Clinical trial NCT04936074: Fusion or no Fusion After Decompression of the Spinal Cord in Patients With Degenerative Cervical Myelopathy
Official title: Comparison of Posterior Muscle-preserving Selective Laminectomy and Laminectomy With Fusion for Treating Degenerative Cervical Myelopathy: Myelopathy Randomized Controlled Trial (MyRanC)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cervical Spondylotic Myelopathy
Keywords: Cervical fusion
Cervical spine
Laminectomy
Spinal surgery
Randomized controlled trial
Lead sponsor: Uppsala University Hospital
Sponsor class: OTHER
Collaborators: name: Karolinska Institutet
name: Linkoeping University
name: Sahlgrenska University Hospital
First posted: 2021-06-23
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

Degenerative cervical myelopathy (DCM) is characterized by neck pain, neck stiffness, weakness, paresthesia, sphincter disturbance and balance disorder. The mean age for symptoms is 64 years and more men than women, 2.7:1, are affected. The most common level is C5-C6. DCM is the predominant cause of spinal cord dysfunction in the elderly worldwide. Surgical options include stand-alone laminectomy, laminectomy and fusion and laminoplasty. The preferable surgical approach is though, a matter of controversy. The objective of this study is to compare stand-alone laminectomy to laminectomy and fusion.

Methods/Design:

This is a multicenter randomized, controlled, parallel group non-inferiority trial. A total of 300 adult participants are allocated in a ratio of 1:1. The primary endpoint is reoperation for any reason within 5 years of follow-up. Sample size and power calculations were performed by estimating the reoperation rate after laminectomy to 3.4% and after laminectomy with fusion to 7.9% based on data from the Swedish spine registry (Swespine) on patients with DCM.

Secondary outcomes are the patient derived modified Japanese orthopaedic association (P-mJOA) score, Neck disability index (NDI), European quality of life five dimensions (EQ-5D), Numeric rating scale (NRS) for neck and arm pain, Hospital anxiety and depression scale (HADS), development of kyphosis measured as the cervical sagittal vertical axis (cSVA) and, death. Clinical and radiological follow-up is performed at 3, 12, 24 and 60 months after surgery. The main inclusion criteria is 1-4 levels of DCM in the subaxial spine, C3-C7, with or without deformity. The REDcap will be used for safe data management. Data will be analyzed in the per protocol (PP) population, defined as randomized patients who are still alive without having emigrated or left the study after five years.

Discussion:

This will be the first randomized controlled trial comparing two of the most common surgical treatments for DCM; the posterior muscle-preserving selective laminectomy and posterior laminectomy with instrumented fusion. The results of the MyRanC study will provide surgical treatment recommendations for DCM. This may result in improvements in surgical treatment and clinical practice regarding DCM.

Detailed description: Background:

Degenerative cervical myelopathy (DCM) is characterized by neck pain and stiffness, weakness and paresthesia of the extremities, sphincter disturbance and bowel and balance disorder. DCM is the most common cause of spinal cord dysfunction in the elderly worldwide (1) and the incidence is 41 per million within North America (2). The mean age for symptoms is 64 years of age, more men than women, 2.7:1, are affected and the most common level is C5-C6 (3).

Mechanism:

DCM is typically the consequence of degenerative disc herniation, osteophyte formation and hypertrophy of the ligamentum flavum that compress the spinal cord. Ossification of the posterior longitudinal ligament (OPLL), which is more prevalent in the Asian population, may also cause compression of the spinal cord.

With non-operative treatments, i.e. medication and physiotherapy, 20-60% of the patients deteriorate neurologically and surgical treatment is indicated (4).

Existing knowledge:

The surgical treatment for DCM is decompression of the spinal cord. Decompression may be achieved with an anterior or posterior approach. Several algorithms have been proposed on whether to choose anterior diskectomy and fusion, anterior corpectomy and fusion, posterior laminectomy with fusion, posterior laminoplasty or, posterior laminectomy alone (5,6). Anterior discectomy/corpectomy with fusion is recommended in patients with a straight or kyphotic spine with compression of less than three levels (6). A posterior approach is recommended in patients with cervical lordosis and compression of more than three levels (7). The WFNS Spine Committee modified these recommendations in 2019 towards a wider use of posterior approaches, e.g. in patients with posterior compression at 1 or 2 levels and patients with a flexible kyphosis (8). It was recommended to address anterior compression with an anterior approach and posterior compression by a posterior approach. Hence, when propensity score matching is performed on the basis of MRI classification and description of the degenerative changes in each patient, anterior and/or posterior compression of the spinal cord, there is no difference between anterior or posterior decompression and fusion approaches (9).

Fusion is recommended in patients with DCM and concurrent signs of instability but there is no definition of instability in the degenerated cervical spine (10). In the traumatic cervical spine, however, instability is defined as \>3.5 mm translation or 11° rotation on lateral flexion-extension radiographs (11) but there are no indications that degenerative changes with intact ligaments and unfractured joints would be unstable in the same way.

Kyphosis of cSVA \> 40 mm (13) has been correlated to worse postoperative outcome (normal cSVA = 17-11 mm) (14). Consequently the recommendation is to correct kyphosis by an anterior approach (8) but a correction does not seem to affect the outcomes (15).

It remains a matter of debate among spinal surgeons whether posterior fusion after laminectomy for DCM, should be mandatory or not. After reports of post-laminectomy kyphosis in the 1970s and 1980s (16) prophylactic fusion has commonly been combined with the laminectomy procedure (9). In a report from 1999, 34% of the patients developed kyphosis or swan neck deformity after laminectomy compared with 7% of patients surgically treated with laminoplasty, using a muscle-preserving technique (17). However, a muscle-preserving technique that retains the facet integrity as well as the extensor musculature may be used when performing posterior laminectomy as well and is observed to maintain sagittal balance after surgery without progression of kyphosis (18).

Distal junction kyphosis (DJK) is a kyphotic angulation of at least 10° at the distal segment adjacent to a fused level and occurs in 24% of patients within a year after fusion surgery (19). Adjacent segment pathology (ASP) is progression of degeneration at the levels adjacent to a fused level and may also necessitate reoperation with decompression and extended fusion surgery (20).

Considering the existence of muscle-preserving laminectomy techniques that can maintain cervical lordosis (26), there is reason to explore the additional value of instrumented fusion in the cervical spine.

Although both methods are widely used, they are yet to be compared in a randomized controlled study.

Need for a trial:

There exists a controversy among spinal surgeons regarding the need for posterior fusion when laminectomy for DCM is performed.

We hypothesize that laminectomy without fusion results in shorter hospital stay and quicker return to an active life, without reduced patient satisfaction, functional scores, or delayed kyphosis.

It is important to achieve good outcome with a single surgery, to spare this frail group of patients from reoperations. Therefore, reoperation for any reason within five years after the primary surgery will be the primary endpoint of the current study. Long-term follow-up radiographs and magnetic resonance imaging (MRI) is needed to assess differences in the subsequent degenerative changes including spondylolisthesis, kyphosis, and adjacent segment pathology (ASP) to compare the two strategies.

Additionally, data from this study can be used to identify risk factors for poor outcome to guide surgical decision making.

Objectives:

* To determine the surgical treatment associated with the lowest frequency of reoperations when treating participants with CSM by performing a non-inferiority study comparing laminectomy alone with laminectomy and fusion.
* To evaluate potential differences in outcome including participant satisfaction, functional scores, late degenerative changes including spondylolisthesis, kyphosis, DJK, ASP and, death.

Study setting:

* Uppsala University Hospital
* Karolinska University Hospital, Stockholm
* Ryhov Hospital, Jönköping
* Sahlgrenska University Hospital, Gothenburg

Sample size:

Based on data from the national Swedish spine registry on patients with CSM, reoperation was estimated to 3.4% after standalone laminectomy and 7.9% after laminectomy and fusion. Five year mortality was estimated to 16.3% in the same population.

We further determined that excluding a 5% excess rate of reoperation in the laminectomy group vs laminectomy and fusion was a clinically relevant target for the study, and therefore set the non-inferiority margin at 5 percentage points (pp).

With a sample size of 300 participants and with regards to mortality and an additional 5% loss due to dropout and emigration, we end up with 236 analyzable patients. This results in a power of 87% based on simulation using rerandomization.

Recruitment:

All participants diagnosed with DCM referred for surgical consultation to the orthopedic or neurosurgery departments at the participating centers will be eligible for the study. Oral and written information about the study will be given at the routine physiotherapist appointment before the scheduled doctor's appointment and repeated by the treating surgeon at the following consultation. Participants may be enrolled if they meet the inclusion criteria and sign informed consent.

Allocation:

Participants will be allocated to either standalone laminectomy or laminectomy and fusion through randomization with a 1:1 ratio using the REDcap software (Research Electronic Data Capture), after informed consent and agreement to be included in the study. After inserting the patient´s personal number into REDcap the program reports the random allocation of the patient according to the pre-constructed randomization list. The randomization is stratified for center and participant sex, i.e. using separate lists for each center and sex. The allocation sequence utilizes balanced blocks of three different sizes occurring in random sequence. The principal investigator and study collaborators are blinded to the sequence, the block sizes and block sequence.

Blinding:

Trial participants will not be blinded after assignment to interventions as they have online access to their medical records by a centrally managed system.

The outcome assessors and data analysts will be blinded by using a coding system for the treatment groups.

Dropouts:

Dropouts may be one out of two entities; 1) the participant actively leaves the study or, 2) the participant has died or do not show up on follow-ups for unclear reasons. In case 1, the participant will not be part of the study anymore and data will not be retrieved from other information sources. In case 2, information about living participants will be retrieved from the medical records, radiographs, and the Swedish patient registry.

Statistical methods:

To test for non-inferiority, a two-sided 95% confidence interval (CI) for the difference in failure rates between the two groups will be computed. To account for sparsity of events, the CI will be computed using rerandomization techniques,10 blocked on sex, since the randomization was stratified on sex. Non-inferiority will be claimed if the upper limit of the CI is less than 5 pp. If non-inferiority is demonstrated, superiority will also be tested using the same CI, although the study is likely underpowered to detect this.

All endpoints will be analyzed in the per protocol (PP) population, defined as randomized patients who are still alive without having emigrated or left the study after five years.

The secondary outcomes listed above will be analyzed using ordinal regression models, adjusted for sex. In addition, each secondary endpoint will be dichotomized and analyzed using logistic regression. The dichotomization will be done by comparing baseline and follow-up data, either based on MCID when applicable, or else by defining success as an improvement from baseline. All secondary endpoints will be analyzed at 1, 2 and 5 years of follow-up, but not until the study is closed and the primary results is published.

The study statistician is Lars Lindhagen at Uppsala Clinical Research Center.

Data collection:

Questionnaires including baseline questionnaires and postal follow-up questionnaires as well as validated PROMs will be distributed the participants preoperatively. Postoperatively the participants are routinely followed via the Swespine (swespine.se) and follow-up questionnaires and PROMS will be retrieved from Swespine.41,49,50

Closing statement:

Degenerative cervical myelopathy is the most common cause of spinal cord dysfunction in the elderly worldwide and the incidence is 41 per million within North America. Until now there is no consensus whether to fuse or not when laminectomy is performed and the choice of surgical method is mainly up to the surgeon's preference.

This will be the first randomized controlled trial comparing two of the most common surgical treatments for DCM; the posterior muscle-preserving selective laminectomy and posterior laminectomy with instrumented fusion.

Eligibility criteria: Inclusion Criteria:

* Age \>18 years
* 1-4 levels of cervical degenerative myelopathy in the subaxial spine, C3-C7, without or with deformity not exceeding exclusion criteria, see below.
* Eligible for both treatments
* Ability to understand and read Swedish language
* Symptomatic myelopathy with at least one clinical sign of myelopathy
* No previous spine surgery
* Psychosocially, mentally, and physically able to fully comply with this protocol, including adhering to scheduled visits, treatment plan, completing forms, and other study procedures
* Personally, signed and dated informed consent document prior to any study-related procedures, indicating that the patient has been informed of all pertinent aspects of the trial

  * Definition of kyphosis - cSVA \> 40 mm and/or C2-C7 Cobb \> 10° kyphosis. Definition of spondylolisthesis - anterior slippage of \> 2 mm on cervical radiographs taken in the neutral position.

Exclusion Criteria:

* Local kyphosis; a modified K-line minimum interval distance (INT) of \<4 mm
* Spondylolisthesis \>4 mm and simultaneous translation \>2 mm on lateral flexion/extension radiographs
* Soft disc herniations only (no signs of osteophyte formation and hypertrophy of the ligamentum flavum)
* Active infection
* Neoplasm
* Trauma
* Inflammatory disease (i.e., rheumatoid arthritis or ankylosing spondylitis or DISH)
* Systemic disease including HIV
* Lumbar or thoracic spinal disease to the extent that surgical consideration is probable or anticipated within 6 months after the cervical surgical treatment (significant lumbar stenosis as defined by Schizas C or worse).
* OPLL
* Parkinson´s disease
* Drug abuse, dementia, or other reason to suspect poor adherence to follow-up
* Previous cervical spine surgery

Primary outcomes:
measure: The primary endpoint will be reoperation for any reason to reflect whether laminectomy alone or laminectomy with instrumented fusion results in fewer reoperations without increasing the frequency of complications.
timeFrame: Recorded at 5 years of follow-up
Secondary outcomes:
measure: Change from baseline in myelopathy score on the patient derived modified Japanese Orthopedic Association scale (P-mJOA) at 2 years.
timeFrame: Measured at baseline and 2 years of follow-up
measure: Change from baseline in participants disability score on the Neck disability index (NDI) at 2 years.
timeFrame: Measured at baseline and 2 years of follow-up
measure: Change from baseline in myelopathy score on the Nurick scale at 2 years.
timeFrame: Measured at baseline and 2 years of follow-up
measure: Change from baseline in the patient Quality of life five dimensions (EQ-5D index) at 2 years.
timeFrame: Measured at baseline and 2 years of follow-up
measure: Change from baseline in pain scores on the Numeric rating scale (NRS) at 2 years.
timeFrame: Measured at 2 years of follow-up
measure: Change at baseline in number of participants with psychological impairment on the Hospital anxiety and depression scale (HADS) in both groups.
timeFrame: Measured at baseline
measure: Change in number of satisfied participants on the patient global assessment in both groups at 2 years.
timeFrame: Measured at baseline and 2 years of follow-up
measure: Change from baseline in myelopathy on the 10-s grip and release test at 2 years.
timeFrame: Measured at baseline and 2 years of follow-up
measure: Change from baseline in myelopathy on the 10-s foot-tapping speed test at 2 years.
timeFrame: Measured at baseline and 2 years of follow-up
measure: Difference in number of participants with treatment-related adverse events in both groups at 5 years.
timeFrame: Recorded at 5 years of follow-up
measure: Change from baseline in sagittal alignment on neutral radiographs at 5 years.
timeFrame: Assessed preoperatively and at 5 years of follow-up
measure: Number of participants with change in adjacent segment pathology (ASP) on MRIs from baseline to 5 years of follow-up.
timeFrame: Assessed preoperatively and at 5 years of follow-up
measure: Number of participants with change in compression of the spinal cord on the index level on MRIs from baseline to 5 years of follow-up.
timeFrame: Assessed preoperatively and at 5 years of follow-up
measure: Change in direct costs between the groups at 1 year of follow-up.
timeFrame: Recorded at 1 year of follow-up.
measure: Change in indirect societal costs at one years of follow-up.
timeFrame: Recorded at 1 year of follow-up
measure: Mortality
timeFrame: Recorded at 5 years of follow-up
Other outcomes:
Locations:
city: Uppsala
country: Sweden
facility: Academic Hospital of Uppsala
Study officials:
affiliation: Uppsala University Hospital
name: Anna MacDowall, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Northover JR, Wild JB, Braybrooke J, Blanco J. The epidemiology of cervical spondylotic myelopathy. Skeletal Radiol. 2012 Dec;41(12):1543-6. doi: 10.1007/s00256-012-1388-3. Epub 2012 Mar 17.
citation: Kalsi-Ryan S, Karadimas SK, Fehlings MG. Cervical spondylotic myelopathy: the clinical phenomenon and the current pathobiology of an increasingly prevalent and devastating disorder. Neuroscientist. 2013 Aug;19(4):409-21. doi: 10.1177/1073858412467377. Epub 2012 Nov 30.
citation: Nouri A, Tetreault L, Singh A, Karadimas SK, Fehlings MG. Degenerative Cervical Myelopathy: Epidemiology, Genetics, and Pathogenesis. Spine (Phila Pa 1976). 2015 Jun 15;40(12):E675-93. doi: 10.1097/BRS.0000000000000913.
citation: Karadimas SK, Erwin WM, Ely CG, Dettori JR, Fehlings MG. Pathophysiology and natural history of cervical spondylotic myelopathy. Spine (Phila Pa 1976). 2013 Oct 15;38(22 Suppl 1):S21-36. doi: 10.1097/BRS.0b013e3182a7f2c3.
citation: Kato S, Nouri A, Wu D, Nori S, Tetreault L, Fehlings MG. Comparison of Anterior and Posterior Surgery for Degenerative Cervical Myelopathy: An MRI-Based Propensity-Score-Matched Analysis Using Data from the Prospective Multicenter AOSpine CSM North America and International Studies. J Bone Joint Surg Am. 2017 Jun 21;99(12):1013-1021. doi: 10.2106/JBJS.16.00882.
citation: Albert TJ, Vacarro A. Postlaminectomy kyphosis. Spine (Phila Pa 1976). 1998 Dec 15;23(24):2738-45. doi: 10.1097/00007632-199812150-00014.
citation: Nori S, Shiraishi T, Aoyama R, Ninomiya K, Yamane J, Kitamura K, Ueda S. Muscle-Preserving Selective Laminectomy Maintained the Compensatory Mechanism of Cervical Lordosis After Surgery. Spine (Phila Pa 1976). 2018 Apr 15;43(8):542-549. doi: 10.1097/BRS.0000000000002359.
citation: Parker SL, Godil SS, Shau DN, Mendenhall SK, McGirt MJ. Assessment of the minimum clinically important difference in pain, disability, and quality of life after anterior cervical discectomy and fusion: clinical article. J Neurosurg Spine. 2013 Feb;18(2):154-60. doi: 10.3171/2012.10.SPINE12312. Epub 2012 Nov 23.
citation: Carreon LY, Glassman SD, Campbell MJ, Anderson PA. Neck Disability Index, short form-36 physical component summary, and pain scales for neck and arm pain: the minimum clinically important difference and substantial clinical benefit after cervical spine fusion. Spine J. 2010 Jun;10(6):469-74. doi: 10.1016/j.spinee.2010.02.007. Epub 2010 Apr 1.
citation: Landriel Ibanez FA, Hem S, Ajler P, Vecchi E, Ciraolo C, Baccanelli M, Tramontano R, Knezevich F, Carrizo A. A new classification of complications in neurosurgery. World Neurosurg. 2011 May-Jun;75(5-6):709-15; discussion 604-11. doi: 10.1016/j.wneu.2010.11.010.
citation: Kato S, Nouri A, Wu D, Nori S, Tetreault L, Fehlings MG. Impact of Cervical Spine Deformity on Preoperative Disease Severity and Postoperative Outcomes Following Fusion Surgery for Degenerative Cervical Myelopathy: Sub-analysis of AOSpine North America and International Studies. Spine (Phila Pa 1976). 2018 Feb 15;43(4):248-254. doi: 10.1097/BRS.0000000000002307.
citation: Kawasaki M, Tani T, Ushida T, Ishida K. Anterolisthesis and retrolisthesis of the cervical spine in cervical spondylotic myelopathy in the elderly. J Orthop Sci. 2007 May;12(3):207-13. doi: 10.1007/s00776-007-1122-5. Epub 2007 May 31.
citation: Shamji MF, Mohanty C, Massicotte EM, Fehlings MG. The Association of Cervical Spine Alignment with Neurologic Recovery in a Prospective Cohort of Patients with Surgical Myelopathy: Analysis of a Series of 124 Cases. World Neurosurg. 2016 Feb;86:112-9. doi: 10.1016/j.wneu.2015.09.044. Epub 2015 Sep 25.
citation: White AA 3rd, Johnson RM, Panjabi MM, Southwick WO. Biomechanical analysis of clinical stability in the cervical spine. Clin Orthop Relat Res. 1975;(109):85-96. doi: 10.1097/00003086-197506000-00011.
citation: Schizas C, Theumann N, Burn A, Tansey R, Wardlaw D, Smith FW, Kulik G. Qualitative grading of severity of lumbar spinal stenosis based on the morphology of the dural sac on magnetic resonance images. Spine (Phila Pa 1976). 2010 Oct 1;35(21):1919-24. doi: 10.1097/BRS.0b013e3181d359bd.
citation: Wilson JRF, Badhiwala JH, Moghaddamjou A, Martin AR, Fehlings MG. Degenerative Cervical Myelopathy; A Review of the Latest Advances and Future Directions in Management. Neurospine. 2019 Sep;16(3):494-505. doi: 10.14245/ns.1938314.157. Epub 2019 Aug 26.
citation: Woods BI, Hohl J, Lee J, Donaldson W 3rd, Kang J. Laminoplasty versus laminectomy and fusion for multilevel cervical spondylotic myelopathy. Clin Orthop Relat Res. 2011 Mar;469(3):688-95. doi: 10.1007/s11999-010-1653-5.
citation: Badiee RK, Mayer R, Pennicooke B, Chou D, Mummaneni PV, Tan LA. Complications following posterior cervical decompression and fusion: a review of incidence, risk factors, and prevention strategies. J Spine Surg. 2020 Mar;6(1):323-333. doi: 10.21037/jss.2019.11.01.
citation: Stromqvist B, Jonsson B, Fritzell P, Hagg O, Larsson BE, Lind B. The Swedish National Register for lumbar spine surgery: Swedish Society for Spinal Surgery. Acta Orthop Scand. 2001 Apr;72(2):99-106. doi: 10.1080/000164701317323327. No abstract available.
citation: Stromqvist B, Fritzell P, Hagg O, Jonsson B; Swedish Society of Spinal Surgeons. The Swedish Spine Register: development, design and utility. Eur Spine J. 2009 Aug;18 Suppl 3(Suppl 3):294-304. doi: 10.1007/s00586-009-1043-4. Epub 2009 Jun 4.
citation: Nurick S. The pathogenesis of the spinal cord disorder associated with cervical spondylosis. Brain. 1972;95(1):87-100. doi: 10.1093/brain/95.1.87. No abstract available.
citation: Tetreault L, Nouri A, Kopjar B, Cote P, Fehlings MG. The Minimum Clinically Important Difference of the Modified Japanese Orthopaedic Association Scale in Patients with Degenerative Cervical Myelopathy. Spine (Phila Pa 1976). 2015 Nov;40(21):1653-9. doi: 10.1097/BRS.0000000000001127.
citation: Rhee JM, Shi WJ, Cyriac M, Kim JY, Zhou F, Easley KA, Patel A. The P-mJOA: A Patient-derived, Self-reported Outcome Instrument for Evaluating Cervical Myelopathy: Comparison with the mJOA. Clin Spine Surg. 2018 Mar;31(2):E115-E120. doi: 10.1097/BSD.0000000000000591.
citation: Young IA, Cleland JA, Michener LA, Brown C. Reliability, construct validity, and responsiveness of the neck disability index, patient-specific functional scale, and numeric pain rating scale in patients with cervical radiculopathy. Am J Phys Med Rehabil. 2010 Oct;89(10):831-9. doi: 10.1097/PHM.0b013e3181ec98e6.
citation: Machino M, Imagama S, Ando K, Kobayashi K, Hida T, Ito K, Tsushima M, Matsumoto A, Tanaka S, Morozumi M, Ito K, Kato F, Nishida Y, Ishiguro N. Prospective Comparison of Age- and Sex-related Differences in Quantifiable 10-S Grip and Release and 10-S Step Test Results for Diagnosis of Cervical Spondylotic Myelopathy in 454 Patients With Cervical Spondylotic Myelopathy and 818 Asymptomatic Subjects. Spine (Phila Pa 1976). 2017 Apr 15;42(8):578-585. doi: 10.1097/BRS.0000000000001849.
citation: Enoki H, Tani T, Ishida K. Foot Tapping Test as Part of Routine Neurologic Examination in Degenerative Compression Myelopathies: A Significant Correlation between 10-sec Foot-tapping Speed and 30-m Walking Speed. Spine Surg Relat Res. 2019 Jan 15;3(3):207-213. doi: 10.22603/ssrr.2018-0033. eCollection 2019.
citation: Lofgren H, Osman A, Blomqvist A, Vavruch L. Sagittal Alignment After Laminectomy Without Fusion as Treatment for Cervical Spondylotic Myelopathy: Follow-up of Minimum 4 Years Postoperatively. Global Spine J. 2020 Jun;10(4):425-432. doi: 10.1177/2192568219858302. Epub 2019 Jun 26.
citation: Tatter C, Fletcher-Sandersjoo A, Persson O, Burstrom G, Grane P, Edstrom E, Elmi-Terander A. Incidence and predictors of kyphotic deformity following resection of cervical intradural tumors in adults: a population-based cohort study. Acta Neurochir (Wien). 2020 Nov;162(11):2905-2913. doi: 10.1007/s00701-020-04416-4. Epub 2020 Jun 16.
citation: Blackwelder WC. "Proving the null hypothesis" in clinical trials. Control Clin Trials. 1982 Dec;3(4):345-53. doi: 10.1016/0197-2456(82)90024-1.
citation: White IR, Royston P, Wood AM. Multiple imputation using chained equations: Issues and guidance for practice. Stat Med. 2011 Feb 20;30(4):377-99. doi: 10.1002/sim.4067. Epub 2010 Nov 30.