Randomized Controlled Trial of Durotomy as an Adjunct to Routine Decompressive Surgery for Dogs With Severe Acute Spinal Cord Injury.

Although many interventions for acute spinal cord injury (SCI) appear promising in experimental models, translation directly from experimental animals to human patients is a large step that can be problematic. Acute SCI occurs frequently in companion dogs and may provide a model to ease translation. Recently, incision of the dura has been highlighted in both research animals and human patients as a means of reducing intraspinal pressure, with a view to improving perfusion of the injured tissue and enhancing functional recovery. Observational clinical data in humans and dogs support the notion that it may also improve functional outcome. Here, we report the results of a multi-center randomized controlled trial of durotomy as an adjunct to traditional decompressive surgery for treatment of severe thoracolumbar SCI caused by acute intervertebral disc herniation in dogs. Sample-size calculation was based on the proportion of dogs recovering ambulation improving from an expected 55% in the traditional surgery group to 70% in the durotomy group. Over a 3.5-year period, we enrolled 140 dogs, of which 128 had appropriate duration of follow-up. Overall, 65 (51%) dogs recovered ambulation. Recovery in the traditional decompression group was 35 of 62 (56%) dogs, and in the durotomy group 30 of 66 (45%) dogs, associated with an odds ratio of 0.643 (95% confidence interval: 0.320-1.292) and z-score of -1.24. This z-score indicates trial futility to reach the target 15% improvement over traditional surgery, and the trial was terminated at this stage. We conclude that durotomy is ineffective in improving functional outcome for severe acute thoracolumbar SCI in dogs. In the future, these data can be compared with similar data from clinical trials on duraplasty in human patients and will aid in determining the predictive validity of the "companion dog model" of acute SCI.

What is the value of statistical testing of observational data?

Statistical analysis of medical data aims to reveal patterns that can aid in decision making for future cases and, hopefully, improve patient outcomes. Large and bias-free datasets, such as those produced in formal randomized clinical trials, are necessary to make such analyses as reliable as possible. For a host of reasons, randomized trials are, unfortunately, relatively uncommon in veterinary medicine and surgery, implying that less ideal datasets (mostly observational data) must form the basis for much of our decision making regarding treatment of individual patients under our care. In this review, we first describe the common shortcomings of many observational veterinary datasets when viewed in comparison with their optimal counterparts and highlight how the deficiencies can lead to unreliable conclusions. We illustrate how many of the interpretative problems associated with observational data, predominantly various forms of bias, are not solved, and may even be exacerbated, by statistical analysis. We emphasize the need to examine summary data and its derivation in detail without being lured into relying upon P values to draw conclusions and advocate for completely omitting statistical analysis of many observational datasets. Finally, we present some suggestions for alternative statistical methods, such as propensity scoring and Bayesian methods, which might help reduce the risk of drawing unwarranted, and overconfident, conclusions from imperfect data.

Circulating neutrophil activation in dogs with naturally occurring spinal cord injury secondary to intervertebral disk herniation.

OBJECTIVE: To investigate the time course of circulating neutrophil priming and activity in dogs with spinal cord injury secondary to intervertebral disk herniation that undergo decompressive surgery. ANIMALS: 9 dogs with spinal cord injury and 9 healthy dogs (controls). PROCEDURES: For dogs with spinal cord injury, blood samples were collected on the day of hospital admission and 3, 7, 30, and 90 days after injury and decompressive surgery. A single blood sample was collected from the control dogs. Flow cytometry analysis was performed on isolated neutrophils incubated with antibody against CD11b and nonfluorescent dihydrorhodamine 123, which was converted to fluorescent rhodamine 123 to measure oxidative burst activity. RESULTS: Expression of CD11b was increased in dogs with spinal cord injury 3 days after injury and decompressive surgery, relative to day 7 expression. Neutrophils expressed high oxidative burst activity both 3 and 7 days after injury and decompressive surgery, compared with activity in healthy dogs. CLINICAL RELEVANCE: For dogs with spinal cord injury, high CD11b expression 3 days after injury and decompressive surgery was consistent with findings for rodents with experimentally induced spinal cord injury. However, the high oxidative burst activity 3 and 7 days after injury and decompressive surgery was not consistent with data from other species, and additional studies on inflammatory events in dogs with naturally occurring spinal cord injury are needed.

Brachial artery thrombosis in a dog causing monoparesis mimicking nerve sheath tumor.

There are few differential diagnoses for non-orthopedic thoracic limb lameness in adult dogs aside from nerve tumors and disk-associated nerve compression; this report introduces another etiology. A 9-year-old male castrated mixed dog presented with an episodic history of nonweight-bearing thoracic limb lameness. Additional clinical signs included an atrophied thoracic limb with cool paw pads and painful axillary region. Magnetic resonance imaging, computed tomography, ultrasound, and exploratory surgery confirmed a chronic thrombus of the right brachial artery. No underlying cause for the thrombus was identified. The dog has been successfully managed on long-term rivaroxaban and clopidogrel. Follow-up ultrasound of the thrombus suggested early remodeling.

Variation in biochemistry test results between annual wellness visits in apparently healthy Golden Retrievers.

BACKGROUND: Annual wellness testing is widely recommended for apparently healthy dogs, but there is little data to assist with distinguishing normal variation from clinically important changes. OBJECTIVES: To define variability in biochemistry analytes between annual wellness tests in healthy Golden Retrievers. ANIMALS: Four hundred thirty-four Golden Retrievers undergoing annual health assessments by their primary care veterinarians as part of a prospective cohort study. METHODS: Changes in 23 biochemistry analytes were calculated between year 1 and year 2 health checks for 196 dogs classified as healthy for ≥3 consecutive years. Using a direct nonparametric method, annual change intervals were constructed to define normal variability. A validation cohort of 238 dogs without a diagnosis of systemic disease for ≥3 consecutive years were compared with the reference and annual change intervals, and the proportions of dogs outside annual change intervals and a population-based reference interval were compared by using a McNemar test. RESULTS: Annual change intervals were calculated based on 190 dogs after outlier removal. For all 23 analytes, >90% of dogs in the validation cohort were within the annual change interval. There were no significant differences in the classification by reference versus annual change intervals. CONCLUSIONS AND CLINICAL IMPORTANCE: The annual change intervals met performance requirements for classification of dogs that did not develop systemic disease in the year following wellness testing as normal.

Cerebrospinal fluid flow on time-spatial labeling inversion pulse images before and after treatment of congenital hydrocephalus in a dog.

A 3-month-old male cross-breed dog presented with signs of progressive diffuse brain disease. Noncommunicating congenital hydrocephalus concurrent with cervical syringomyelia was diagnosed on magnetic resonance images. On time-spatial labeling inversion pulse (Time-SLIP) images CSF flow through the mesencephalic aqueduct was poorly defined and there was flow into the syrinx across the craniocervical junction. After percutaneous ventricular drainage and ventriculoperitoneal shunting, CSF flow through the aqueduct was clearly detected and flow into the syrinx disappeared. In addition, CSF flow in the subarachnoid space at the pons and ventral aspect of the cervical subarachnoid space was restored. Signs of neurological dysfunction improved after ventriculoperitoneal shunting and the cerebral parenchyma was increased in thickness on 2-year follow-up computed tomography images. Patterns of CSF flow on Time-SLIP images before and after CSF drainage or ventriculoperitoneal shunting aid in clarifying disease pathogenesis and confirm effects of CSF drainage.

Association of magnetic resonance assessed disc degeneration and late clinical recurrence in dogs treated surgically for thoracolumbar intervertebral disc extrusions.

BACKGROUND: Radiographic signs of intervertebral disc mineralization are thought to indicate sites of future recurrence of disc extrusion (Hansen type I) but the relationship between evidence of disc degeneration on magnetic resonance imaging (MRI) and future disc extrusion with recurrence of clinical signs has not been examined. OBJECTIVES: To examine the relationship between MRI-assessed degeneration of thoracolumbar intervertebral discs and late recurrence of clinical signs in dogs presented with acute thoracolumbar intervertebral disc extrusion and treated by hemilaminectomy alone. ANIMALS: Ninety-two client-owned dogs presented to 2 referral hospitals between 2009 and 2014. METHODS: Retrospective analysis of association between clinical signs consistent with recurrent thoracolumbar intervertebral disc extrusion and MRI evidence of disc degeneration in dogs undergoing hemilaminectomy for acute thoracolumbar intervertebral disc extrusion. Univariable and multivariable Cox regression analyses were used to explore associations between recurrence of clinical signs and several characteristics of T10-L3 discs at initial diagnosis. RESULTS: Ninety-two cases were included, of which 42 (46%) were Dachshunds and median age was 5.3 years. Clinical signs recurred in 33/92 (36%) dogs. Finding a completely degenerate disc in the T10 to L3 region (in addition to the operated site) at the time of surgery was associated with a hazard ratio of 2.92 (95% confidence interval: 1.37-6.20) for recurrence of clinical signs. CONCLUSIONS AND CLINICAL IMPORTANCE: Our results suggest that in cases of thoracolumbar intervertebral disc extrusion in dogs, recurrence of signs is likely if at least 1 completely degenerate disc in addition to the currently symptomatic disc is visible on MRI.

Clinical Trial Design-A Review-With Emphasis on Acute Intervertebral Disc Herniation.

There is a clear need for new methods of treatment of acute disc herniation in dogs, most obviously to address the permanent loss of function that can arise because of the associated spinal cord injury. Clinical trials form the optimal method to introduce new therapies into everyday clinical practice because they are a reliable source of unbiased evidence of effectiveness. Although many designs are available, parallel cohort trials are most widely applicable to acute disc herniation in dogs. In this review another key trial design decision-that between pragmatic and explanatory approaches-is highlighted and used as a theme to illustrate the close relationship between trial objective and design. Acute disc herniation, and acute spinal cord injury, is common in dogs and there is a multitude of candidate interventions that could be trialed. Most current obstacles to large-scale clinical trials in dogs can be overcome by collaboration and cooperation amongst interested veterinarians.

Emerging and Adjunctive Therapies for Spinal Cord Injury Following Acute Canine Intervertebral Disc Herniation.

Some dogs do not make a full recovery following medical or surgical management of acute canine intervertebral disc herniation (IVDH), highlighting the limits of currently available treatment options. The multitude of difficulties in treating severe spinal cord injury are well-recognized, and they have spurred intense laboratory research, resulting in a broad range of strategies that might have value in treating spinal cord-injured dogs. These include interventions that aim to directly repair the spinal cord lesion, promote axonal sparing or regeneration, mitigate secondary injury through neuroprotective mechanisms, or facilitate functional compensation. Despite initial promise in experimental models, many of these techniques have failed or shown mild efficacy in clinical trials in humans and dogs, although high quality evidence is lacking for many of these interventions. However, the continued introduction of new options to the veterinary clinic remains important for expanding our understanding of the mechanisms of injury and repair and for development of novel and combined strategies for severely affected dogs. This review outlines adjunctive or emerging therapies that have been proposed as treatment options for dogs with acute IVDH, including discussion of local or lesion-based approaches as well as systemically applied treatments in both acute and subacute-to-chronic settings. These interventions include low-level laser therapy, electromagnetic fields or oscillating electrical fields, adjunctive surgical techniques (myelotomy or durotomy), systemically or locally-applied hypothermia, neuroprotective chemicals, physical rehabilitation, hyperbaric oxygen therapy, electroacupuncture, electrical stimulation of the spinal cord or specific peripheral nerves, nerve grafting strategies, 4-aminopyridine, chondroitinase ABC, and cell transplantation.

Ambulation in Dogs With Absent Pain Perception After Acute Thoracolumbar Spinal Cord Injury.

Acute thoracolumbar spinal cord injury (SCI) is common in dogs frequently secondary to intervertebral disc herniation. Following severe injury, some dogs never regain sensory function to the pelvic limbs or tail and are designated chronically "deep pain negative." Despite this, a subset of these dogs develop spontaneous motor recovery over time including some that recover sufficient function in their pelvic limbs to walk independently without assistance or weight support. This type of ambulation is commonly known as "spinal walking" and can take up to a year or more to develop. This review provides a comparative overview of locomotion and explores the physiology of locomotor recovery after severe SCI in dogs. We discuss the mechanisms by which post-injury plasticity and coordination between circuitry contained within the spinal cord, peripheral sensory feedback, and residual or recovered supraspinal connections might combine to underpin spinal walking. The clinical characteristics of spinal walking are outlined including what is known about the role of patient or injury features such as lesion location, timeframe post-injury, body size, and spasticity. The relationship between the emergence of spinal walking and electrodiagnostic and magnetic resonance imaging findings are also discussed. Finally, we review possible ways to predict or facilitate recovery of walking in chronically deep pain negative dogs. Improved understanding of the mechanisms of gait generation and plasticity of the surviving tissue after injury might pave the way for further treatment options and enhanced outcomes in severely injured dogs.

Variability in Open-Field Locomotor Scoring Following Force-Defined Spinal Cord Injury in Rats: Quantification and Implications.

Spinal cord injury research in experimental animals aims to define mechanisms of tissue damage and identify interventions that can be translated into effective clinical therapies. Highly reliable models of injury and outcome measurement are essential to achieve these aims and avoid problems with reproducibility. Functional scoring is a critical component of outcome assessment and is currently commonly focused on open field locomotion (the "BBB score"). Here we analyze variability of observed locomotor outcome after a highly regulated spinal cord contusion in a large group of rats that had not received any therapeutic intervention. Our data indicate that, despite tight regulation of the injury severity, there is considerable variability in open-field score of individual rats at 21 days after injury, when the group as a whole reaches a functional plateau. The bootstrapped reference interval (that defines boundaries that contain 95% scores in the population without regard for data distributional character) for the score at 21 days was calculated to range from 2.3 to 15.9 on the 22-point scale. Further analysis indicated that the mean day 21 score of random groups of 10 individuals drawn by bootstrap sampling from the whole study population varies between 9.5 and 13.5. Wide variability between individuals implies that detection of small magnitude group-level treatment effects will likely be unreliable, especially if using small experimental group sizes. To minimize this problem in intervention studies, consideration should be given to assessing treatment effects by comparing proportions of animals in comparator groups that attain pre-specified criterion scores.

Association between anesthesia duration and outcome in dogs with surgically treated acute severe spinal cord injury caused by thoracolumbar intervertebral disk herniation.

BACKGROUND: Retrospective research recently identified a possible relationship between duration of surgery and outcome in severely affected dogs treated surgically for acute thoracolumbar intervertebral disk herniation (TL-IVDH). HYPOTHESIS: That increased duration of surgery is associated with poorer outcome in dogs with absent pain perception treated surgically for TL-IVDH. ANIMALS: Two hundred ninety-seven paraplegic dogs with absent pain perception surgically treated for acute TL-IVDH. METHODS: Retrospective cohort study. Medical records of 5 institutions were reviewed. Inclusion criteria were paraplegia with absence of pain perception, surgical treatment of TL-IVDH, and 1-year postoperative outcome (ambulatory: yes or no). Canine data, outcome, and surgery and total anesthesia duration were retrieved. RESULTS: In this study, 183/297 (61.6%) dogs were ambulatory within 1 year, 114 (38.4%) dogs failed to recover, including 74 dogs (24.9%) euthanized because of progressive myelomalacia. Median anesthesia duration in dogs that regained ambulation within 1 year of surgery (4.0 hours, interquartile range [IQR] 3.2-5.1) was significantly shorter than those that did not (4.5 hours, IQR 3.7-5.6, P = .01). Multivariable logistic regression demonstrated a significant negative association between both duration of surgery and total anesthesia time and ambulation at 1 year when controlling for body weight and number of disk spaces operated on. CONCLUSIONS AND CLINICAL IMPORTANCE: Findings support a negative association between increased duration of anesthesia and outcome in this group of dogs. However, the retrospective nature of the data does not imply a causal relationship.

Repeated surgical treatment and long-term outcome of a cat with vertebral vascular hamartoma.

A 30-month-old Maine Coon presented with progressive proprioceptive ataxia, paraparesis, thoracolumbar pain, and decreased appetite. An extradural mass was detected within the left side of the 13th thoracic vertebral canal that compressed the spinal cord on magnetic resonance (MR) and was considered to be mineralized on computed tomography (CT) images. The resected mass was diagnosed as a vertebral vascular hamartoma. Clinical signs improved, but recurrence was diagnosed by MR and CT imaging at 7 months after surgery. Repeated excisional surgery yielded the same diagnosis and the clinical signs abated. Fifteen months after the second surgery, there was apparent vertebral deformation, but there was no further change on CT images by 29 months.

Extended durotomy to treat severe spinal cord injury after acute thoracolumbar disc herniation in dogs.

OBJECTIVE: To report recovery of ambulation of dogs treated with extended thoracolumbar durotomy for severe spinal cord injury caused by intervertebral disc herniation. STUDY DESIGN: Descriptive cohort. ANIMALS: Twenty-six consecutive paraplegic dogs presented with loss of deep pain sensation after acute thoracolumbar intervertebral disc herniation. METHODS: Each dog underwent routine diagnostic assessment and surgery for removal of extradural herniated intervertebral disc, followed by a four-vertebral body length durotomy centered on the herniated disc. Each dog was followed up until it was able to walk 10 steps without assistance or until 6 months after surgery. RESULTS: Sixteen of 26 dogs recovered to walk unaided (all but one also recovered fecal and urinary continence), and six dogs did not; four dogs were lost to follow-up. One dog was euthanized because of signs consistent with progressive myelomalacia. There was no evidence of detrimental effects of durotomy within the period of study. Using Bayesian analysis, we found a point estimate of successful outcome of 71% with 95% credible interval from 52% to 87%. CONCLUSION: Extended durotomy seemed to improve the outcome of dogs in our case series without increase in morbidity. CLINICAL SIGNIFICANCE: Extended durotomy appears safe and may improve the outcome of dogs with severe thoracolumbar mixed contusion and compressive injuries associated with acute intervertebral disc extrusion.

Development of an International Canine Spinal Cord Injury observational registry: a collaborative data-sharing network to optimize translational studies of SCI.

STUDY DESIGN: Prospective cross-sectional cohort study. OBJECTIVES: The canine spontaneous model of spinal cord injury (SCI) is as an important pre-clinical platform as it recapitulates key facets of human injury in a naturally occurring context. The establishment of an observational canine SCI registry constitutes a key step in performing epidemiologic studies and assessing the impact of therapeutic strategies to enhance translational research. Further, accumulating information on dogs with SCI may contribute to current "big data" approaches to enhance understanding of the disease using heterogeneous multi-institutional, multi-species datasets from both pre-clinical and human studies. SETTING: Multiple veterinary academic institutions across the United States and Europe. METHODS: Common data elements recommended for experimental and human SCI studies were reviewed and adapted for use in a web-based registry, to which all dogs presenting to member veterinary tertiary care facilities were prospectively entered over ~1 year. RESULTS: Analysis of data accumulated during the first year of the registry suggests that 16% of dogs with SCI present with severe, sensorimotor-complete injury and that 15% of cases are seen by a tertiary care facility within 8 h of injury. Similar to the human SCI population, 34% were either overweight or obese. CONCLUSIONS: Severity of injury and timing of presentation suggests that neuroprotective studies using the canine clinical model could be conducted efficiently using a multi-institutional approach. Additionally, pet dogs with SCI experience similar comorbidities to people with SCI, in particular obesity, and could serve as an important model to evaluate the effects of this condition.

Therapeutic efficacy of microtube-embedded chondroitinase ABC in a canine clinical model of spinal cord injury.

See Moon and Bradbury (doi:10.1093/brain/awy067) for a scientific commentary on this article.Many hundreds of thousands of people around the world are living with the long-term consequences of spinal cord injury and they need effective new therapies. Laboratory research in experimental animals has identified a large number of potentially translatable interventions but transition to the clinic is not straightforward. Further evidence of efficacy in more clinically-relevant lesions is required to gain sufficient confidence to commence human clinical trials. Of the many therapeutic candidates currently available, intraspinally applied chondroitinase ABC has particularly well documented efficacy in experimental animals. In this study we measured the effects of this intervention in a double-blinded randomized controlled trial in a cohort of dogs with naturally-occurring severe chronic spinal cord injuries that model the condition in humans. First, we collected baseline data on a series of outcomes: forelimb-hindlimb coordination (the prespecified primary outcome measure), skin sensitivity along the back, somatosensory evoked and transcranial magnetic motor evoked potentials and cystometry in 60 dogs with thoracolumbar lesions. Dogs were then randomized 1:1 to receive intraspinal injections of heat-stabilized, lipid microtube-embedded chondroitinase ABC or sham injections consisting of needle puncture of the skin. Outcome data were measured at 1, 3 and 6 months after intervention; skin sensitivity was also measured 24 h after injection (or sham). Forelimb-hindlimb coordination was affected by neither time nor chondroitinase treatment alone but there was a significant interaction between these variables such that coordination between forelimb and hindlimb stepping improved during the 6-month follow-up period in the chondroitinase-treated animals by a mean of 23%, but did not change in controls. Three dogs (10%) in the chondroitinase group also recovered the ability to ambulate without assistance. Sensitivity of the dorsal skin increased at 24 h after intervention in both groups but subsequently decreased to normal levels. Cystometry identified a non-significant improvement of bladder compliance at 1 month in the chondroitinase-injected dogs but this did not persist. There were no overall differences between groups in detection of sensory evoked potentials. Our results strongly support a beneficial effect of intraspinal injection of chondroitinase ABC on spinal cord function in this highly clinically-relevant model of chronic severe spinal cord injury. There was no evidence of long-term adverse effects associated with this intervention. We therefore conclude that this study provides strong evidence in support of initiation of clinical trials of chondroitinase ABC in humans with chronic spinal cord injury.

When neuroscience met clinical pathology: partitioning experimental variation to aid data interpretation in neuroscience.

In animal experiments, neuroscientists typically assess the effectiveness of interventions by comparing the average response of groups of treated and untreated animals. While providing useful insights, focusing only on group effects risks overemphasis of small, statistically significant but physiologically unimportant, differences. Such differences can be created by analytical variability or physiological within-individual variation, especially if the number of animals in each group is small enough that one or two outlier values can have considerable impact on the summary measures for the group. Physicians face a similar dilemma when comparing two results from the same patient. To determine whether the change between two values reflects disease progression or known analytical and physiological variation, the magnitude of the difference between two results is compared to the reference change value. These values are generated by quantifying analytical and within-individual variation, and differences between two results from the same patient are considered clinically meaningful only if they exceed the combined effect of these two sources of 'noise'. In this article, we describe how the reference change interval can be applied within neuroscience. This form of analysis provides a measure of outcome at an individual level that complements traditional group-level comparisons, and therefore, introduction of this technique into neuroscience can enrich interpretation of experimental data. It can also safeguard against some of the possible misinterpretations that may occur during analysis of the small experimental groups that are common in neuroscience and, by illuminating analytical error, may aid in design of more efficient experimental methods.

Choices and Decisions in Decompressive Surgery for Thoracolumbar Intervertebral Disk Herniation.

Once decompressive surgery has been elected, the approach that maximizes the likelihood of gaining access to the herniated material for complete removal should be chosen. In most cases, a procedure that optimizes access to the ventrolateral aspect of the spinal cord will be advantageous but it is important to tailor the details of the surgical procedure to suit individual patients. Decompressive surgery for chronic (type II) herniations will frequently demand a ventral approach with partial corpectomy.

The Role of Fenestration in Management of Type I Thoracolumbar Disk Degeneration.

Fenestration offers the advantages of prophylaxis without the need for specialized instrumentation and imaging. Currently there is a lack of equipoise regarding the efficacy of fenestration relative to decompression for treatment of acute canine intervertebral disk herniation; most veterinary spinal surgeons do not consider the 2 procedures equivalently efficacious. Therapeutic fenestration should perhaps be given greater consideration, especially if advanced imaging shows only mild to moderate spinal cord compression or there are restrictions on the duration of surgery, when it might be better to spend the time on fenestration rather than decompression.