (0.1) group (IL-1ß and adiponectin [0.1 µg/ml] treatment), and IL-1ß+Ad (1.0) group (IL-1ß and adiponectin [1.0 µg/ml]). Real-time reverse transcription-polymerase chain reaction was performed to evaluate messenger-RNA (mRNA) expression of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). RESULTS: Adiponectin was widely expressed in human subcutaneous and epidural adipose tissue. In rat IVD tissue, adiponectin was not observed in NP and AF. However, both AdipoR1 and AdipoR2 were widely expressed in both human and rat IVD tissues, with no significant differences in expression levels between receptors. Furthermore, expression levels of AdipoR1 and AdipoR2 were gradually decreased with increased IVD degeneration severity. Interestingly, mRNA expression levels of TNF-α and IL-6 were significantly upregulated by IL-1ß stimulation. TNF-α expression in the IL-1ß+Ad 1.0 group was significantly lower than that in the IL-1ß group in both NP and AF cells (P < 0.05). Finally, IL-6 expression was not affected by adiponectin treatment in IVD cells. CONCLUSIONS: This study investigated for the first time the expression of adiponectin receptors in human and rat IVD cells. The findings indicate that adiponectin produced by the systemic or epidural adipose tissue may be involved in the pathomechanism of IVD degeneration.

Recombinant human SIRT1 protects against nutrient deprivation-induced mitochondrial apoptosis through autophagy induction in human intervertebral disc nucleus pulposus cells.

INTRODUCTION: Nutrient deprivation is a likely contributor to intervertebral disc (IVD) degeneration. Silent mating type information regulator 2 homolog 1 (SIRT1) protects cells against limited nutrition by modulation of apoptosis and autophagy. However, little evidence exists regarding the extent to which SIRT1 affects IVD cells. Therefore, we conducted an in vitro study using human IVD nucleus pulposus (NP) cells. METHODS: Thirty-two IVD specimens were obtained from patients who underwent surgical intervention and were categorized based on Pfirrmann IVD degeneration grades. Cells were isolated from the NP and cultured in the presence of recombinant human SIRT1 (rhSIRT1) under different serum conditions, including 10 % (v/v) fetal bovine serum (FBS) as normal nutrition (N) and 1 % (v/v) FBS as low nutrition (LN). 3-Methyladenine (3-MA) was used to inhibit autophagy. Autophagic activity was assessed by measuring the absorbance of monodansylcadaverine and immunostaining and Western blotting for light chain 3 and p62/SQSTM1. Apoptosis and pathway analyses were performed by flow cytometry and Western blotting. RESULTS: Cells cultured under LN conditions decreased in number and exhibited enhanced autophagy compared with the N condition. Medium supplementation with rhSIRT1 inhibited this decrease in cell number and induced an additional increase in autophagic activity (P < 0.05), whereas the combined use of rhSIRT1 and 3-MA resulted in drastic decreases in cell number and autophagy (P < 0.05). The incidence of apoptotic cell death increased under the LN condition, which was decreased by rhSIRT1 (P < 0.05) but increased further by a combination of rhSIRT1 and 3-MA (P < 0.05). Under LN conditions, NP cells showed a decrease in antiapoptotic Bcl-2 and an increase in proapoptotic Bax, cleaved caspase 3, and cleaved caspase 9, indicating apoptosis induction via the mitochondrial pathway. These changes were suppressed by rhSIRT1 but elevated further by rhSIRT1 with 3-MA, suggesting an effect of rhSIRT1-induced autophagy on apoptosis inhibition. Furthermore, the observed autophagy and apoptosis were more remarkable in cells from IVDs of Pfirrmann grade IV than in those from IVDs of Pfirrmann grade II. CONCLUSIONS: SIRT1 protects against nutrient deprivation-induced mitochondrial apoptosis through autophagy induction in human IVD NP cells, suggesting that rhSIRT1 may be a potent treatment agent for human degenerative IVD disease.

Functional impact of integrin α5ß1 on the homeostasis of intervertebral discs: a study of mechanotransduction pathways using a novel dynamic loading organ culture system.

BACKGROUND CONTEXT: Intervertebral disc (IVD) degeneration, a major cause of low back pain, is considered to be induced by daily mechanical loading. Mechanical stress is widely known to affect cell survival and extracellular matrix metabolism in many cell types. Although the involvement of integrin α5ß1 transmembrane mechanoreceptor in IVD degeneration has been reported, the precise function of integrin α5ß1 remains obscure. PURPOSE: To reflect IVD tissue response to mechanical stress using a dynamic loading organ culture system and elucidate the functional impact of integrin α5ß1 on the pathomechanism of IVD degeneration. STUDY DESIGN: An ex vivo study using a dynamic loading organ culture system. METHODS: Ninety-six rat IVD explants were examined. Intervertebral discs were subjected to 1.3 MPa, 1.0 Hz dynamic compressive load in the presence or absence of an Arg-Gly-Asp (RGD) peptide with affinity to the fibronectin binding-site of integrin α5ß1. Cell viability and histomorphology were assessed. The localization of integrin α5ß1 in the IVD was assessed by immunohistochemistry. Gene expression levels of IVD cells were evaluated using real-time reverse transcription-polymerase chain reaction. RESULTS: In the nucleus pulposus (NP), cell density and viability were reduced by dynamic compressive load. Histologic degenerative alterations, mainly seen in the NP, were the morphologic changes of NP cells. In both NP and annulus fibrosus (AF), immunohistochemistry revealed localization of integrin α5ß1 and that the messenger-RNA expression of integrin α5ß1 was increased by dynamic load. Dynamic load induced a catabolic effect, the stimulation of matrix metalloproteinase-3 and -13 gene expressions by NP and AF cells. The RGD peptide partially blocked the histologic alterations and the catabolic effect. CONCLUSIONS: The dynamic loading organ culture system simulated cellular responses to mechanical loading of the IVD. Our results suggest that IVD cells recognize the mechanical stress through RGD integrins, particularly the α5ß1 subtype that is highly expressed in NP and AF cells. Further experiments using this system will provide information about pathomechanisms of IVD degeneration through the mechanotransduction pathways.