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1.  Cervical spondylomyelopathy in Great Danes: A magnetic resonance imaging morphometric study 
Morphometric investigations comparing normal and affected animals increase our understanding of spinal diseases in dogs. The aim of this study was to generate morphometric data for osseous-associated cervical spondylomyelopathy (CSM) in Great Danes (GDs). Magnetic resonance imaging (MRI) morphometric features of the cervical vertebral column of GDs with and without clinical signs of CSM were characterized and compared. Thirty client-owned GDs were prospectively enrolled, including 15 clinically normal and 15 CSM-affected GDs. All dogs underwent MRI of the cervical to thoracic vertebral column (C2–C3 through T1–T2). Areas of the cranial and caudal articular processes, and the height, width and areas of the vertebral canal and spinal cord were determined. Middle foraminal heights were measured. Intervertebral disc width was measured before and after traction. Intraobserver and interobserver agreement were calculated. CSM-affected GDs had larger areas of the caudal articular processes from C2–C3 through T1–T2. In CSM-affected GDs, the vertebral canal and spinal cord areas were significantly smaller at C5–C6 and C6–C7, the vertebral canal width was significantly narrower at C6–C7 and C7–T1, and the spinal cord width was significantly narrower at C5–C6 and C6–C7. Middle foraminal height was smaller in CSM-affected GDs from C3–C4 through C7-T1. Neutral intervertebral disc widths were smaller in CSM-affected GDs. It was concluded that the cervical vertebral canal dimensions are significantly different between normal and CSM-affected GDs. Absolute vertebral canal stenosis and severe foraminal stenosis involving the cervical vertebrae distinguish CSM-affected from clinically normal GDs. These findings are relevant to the pathogenesis of osseous-associated CSM and should be taken into consideration when performing imaging studies and planning surgery.
PMCID: PMC4169205  PMID: 24888675
Canine; Osseous-associated cervical; spondylomyelopathy; Spinal cord; Stenosis; Wobbler syndrome
2.  Magnetic resonance imaging features of Great Danes with and without clinical signs of cervical spondylomyelopathy 
To characterize and compare the MRI morphological features of the cervical vertebral column of Great Danes with and without clinical signs of cervical spondylomyelopathy (CSM).
Prospective cohort study.
30 Great Danes (15 clinically normal and 15 CSM-affected).
All dogs underwent MRI of the cervical vertebral column (C2–3 through T1–2). Features evaluated included sites of subarachnoid space compression, spinal cord compression, or both; degree, cause, and direction of compression; MRI signal changes of the spinal cord; articular process (facet) joint characteristics; internal vertebral venous plexus visibility; and presence of extradural synovial cysts as well as presence and degree of intervertebral disk degeneration and foraminal stenosis.
Clinically normal and CSM-affected dogs had 11 and 61 compressive sites, respectively, detected with MRI. All CSM-affected dogs had ≥ 1 site of spinal cord compression. No signal changes were observed in spinal cords of normal dogs, whereas 14 sites of hyperintensity were found in 9 CSM-affected dogs. Foraminal stenosis was present in 11 clinically normal and all CSM-affected dogs. The number of stenotic foraminal sites was significantly greater in the CSM-affected group, and severe stenosis appeared to be more common in this group than in the clinically normal group. Significant differences were identified between clinically normal and CSM-affected dogs with regard to amount of synovial fluid evident, regularity of articular surfaces, degree of articular process joint proliferation, and internal vertebral venous plexus visibility.
Conclusions and Clinical Relevance
Abnormalities were detected with MRI in several clinically normal Great Danes. Severe spinal cord compression, number of stenotic foraminal sites, and signal changes within the spinal cord distinguished CSM-affected from clinically normal Great Danes.
PMCID: PMC4213553  PMID: 25075822
3.  Force Plate Gait Analysis in Doberman Pinschers with and without Cervical Spondylomyelopathy 
The most accepted means of evaluating the response of a patient with cervical spondylomyelopathy (CSM) to treatment is subjective and based on the owner and clinician's perception of the gait.
To establish and compare kinetic parameters based on force plate gait analysis between normal and CSM-affected Dobermans.
Nineteen Doberman Pinschers: 10 clinically normal and 9 with CSM.
Force plate analysis was prospectively performed in all dogs. At least 4 runs of ipsilateral limbs were collected from each dog. Eight force platform parameters were evaluated, including peak vertical force (PVF) and peak vertical impulse (PVI), peak mediolateral force (PMLF) and peak mediolateral impulse, peak braking force and peak braking impulse, and peak propulsive force (PPF) and peak propulsive impulse. In addition, the coefficient of variation (CV) for each limb was calculated for each parameter. Data analysis was performed by a repeated measures approach.
PMLF (P = .0062), PVI (P = .0225), and PPF (P = .0408) were found to be lower in CSM-affected dogs compared with normal dogs. Analysis by CV as the outcome indicated more variability in PVF in CSM-affected dogs (P = 0.0045). The largest difference in the CV of PVF was seen in the thoracic limbs of affected dogs when compared with the thoracic limbs of normal dogs (P = 0.0019).
Conclusions and Clinical Importance
The CV of PVF in all 4 limbs, especially the thoracic limbs, distinguished clinically normal Dobermans from those with CSM. Other kinetic parameters less reliably distinguished CSM-affected from clinically normal Dobermans.
PMCID: PMC4025962  PMID: 23278957
Cervical vertebral instability; Dog; Kinetic; Wobbler
4.  Three-Dimensional Kinematic Gait Analysis of Doberman Pinschers with and without Cervical Spondylomyelopathy 
The optimal treatment of cervical spondylomyelopathy (CSM) is controversial, with the owner’s and clinician’s perception of gait improvement often being used as outcome measures. These methods are subjective and suffer from observer bias.
To establish kinematic gait parameters utilizing digital motion capture in normal Doberman Pinschers and compare them with CSM-affected Dobermans.
Nineteen Doberman Pinschers; 10 clinically normal and 9 with CSM.
All dogs were enrolled prospectively and fitted with a Lycra® body suit, and motion capture was performed and used to reconstruct a 3-D stick diagram representation of each dog based on 32 reflective markers, from which several parameters were measured. These included stride duration, length, and height; maximal and minimal spinal angles; elbow and stifle flexion and extension; and maximum and minimum distances between the thoracic and pelvic limbs. A random-effects linear regression model was used to compare parameters between groups.
Significant differences between groups included smaller minimum (mean = 116 mm; P = .024) and maximum (mean = 184 mm; P = .001) distance between the thoracic limbs in CSM-affected dogs. Additionally, thoracic limb stride duration was also smaller (P = .009) in CSM-affected dogs (mean = 0.7 seconds) when compared with normal dogs (mean = 0.8 seconds). In the pelvic limbs, the average stifle flexion (mean = 100°; P = .048) and extension (mean = 136°; P = .009), as well as number of strides (mean = 2.7 strides; P = .033) were different between groups.
Conclusions and Clinical Importance
Our findings suggest that computerized gait analysis reveals more consistent kinematic differences in the thoracic limbs, which can be used as future objective outcome measures.
PMCID: PMC4157597  PMID: 23194100
Cervical instability; Digital motion capture; Dog; Wobbler
Great Danes are predisposed to osseous-associated cervical spondylomyelopathy (Wobbler syndrome). The first aim of this prospective study was to compare values measured using previously published intravertebral and intervertebral ratio methods and a novel ventrodorsal ratio method in radiographs of clinically normal and affected Great Danes. The second aim was to determine whether these ratios could be used as predictors of sites of spinal cord compression based on magnetic resonance imaging (MRI). Thirty dogs (15 normal, 15 affected) were prospectively enrolled. Lateral and ventrodorsal radiographs were obtained and six measurements were recorded from C3-T1. For each vertebral location, intravertebral ratios and intervertebral ratios were calculated from lateral views, and the ratio of the distance between the articular process joints vs. vertebral body width (novel ventrodorsal ratio) was calculated from ventrodorsal views. Values for these three ratios were compared, by vertebral location and dog group. Intravertebral and intervertebral ratios did not differ between dog groups. The ventrodorsal ratio was significantly smaller in affected Great Danes at C5–6 (P = 0.005) and C6–7 (P <0.001). The ventrodorsal ratio was significantly associated with MRI presence of spinal cord compression. For each 0.1 unit increase in this ratio value, there was a 65% decrease in the odds of spinal cord compression being present at that site, independent of vertebral location (P = 0.002). Findings from this study supported use of the novel ventrodorsal ratio as an initial radiographic screening method for Great Danes with suspected cervical spondylomyelopathy.
PMCID: PMC4163098  PMID: 24698393
cervical spine; dog; radiography; vertebra; wobbler syndrome
6.  Clinical and magnetic resonance imaging (MRI) findings in 26 dogs with canine osseous-associated cervical spondylomyelopathy 
The Canadian Veterinary Journal  2014;55(2):169-174.
The potential link between degenerative changes seen on magnetic resonance imaging (MRI) in osseous-associated cervical spondylomyelopathy (OA-CSM) and clinical signs has not been explored. Our goal was to retrospectively evaluate MRI findings, while investigating potential correlations between these changes, signalment, and clinical signs. Twenty-six dogs diagnosed with OA-CSM were included in the study. Clinical signs were converted into a Modified Frankel Score (MFS) and MRI findings were assessed and graded. Giant breeds had multiple compressed sites and presented at a younger age than large breeds, suggesting a different underlying pathophysiology. Spinal cord compression, most commonly bilateral, was present in 36.8% of intervertebral spaces. Synovial fluid loss and articular process sclerosis were the most common degenerative changes. Most dogs showed identical MFS scores, and no significant correlations were found between MFS and MRI changes. More detailed functional scales should be used to investigate this in the future.
PMCID: PMC3894878  PMID: 24489397
7.  Cytokine Concentrations in the Cerebrospinal Fluid of Great Danes with Cervical Spondylomyelopathy 
Chronic inflammation is involved in the pathogenesis of human cervical spondylotic myelopathy and could also play a role in cervical spondylomyelopathy (CSM) in dogs.
That cerebrospinal fluid (CSF) cytokine concentrations would differ between clinically normal (control) and CSM-affected Great Danes (GDs), with affected GDs showing higher levels of inflammatory cytokines, such as interleukin (IL)-6 and monocyte chemoattractant protein-1/chemokine ligand 2 (MCP-1/CCL2).
Client-owned GDs: 15 control, 15 CSM-affected.
Prospective study. Dogs underwent cervical vertebral column magnetic resonance imaging and collection of CSF from the cerebellomedullary cistern. Cytokine concentrations were measured using a commercially available canine multiplex immunoassay. Cytokine concentrations were compared between groups. Associations with the administration of anti-inflammatory medications, disease duration and severity, severity of spinal cord (SC) compression, and SC signal changes were investigated in affected GDs.
Affected GDs had significantly lower MCP-1/CCL2 (mean 138.03 pg/mL, 95% confidence interval [CI] = 114.85–161.20) than control GDs (212.89 pg/mL, 95% CI = 165.68–260.11, P = .028). In affected GDs, MCP-1/CCL2 concentrations correlated inversely with the severity of SC compression. There were no associations with administration of anti-inflammatory medications, disease duration, or disease severity. IL-6 concentrations were significantly higher (2.20 pg/mL, 95% CI = 1.92–2.47, P < .001) in GDs with SC signal changes.
Conclusions and Clinical Importance
Lower MCP-1/CCL2 in CSM-affected GDs might compromise clearance of axonal and myelin debris, delay axon regeneration, and affect recovery. Higher IL-6 in CSM-affected GDs with SC signal changes suggests more severe inflammation in this group.
PMCID: PMC4169188  PMID: 24965833
Biomarker; Dog; Spinal cord disease; Wobbler syndrome
8.  Direct repair of defects in lumbar spondylolysis with a new pedicle screw hook fixation: clinical, functional and Ct-assessed study 
European Spine Journal  2007;16(10):1650-1658.
Spondylolysis is a common entity, a minority of people affected by this disease need medical care, and only a few require surgery. Reconstruction of the pars interarticularis is an interesting alternative to segmental fusion; this technique has the advantage of preserving segmental motion. Most authors report good results for young patients without intervertebral disk or facet degenerative changes. Moreover Louis also showed good to excellent results with his technique carried out among people who presented a satisfactory disk height (equal to two thirds of normal height). This could extend the number of patients for whom pars interarticularis repair could be proposed. In this study, the limit of reconstruction was set at grade 3of the Pfirrmann’s classification. The fixation of the isthmus was done with a new kind of pedicle screw hook system. This stable and strong device is easy to use, allows an anatomic pars interarticularis reconstruction of spondylolysis and avoids a postoperative bracing. Twenty-three patients were assessed in this study, the mean age at operation was 34 (range 16–52 years) and the average follow-up was for 59 months (range 6–113 months). Eight patients showed moderate degenerative disk disease before the surgery and 12 patients had a grade 1 spondylolisthesis. The visual analogical scale, the Oswestry disability index (ODI) and the modified Prolo score were used for assessment of pain and clinical outcome before and after surgery. The results were from “excellent” to “good” for twenty patients (87%) and “fair” for three of them (13%). The consolidation of the isthmus was assessed at the end of the study (CT-scan); the fusion rate was observed in 91%. Among patients aged less than 30 years results are from “good”, to “excellent” in all cases and consolidation was always observed. All of them showed normal disc signal before the surgery. In the group aged more than 30 years, the results varied from “good” to “excellent’ in 73% and fusion of the defect was discovered in 82% of cases. Eight of them (73%) had moderate disk signal modification before the surgery. All people with fair results displayed moderate disk degeneration signs at MRI before surgery; but two of those three patients had a failure of defect consolidation too and it is also associated with poor results by several authors. No complication was found in this series. According to the good results reported by Louis and upto the current finding, the authors believe that pars interarticularis repair can be carried out on patients with moderate degenerative disk disease; the stage 3 of Pfirrmann’s classification seems a good limit. The Bone and joint research (B.J.R. system) is readily usable by any surgeon using pedicle screw systems and having a short learning curve. No device failure has been observed in this series.
PMCID: PMC2078304  PMID: 17520298
Pars interarticularis repair; Lumbar spondylolysis; Functional outcome; Surgery; Pedicular screw hook fixation
9.  Quantitative evaluation of an automatic segmentation method for 3D reconstruction of intervertebral scoliotic disks from MR images 
BMC Medical Imaging  2012;12:26.
For some scoliotic patients the spinal instrumentation is inevitable. Among these patients, those with stiff curvature will need thoracoscopic disk resection. The removal of the intervertebral disk with only thoracoscopic images is a tedious and challenging task for the surgeon. With computer aided surgery and 3D visualisation of the interverterbral disk during surgery, surgeons will have access to additional information such as the remaining disk tissue or the distance of surgical tools from critical anatomical structures like the aorta or spinal canal. We hypothesized that automatically extracting 3D information of the intervertebral disk from MR images would aid the surgeons to evaluate the remaining disk and would add a security factor to the patient during thoracoscopic disk resection.
This paper presents a quantitative evaluation of an automatic segmentation method for 3D reconstruction of intervertebral scoliotic disks from MR images. The automatic segmentation method is based on the watershed technique and morphological operators. The 3D Dice Similarity Coefficient (DSC) is the main statistical metric used to validate the automatically detected preoperative disk volumes. The automatic detections of intervertebral disks of real clinical MR images are compared to manual segmentation done by clinicians.
Results show that depending on the type of MR acquisition sequence, the 3D DSC can be as high as 0.79 (±0.04). These 3D results are also supported by a 2D quantitative evaluation as well as by robustness and variability evaluations. The mean discrepancy (in 2D) between the manual and automatic segmentations for regions around the spinal canal is of 1.8 (±0.8) mm. The robustness study shows that among the five factors evaluated, only the type of MRI acquisition sequence can affect the segmentation results. Finally, the variability of the automatic segmentation method is lower than the variability associated with manual segmentation performed by different physicians.
This comprehensive evaluation of the automatic segmentation and 3D reconstruction of intervertebral disks shows that the proposed technique used with specific MRI acquisition protocol can detect intervertebral disk of scoliotic patient. The newly developed technique is promising for clinical context and can eventually help surgeons during thoracoscopic intervertebral disk resection.
PMCID: PMC3443448  PMID: 22856667
10.  Polymorphisms within the canine MLPH gene are associated with dilute coat color in dogs 
BMC Genetics  2005;6:34.
Pinschers and other dogs with coat color dilution show a characteristic pigmentation phenotype. The fur colors are a lighter shade, e.g. silvery grey (blue) instead of black and a sandy color (Isabella fawn) instead of red or brown. In some dogs the coat color dilution is sometimes accompanied by hair loss and recurrent skin inflammation, the so called color dilution alopecia (CDA) or black hair follicular dysplasia (BHFD). In humans and mice a comparable pigmentation phenotype without any documented hair loss is caused by mutations within the melanophilin gene (MLPH).
We sequenced the canine MLPH gene and performed a mutation analysis of the MLPH exons in 6 Doberman Pinschers and 5 German Pinschers. A total of 48 sequence variations was identified within and between the breeds. Three families of dogs showed co-segregation for at least one polymorphism in an MLPH exon and the dilute phenotype. No single polymorphism was identified in the coding sequences or at splice sites that is likely to be causative for the dilute phenotype of all dogs examined. In 18 German Pinschers a mutation in exon 7 (R199H) was consistently associated with the dilute phenotype. However, as this mutation was present in homozygous state in four dogs of other breeds with wildtype pigmentation, it seems unlikely that this mutation is truly causative for coat color dilution. In Doberman Pinschers as well as in Large Munsterlanders with BHFD, a set of single nucleotide polymorphisms (SNPs) around exon 2 was identified that show a highly significant association to the dilute phenotype.
This study provides evidence that coat color dilution is caused by one or more mutations within or near the MLPH gene in several dog breeds. The data on polymorphisms that are strongly associated with the dilute phenotype will allow the genetic testing of Pinschers to facilitate the breeding of dogs with defined coat colors and to select against Large Munsterlanders carrying BHFD.
PMCID: PMC1183202  PMID: 15960853
11.  Association between CT-evaluated lumbar lordosis and features of spinal degeneration, evaluated in supine position 
Background Context
Few studies have directly evaluated the association of lumbar lordosis and segmental wedging of the vertebral bodies and intervertebral disks with prevalence of spinal degenerative features.
To evaluate the association of CT-evaluated lumbar lordosis, segmental wedging of the vertebral bodies and that of the intervertebral disks with various spinal degeneration features.
Study design
This cross-sectional study was a nested project to the Framingham Heart Study.
A random consecutive subset of 191 participants chosen from the 3590 participants enrolled in the Framingham Heart Study who underwent multi-detector CT to assess aortic calcification.
Outcome Measures
Physiologic Measures
Dichotomous variables indicating the presence of intervertebral disc narrowing, facet joint osteoarthritis, spondylolysis, spondylolisthesis and spinal stenosis and density (in Hounsfield units) of multifidus and erector spinae muscles were evaluated on supine CT, as well as the lordosis angle (LA) and the wedging of the vertebral bodies and intervertebral disks. Sum of vertebral bodies wedging (ΣB) and sum of intervertebral discs wedging (ΣD) were used in analyses.
Mean values (±SD) of LA, ΣB and ΣD were calculated in males and females and compared using the t-test. Mean values (±SD) of LA, ΣB and ΣD in 4 age groups: <40, 40–49, 50–59 and 60+ years were calculated. We tested the linear relationship between LA, ΣB and ΣD and age groups. We evaluated the association between each spinal degeneration feature and LA, ΣB and ΣD using multiple logistic regression analysis where studied degeneration features were the dependent variable and all LA, ΣB and ΣD (separately) as well as age, sex, and BMI were independent predictors.
LA was slightly lower than the normal range for standing individuals, and no difference was found between males and females (p=0.4107). However, the sex differences in sum of vertebral bodies wedging (ΣB) and sum of intervertebral discs wedging (ΣD) were statistically significant (0.0001 and 0.001, respectively). Females exhibit more dorsal wedging of the vertebral bodies and less dorsal wedging of the intervertebral discs than do males. All these parameters showed no association (p>0.05) with increasing age.
LA showed statistically significant association with presence of spondylolysis (OR(95%CI): 1.08(1.02–1.14)) and with density of multifidus (1.06 (1.01–1.11). as well as a marginally significant association with isthmic spondylolisthesis (1.07(1.00–1.14). ΣB showed a positive association with degenerative spondylolisthesis and disc narrowing ((1.14(1.06–1.23) and 1.04 (1.00–1.08), correspondingly), whereas ΣD showed negative one (0.93(0.87–0.98) and (0.93(0.89–0.97), correspondingly).
Significant associations were found between lumbar lordosis evaluated in supine position and segmental wedging of the vertebral bodies and intervertebral disks and prevalence of spondylolysis and spondylolisthesis. Additional studies are needed, to evaluate the association between spondylolysis, isthmic and degenerative spondylolisthesis and vertebral and disc wedging at segmental level.
PMCID: PMC3686271  PMID: 21474082
computer tomography; spine; degeneration; lordosis; segmental wedging angle; vertebral body; intervertebral disc
12.  Hypovitaminosis D and Cervical Disk Herniation among Adults Undergoing Spine Surgery 
Global Spine Journal  2013;3(4):231-236.
Study Design Single-center, retrospective study.
Objective Suboptimal concentrations of vitamin D have been linked to hip and knee osteoarthritis in large, population-based cohort studies. We sought to examine the association of vitamin D levels with intervertebral disk disease.
Methods From January 2010 through May 2011, 91 consecutive, eligible adult spine surgery patients who had undergone cervical magnetic resonance imaging (MRI) and preoperative serum 25-hydroxyvitamin D (s25D) measurement were retrospectively included. MRI was read for C2–T1 disk herniation and degeneration (grades I to V). Logistic regressions were performed.
Results Compared with the 384 disks of nondeficient patients, 162 disks of vitamin D-deficient (< 20 ng/mL) patients were more frequently herniated (40% versus 27%, p = 0.004); deficiency was not predictive of individual disk grade (unadjusted odds ratio [uOR] = 0.98, p = 0.817). On regression analysis, deficiency was associated with increased number of herniations per patient (uOR = 2.17, 95% confidence interval [CI] = 1.22 to 3.87, p = 0.009; adjusted odds ratio [aOR] = 2.12, 95% CI = 1.11 to 4.03, p = 0.023). When disks were analyzed individually, and levels (e.g., C5 to C6), additionally controlled for, deficiency correlated with greater likelihood of herniation per disk (uOR = 1.81, 95% CI = 1.22 to 2.66, p = 0.003; aOR = 2.06, 95% CI = 1.25 to 3.41, p = 0.005).
Conclusion Among adults undergoing spine surgery at our institution, vitamin D deficiency was associated with cervical disk herniation. Considering the current epidemics of vitamin D insufficiency and neck pain, further investigation is warranted, as these data were retrospectively collected and subject to sampling bias.
PMCID: PMC3854581  PMID: 24436874
vitamin D; hypovitaminosis D; cervical spine; disk herniation; disk disease
13.  Novel Imaging of the Intervertebral Disk and Pain 
Global Spine Journal  2013;3(3):127-132.
T-1-rho (T1ρ) magnetic resonance imaging (MRI) and disc height ratio (DHR) are potential biomarkers of degenerative disk disease (DDD) related to biochemical composition and morphology of the intervertebral disk (IVD), respectively. To objectively detect DDD at an early stage, the hypothesis was tested that the average T1ρ relaxation time of the nucleus pulposus (NP) correlates with the disk height of degenerate IVDs, measured by MRI. Studies were performed on a 3-T Siemens Tim Trio clinical MRI scanner (Siemens Healthcare, Malvern, Pennsylvania, United States) on patients being treated for low back pain whose disks were categorized into (1) painful and (2) nonpainful subgroups based on provocative diskography and (3) age-matched healthy controls. Painful disks presented both low DHR and T1ρ values, nonpainful disks measured the highest DHR and extended to a higher range of T1ρ, and control disks presented a midrange DHR with the highest T1ρ values. T1ρ MRI evaluated in the NP of IVDs may be useful to establish a threshold (120 milliseconds here) above which indicates a healthy disk, and disks measuring low NP T1ρ (50 to 120 milliseconds here) would require disk height analysis to further categorize the disk. Combining T1ρ MRI and disk height analysis may hold promise in predicting painful disks without provocative diskography, and predictive models should be developed.
PMCID: PMC3854607  PMID: 24436863
T1rho; MRI; disk degeneration; disk pain; biomarker; disk height
14.  Traumatic intervertebral disc lesion – magnetic resonance imaging as a criterion for or against intervertebral fusion 
European Spine Journal  2001;10(2):154-163.
Lesions of the intervertebral disc accompanying vertebral fractures are the subject of controversy and discussion regarding the extent and manner of surgical intervention. The question of when to perform disc resection and intervertebral fusion, in particular, has not been answered satisfactorily. In order to evaluate short- and medium-term lesions of the discoligamentous complex associated with thoracolumbar burst fractures, magnetic resonance images made after stabilisation and again after implant removal were compared. Between 1997 and 1998, 20 patients who had suffered thoracolumbar burst fractures (AO classification A3 and B1 [26]) underwent posterior reduction and stabilisation using a Universal Spine System (USS, Synthes, Switzerland) titanium internal fixator. The implant was removed after an average of 10 months. Magnetic resonance imaging (MRI) scans were performed 1 week after both operations, allowing the changes in a total of 40 intervertebral discs adjacent to the fractured vertebral body to be investigated. The analysis was based on signal intensity of the intervertebral disc in T2-weighted scans and on morphological criteria.
A total of 81% of the discs with initially normal T2-weighted signal showed the same signal after implant removal; 5 discs with initially increased signal intensity in T2-weighted scans normalised, 5 showed a decrease in intensity and 3 suffered a partial loss of signal. Among the 9 discs with initially decreased T2-weighted signal, only one had normalised by the time the implant was removed. A total of 86% of the 14 morphologically intact discs retained their structural integrity. Of the 25 discs with minor defects, only one could be considered as intact after implant removal, 15 remained the same and 9 deteriorated in structure. No disruption of the fibrous ring or of the posterior longitudinal ligament was observed, nor was there any prolapse of intervertebral discs. When the intervertebral disk is intact and has normal morphology and a normal T2-weighted MRI signal, resection or fusion of the fracture adjacent discs appears unjustified. In our opinion, the results do not support the possibility of predicting degradation in those discs that showed an altered T2-weighted signal after the first operation.
PMCID: PMC3611485  PMID: 11345638
Spinal fracture Magnetic resonance imaging Degeneration Disc-preserving procedure
15.  Safety of cervical spine manipulation: are adverse events preventable and are manipulations being performed appropriately? A review of 134 case reports 
Cervical spine manipulation (CSM) is a commonly utilized intervention, but its use remains controversial.
To retrospectively analyze all available documented case reports in the literature describing patients who had experienced severe adverse events (AEs) after receiving CSM to determine if the CSM was used appropriately, and if these types of AEs could have been prevented using sound clinical reasoning on the part of the clinician.
Data sources
PubMed and the Cumulative Index to Nursing and Allied Health were systematically searched for case reports between 1950 and 2010 of AEs following CSM.
Study selection
Case reports were included if they were peer-reviewed; published between 1950 and 2010; case reports or case series; and had CSM as an intervention. Articles were excluded if the AE occurred without CSM (e.g. spontaneous); they were systematic or literature reviews. Data extracted from each case report included: gender; age; who performed the CSM and why; presence of contraindications; the number of manipulation interventions performed; initial symptoms experienced after the CSM; and type of resultant AE.
Data synthesis
Based on the information gathered, CSMs were categorized as appropriate or inappropriate, and AEs were categorized as preventable, unpreventable, or unknown. Chi-square analysis with an alpha level of 0.05 was used to determine if there was a difference in proportion between six categories: appropriate/preventable, appropriate/unpreventable, appropriate/unknown, inappropriate/preventable, inappropriate/unpreventable, and inappropriate/unknown.
One hundred thirty four cases, reported in 93 case reports, were reviewed. There was no significant difference in proportions between appropriateness and preventability, P = .46. Of the 134 cases, 60 (44.8%) were categorized as preventable, 14 (10.4%) were unpreventable and 60 (44.8%) were categorized as ‘unknown’. CSM was performed appropriately in 80.6% of cases. Death resulted in 5.2% (n = 7) of the cases, mostly caused by arterial dissection.
There may have been discrepancies between what was reported in the cases and what actually occurred, since physicians dealing with the effects of the AE, rather than the clinician performing the CSM, published many of the cases.
This review showed that, if all contraindications and red flags were ruled out, there was potential for a clinician to prevent 44.8% of AEs associated with CSM. Additionally, 10.4% of the events were unpreventable, suggesting some inherent risk associated with CSM even after a thorough exam and proper clinical reasoning.
PMCID: PMC3360486  PMID: 23633885
Adverse events; Case reports; Cervical spine; Manipulation; Risk of harm; Safety
16.  Does the sagittal alignment of the cervical spine have an impact on disk degeneration? Minimum 10-year follow-up of asymptomatic volunteers 
European Spine Journal  2009;18(11):1644-1651.
There have been few studies that investigated and clarified the relationships between progression of degenerative changes and sagittal alignment of the cervical spine. The objective of the study was to longitudinally evaluate the relationships among progression of degenerative changes of the cervical spine with age, the development of clinical symptoms and sagittal alignment of the cervical spine in healthy subjects. Out of 497 symptom-free volunteers who underwent MRI and plain radiography of the cervical spine between 1994 and 1996, 113 subjects (45 males and 68 females) who responded to our contacts were enrolled. All subjects underwent another MRI at an average of 11.3 years after the initial study. Their mean age at the time of the initial imaging was 36.6 ± 14.5 years (11–65 years). The items evaluated on MRI were (1) decrease in signal intensity of the intervertebral disks, (2) posterior disk protrusion, and (3) disk space narrowing. Each item was evaluated using a numerical grading system. The subjects were divided into four groups according to the age and sagittal alignment of the cervical spine, i.e., subjects under or over the age of 40 years, and subjects with the lordosis or non-lordosis type of sagittal alignment of the cervical spine. During the 10-year period, progression of decrease in signal intensity of the disk, posterior disk protrusion, and disk space narrowing were recognized in 64.6, 65.5, and 28.3% of the subjects, respectively. Progression of posterior disk protrusion was significantly more frequent in subjects over 40 years of age with non-lordosis type of sagittal alignment. Logistic regression analysis revealed that stiff shoulder was closely correlated with females (P = 0.001), and that numbness of the upper extremity was closely correlated with age (P = 0.030) and male (P = 0.038). However, no significant correlation between the sagittal alignment of the cervical spine and clinical symptoms was detected. Sagittal alignment of the cervical spine had some impact on the progression of degenerative changes of the cervical spine with aging; however, it had no correlation with the occurrence of future clinical symptoms.
PMCID: PMC2899405  PMID: 19609784
Cervical spine; Magnetic resonance imaging (MRI); Sagittal alignment; Aging; Asymptomatic volunteers
17.  Risk factors for development of cervical spondylotic myelopathy: results of a systematic review 
Study design: Systematic review.
Study rationale: Cervical spondylotic myelopathy (CSM) is a common cause of spinal cord dysfunction that may be asymptomatic or may present with severe symptoms. Since CSM has an insidious manifestation, identification of risk factors associated with this condition may aid clinicians in monitoring high-risk patients and implementing appropriate management strategies.
Objective: To assess sociodemographic, clinical, radiographic, and genetic risk factors associated with presence of CSM in patients 18 years or older.
Methods: A systematic review of the literature was performed using PubMed, the National Guideline Clearinghouse Databases, and bibliographies of key articles to assess risk factors associated with CSM. Articles were reviewed by two independent reviewers based on predetermined inclusion and exclusion criteria. Each article was evaluated using a predefined quality-rating scheme.
Results: From 486 citations, eight articles met all inclusion and exclusion criteria. Larger vertebral body and smaller spinal canal and Torg/Pavlov ratio were associated with CSM diagnosis, while gender was not associated with a CSM diagnosis across multiple studies. There were inconsistent reports with respect to increased age as a risk factor for CSM diagnosis.
Conclusion: The limited data available suggests that inherent anatomical features that may contribute to congenital cervical stenosis may be associated with CSM. This systematic review is limited by the small number of high-quality studies evaluating prognostic factors for CSM. The overall strength of evidence for all risk factors evaluated is low.
PMCID: PMC3592758  PMID: 23526904
18.  Comparison of titanium and polyetheretherketone (PEEK) cages in the surgical treatment of multilevel cervical spondylotic myelopathy: a prospective, randomized, control study with over 7-year follow-up 
European Spine Journal  2013;22(7):1539-1546.
Anterior cervical discectomy and fusion (ACDF) with titanium- or polyetheretherketone (PEEK)-cage reconstruction is widely used in the treatment of cervical spondylotic myelopathy (CSM). This study was to compare outcomes of titanium and PEEK cages in the treatment of multilevel CSM.
Between November 2002 and December 2004, a total of 80 patients with 3-level CSM were randomized in a 1:1 ratio to titanium group and PEEK group. The overall follow-up period of the patients ranged from 86 to 116 months (average 99.7 months). Clinical and radiological results were compared between titanium group and PEEK group.
At the final follow-up, the clinical outcomes including JOA score, NDI score, and the excellent and good rates of clinical outcomes in the PEEK group were better than those in the titanium group. More loss of the Cobb angles and the intervertebral height was observed in the titanium group, resulting in the radiological parameters in the titanium group becoming inferior to the PEEK group at the final follow-up. Cage subsidence rates were 34.5 and 5.4 % in the titanium and PEEK groups, respectively. Fusion was observed in all patients of two groups at the final follow-up. Two patients presented with cage dislocation without clinical symptoms in the titanium group.
In surgical treatment of multilevel CSM, PEEK cage is superior to titanium cage in maintenance of intervertebral height and cervical lordosis, resulting in better clinical outcomes in the long-term follow-up.
PMCID: PMC3698331  PMID: 23568254
Anterior cervical discectomy and fusion; Titanium; PEEK; Cervical spondylotic myelopathy
19.  Functional outcome of corpectomy in cervical spondylotic myelopathy 
Indian Journal of Orthopaedics  2009;43(2):205-209.
Cervical spondylotic myelopathy (CSM) is serious consequence of cervical intervertebral disk degeneration. Morbidity ranges from chronic neck pain, radicular pain, headache, myelopathy leading to weakness, and impaired fine motor coordination to quadriparesis and/or sphincter dysfunction. Surgical treatment remains the mainstay of treatment once myelopathy develops. Compared to more conventional surgical techniques for spinal cord decompression, such as anterior cervical discectomy and fusion, laminectomy, and laminoplasty, patients treated with corpectomy have better neurological recovery, less axial neck pain, and lower incidences of postoperative loss of sagittal plane alignment. The objective of this study was to analyze the outcome of corpectomy in cervical spondylotic myelopathy, to assess their improvement of symptoms, and to highlight complications of the procedure.
Materials and Methods:
Twenty-four patients underwent cervical corpectomy for cervical spondylotic myelopathy during June 1999 to July 2005.The anterior approach was used. Each patient was graded according to the Nuricks Grade (1972) and the modified Japanese Orthopaedic Association (mJOA) Scale (1991), and the recovery rate was calculated.
Preoperative patients had a mean Nurick's grade of 3.83, which was 1.67 postoperatively. Preoperative patients had a mean mJOA score of 9.67, whereas postoperatively it was 14.50. The mean recovery rate of patients postoperatively was 62.35% at a mean follow-up of 1 year (range, 8 months to 5 years).The complications included one case (4.17%) of radiculopathy, two cases (8.33%) of graft displacement, and two cases (8.33%) of screw back out/failure.
Cervical corpectomy is a reliable and rewarding procedure for CSM, with functional improvement in most patients.
PMCID: PMC2762259  PMID: 19838372
Cervical corpectomy; cervical spondylotic myelopathy (CSM); cervical decompression; anterior approach
20.  Differential expression of copper-associated and oxidative stress related proteins in a new variant of copper toxicosis in Doberman pinschers 
The role of copper accumulation in the onset of hepatitis is still unclear. Therefore, we investigated a spontaneous disease model of primary copper-toxicosis in Doberman pinschers so to gain insights into the pathophysiology of copper toxicosis, namely on genes involved in copper metabolism and reactive oxygen species (ROS) defences.
We used quantitative real-time PCR to determine differentially expressed genes within a target panel, investigating different groups ranging from copper-associated subclinical hepatitis (CASH) to a clinical chronic hepatitis with high hepatic copper concentrations (Doberman hepatitis, DH). Furthermore, a non-copper associated subclinical hepatitis group (N-CASH) with normal hepatic copper concentrations was added as a control. Most mRNA levels of proteins involved in copper binding, transport, and excretion were around control values in the N-CASH and CASH group. In contrast, many of these (including ATP7A, ATP7B, ceruloplasmin, and metallothionein) were significantly reduced in the DH group. Measurements on defences against oxidative stress showed a decrease in gene-expression of superoxide dismutase 1 and catalase in both groups with high copper. Moreover, the anti-oxidative glutathione molecule was clearly reduced in the DH group.
In the DH group the expression of gene products involved in copper efflux was significantly reduced, which might explain the high hepatic copper levels in this disease. ROS defences were most likely impaired in the CASH and DH group. Overall, this study describes a new variant of primary copper toxicosis and could provide a molecular basis for equating future treatments in dog and in man.
PMCID: PMC1079907  PMID: 15790412
21.  Total disc replacement using a tissue-engineered intervertebral disc in vivo: new animal model and initial results  
Study type: Basic science
Introduction: Chronic back pain due to degenerative disc disease (DDD) is among the most important medical conditions causing morbidity and significant health care costs. Surgical treatment options include disc replacement or fusion surgery, but are associated with significant short- and long-term risks.1 Biological tissue-engineering of human intervertebral discs (IVD) could offer an important alternative.2 Recent in vitro data from our group have shown successful engineering and growth of ovine intervertebral disc composites with circumferentially aligned collagen fibrils in the annulus fibrosus (AF) (Figure 1).3
Tissue-engineered composite disc a Experimental steps to generate composite tissue-engineered IVDs3 b Example of different AF formulations on collagen alignment in the AF. Second harmonic generation and two-photon excited fluorescence images of seeded collagen gels (for AF) of 1 and 2.5 mg/ml over time. At seeding, cells and collagen were homogenously distributed in the gels. Over time, AF cells elongated and collagen aligned parallel to cells. Less contraction and less alignment is noted after 3 days in the 2.5 mg/mL gel. c Imaging-based creation of a virtual disc model that will serve as template for the engineered disc. Total disc dimensions (AF and NP) were retrieved from micro-computer tomography (CT) (left images), and nucleus pulposus (NP) dimensions alone were retrieved from T2-weighted MRI images (right images). Merging of MRI and micro-CT models revealed a composite disc model (middle image)—Software: Microview, GE Healthcare Inc., Princeton, NJ; and slicOmatic v4.3, TomoVision, Montreal, Canada. d Flow chart describing the process for generating multi-lamellar tissue engineered IVDs. IVDs are produced by allowing cell-seeded collagen layers to contract around a cell-seeded alginate core (NP) over time
Objective: The next step is to investigate if biological disc implants survive, integrate, and restore function to the spine in vivo. A model will be developed that allows efficient in vivo testing of tissue-engineered discs of various compositions and characteristics.
Methods: Athymic rats were anesthetized and a dorsal approach was chosen to perform a microsurgical discectomy in the rat caudal spine (Fig. 2,Fig. 3). Control group I (n = 6) underwent discectomy only, Control group II (n = 6) underwent discectomy, followed by reimplantation of the autologous disc. Two treatment groups (group III, n = 6, 1 month survival; group IV, n = 6, 6 months survival) received a tissue-engineered composite disc implant. The rodents were followed clinically for signs of infection, pain level and wound healing. X-rays and magnetic resonance imaging (MRI) were assessed postoperatively and up to 6 months after surgery (Fig. 6,Fig. 7). A 7 Tesla MRI (Bruker) was implemented for assessment of the operated level as well as the adjacent disc (hydration). T2-weighted sequences were interpreted by a semiquantitative score (0 = no signal, 1 = weak signal, 2 = strong signal and anatomical features of a normal disc). Histology was performed with staining for proteoglycans (Alcian blue) and collagen (Picrosirius red) (Fig. 4,Fig. 5).
Disc replacement surgery a Operative situs with native disc that has been disassociated from both adjacent vertebrae b Native disc (left) and tissue-engineered implant (right) c Implant in situ before wound closureAF: Annulus fi brosus, nP: nucleus pulposus, eP: endplate, M: Muscle, T: Tendon, s: skin, art: artery, GP: Growth plate, B: Bone
Disc replacement surgery. Anatomy of the rat caudal disc space a Pircrosirius red stained axial cut of native disc space b Saffranin-O stained sagittal cut of native disc space
Histologies of three separate motion segments from three different rats. Animal one = native IVD, Animal two = status after discectomy, Animal three = tissue-engineered implant (1 month) a–c H&E (overall tissue staining for light micrsocopy) d–f Alcian blue (proteoglycans) g–i Picrosirius red (collagen I and II)
Histology from one motion segment four months after implantation of a bio-engineered disc construct a Picrosirius red staining (collagen) b Polarized light microscopy showing collagen staining and collagen organization in AF region c Increased Safranin-O staining (proteoglycans) in NP region of the disc implant d Higher magnification of figure 5c: Integration between implanted tissue-engineered total disc replacement and vertebral body bone
MRI a Disc space height measurements in flash/T1 sequence (top: implant (714.0 micrometer), bottom: native disc (823.5 micrometer) b T2 sequence, red circle surrounding the implant NP
7 Tesla MRI imaging of rat tail IVDs showing axial images (preliminary pilot data) a Diffusion tensor imaging (DTI) on two explanted rat tail discs in Formalin b Higher magnification of a, showing directional alignment of collagen fibers (red and green) when compared to the color ball on top which maps fibers' directional alignment (eg, fibers directing from left to right: red, from top to bottom: blue) c Native IVD in vivo (successful imaging of top and bottom of the IVD (red) d Gradient echo sequence (GE) showing differentiation between NP (light grey) and AF (dark margin) e GE of reimplanted tail IVD at the explantation level f T1Rho sequence demonstrating the NP (grey) within the AF (dark margin), containing the yellow marked region of interest for value acquisition (preliminary data are consistent with values reported in the literature). g T2 image of native IVD in vivo for monitoring of hydration (white: NP)
Results: The model allowed reproducible and complete discectomies as well as disc implantation in the rat tail spine without any surgical or postoperative complications. Discectomy resulted in immediate collapse of the disc space. Preliminary results indicate that disc space height was maintained after disc implantation in groups II, III and IV over time. MRI revealed high resolution images of normal intervertebral discs in vivo. Eight out of twelve animals (groups III and IV) showed a positive signal in T2-weighted images after 1 month (grade 0 = 4, grade 1 = 4, grade 2 = 4). Positive staining was seen for collagen as well as proteoglycans at the site of disc implantation after 1 month in each of the six animals with engineered implants (group III). Analysis of group IV showed positive T2 signal in five out of six animals and disc-height preservation in all animals after 6 months.
Conclusions: This study demonstrates for the first time that tissue-engineered composite IVDs with circumferentially aligned collagen fibrils survive and integrate with surrounding vertebral bodies when placed in the rat spine for up to 6 months. Tissue-engineered composite IVDs restored function to the rat spine as indicated by maintenance of disc height and vertebral alignment. A significant finding was that maintenance of the composite structure in group III was observed, with increased proteoglycan staining in the nucleus pulposus region (Figure 4d–f). Proteoglycan and collagen matrix as well as disc height preservation and positive T2 signals in MRI are promising parameters and indicate functionality of the implants.
PMCID: PMC3623095  PMID: 23637671
22.  Canine Von Willebrand's Disease: A Common Inherited Bleeding Disorder in Doberman Pinscher Dogs 
The Canadian Veterinary Journal  1986;27(9):315-318.
Von Willebrand's disease is the most common inherited bleeding disorder of dogs occurring with particularly high frequency in Doberman pinscher dogs. Because of its method of transmission (autosomal incomplete dominant), the clinical and laboratory severity of the disease varies considerably. “Stress” may be required to make the increased bleeding tendency clinically apparent. This report describes five cases of Von Willebrand's disease in Doberman pinscher dogs and illustrates the variety of clinical expressions that the disease may take.
PMCID: PMC1680304  PMID: 17422688
Canine Von Willebrand's disease; case reports
Computed tomography (CT) provides excellent bony detail, whereas magnetic resonance (MR) imaging is superior in evaluating the neural structures. The purpose of this prospective study was to assess interobserver and intermethod agreement in the evaluation of cervical vertebral column morphology and lesion severity in Great Danes with cervical spondylomyelopathy by use of noncontrast CT and high-field MR imaging. Fifteen client-owned affected Great Danes were enrolled. All dogs underwent noncontrast CT under sedation and MR imaging under general anesthesia of the cervical vertebral column. Three observers independently evaluated the images to determine the main site of spinal cord compression, direction and cause of the compression, articular process joint characteristics, and presence of foraminal stenosis. Overall intermethod agreement, intermethod agreement for each observer, overall interobserver agreement, and interobserver agreement between pairs of observers were calculated by use of kappa (κ) statistics. The highest overall intermethod agreements were obtained for the main site of compression and direction of compression with substantial agreements (κ = 0.65 and 0.62, respectively), whereas the lowest was obtained for right-sided foraminal stenosis (κ = 0.39, fair agreement). For both imaging techniques, the highest and lowest interobserver agreements were recorded for the main site of compression and degree of articular joint proliferation, respectively. While different observers frequently agree on the main site of compression using both imaging techniques, there is considerable variation between modalities and among observers when assessing articular process characteristics and foraminal stenosis. Caution should be exerted when comparing image interpretations from multiple observers.
PMCID: PMC4136988  PMID: 24547789
cervical spine; CT; dog; MRI; wobbler syndrome
24.  Validation of Genome-Wide Intervertebral Disk Calcification Associations in Dachshund and Further Investigation of the Chromosome 12 Susceptibility Locus 
Frontiers in Genetics  2012;3:225.
Herniation of the intervertebral disk is a common cause of neurological dysfunction in the dog, particularly in the Dachshund. Using the Illumina CanineHD BeadChip, we have previously identified a major locus on canine chromosome 12 nucleotide positions 36,750,205–38,524,449 that strongly associates with intervertebral disk calcification in Danish wire-haired Dachshunds. In this study, targeted resequencing identified two synonymous variants in MB21D1 and one in the 5′-untranslated region of KCNQ5 that associates with intervertebral disk calcification in an independent sample of wire-haired Dachshunds. Haploview identified seven linkage disequilibrium blocks across the disease-associated region. The effect of haplotype windows on disk calcification shows that all haplotype windows are significantly associated with disk calcification. However, our predictions imply that the causal variant(s) are most likely to be found between nucleotide 36,750,205–37,494,845 as this region explains the highest proportion of variance in the dataset. Finally, we develop a risk prediction model for wire-haired Dachshunds. We validated the association of the chromosome 12 locus with disk calcification in an independent sample of wire-haired Dachshunds and identify potential risk variants. Additionally, we estimated haplotype effects and set up a model for prediction of disk calcifications in wire-haired Dachshunds based on genotype data. This genetic prediction model may prove useful in selection of breeding animals in future breeding programs.
PMCID: PMC3485664  PMID: 23125846
canine; intervertebral disk calcification; LD pattern; haplotype effects; resequencing
25.  Clinical perspectives on secular trends of intervertebral foramen diameters in an industrialized European society 
European Spine Journal  2004;13(8):733-739.
Low back pain origins have been a matter of great controversy. While spinal stenosis is now radiologically traceable, the alteration of intervertebral foramen is less clear. The aim of this study was to assess “secular trends” — alterations occurring from one generation to the next — in osseous intervertebral foramina of the major vertebral segments in an industrialized society, and to discuss their possible clinical implication. The macerated “maximum intervertebral foramen width” and “intervertebral foramen height” of all major vertebral levels in 71 nonpathologic Swiss adult skeletons from the nineteenth and early twentieth century, with known individual age and sex and similar geographic and socio-economic background, were measured by sliding caliper at validated landmarks. A secular trend of the increase in “maximum intervertebral foramen width” is found for most levels, with females showing a more prominent alteration. Additionally, the non-pathologic “maximum intervertebral foramen width” does not change with respect to individual age, nor is a significant side difference detectable. “Intervertebral foramen height,” hereby defined as the difference of the dorsal vertebral body height minus pedicle height, demonstrates for most levels, and either sex, an insignificant negative secular trend. Neither stature nor skeletal robustness vary significantly through time within this particular sample. The results of this study, despite obvious inadequacies of methods used, exclude secular narrowing of the “maximum intervertebral foramen width” as the only cause of radiculopathy or spinal stenosis. Furthermore, we found a mild insignificant decrease of the clinically more relevant “intervertebral foramen height.” Nevertheless, the detected short-time variability of the bony intervertebral foramen, independent of individual stature, skeletal robustness or age, argues for an enhanced focus on the understanding of clinically relevant changes of spinal morphology from generation to generation.
PMCID: PMC3454061  PMID: 15057552
Backache; Bone; Pain; Paleopathology; Spinal cord

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