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.

Generalized myokymia, or neuromyotonia, or both in dogs with or without spinocerebellar ataxia.

BACKGROUND: KCNJ10 and CAPN1 variants cause "spinocerebellar" ataxia in dogs, but their association with generalized myokymia and neuromyotonia remains unclear. OBJECTIVE: To investigate the association between KCNJ10 and CAPN1 and myokymia or neuromyotonia, with or without concurrent spinocerebellar ataxia. ANIMALS: Thirty-three client-owned dogs with spinocerebellar ataxia, myokymia neuromytonia, or a combination of these signs. METHODS: Genetic analysis of a cohort of dogs clinically diagnosed with spinocerebellar ataxia, myokymia or neuromyotonia. KCNJ10 c.627C>G and CAPN1 c.344G>A variants and the coding sequence of KCNA1, KCNA2, KCNA6, KCNJ10 and HINT1 were sequenced using DNA extracted from blood samples. RESULTS: Twenty-four Jack Russell terriers, 1 Jack Russell terrier cross, 1 Dachshund and 1 mixed breed with spinocerebellar ataxia were biallelic (homozygous) for the KCNJ10 c.627C>G variant. Twenty-one of those dogs had myokymia, neuromyotonia, or both. One Parson Russell terrier with spinocerebellar ataxia alone was biallelic for the CAPN1 c.344G>A variant. Neither variant was found in 1 Jack Russell terrier with ataxia alone, nor in 3 Jack Russell terriers and 1 Yorkshire terrier with myokymia and neuromyotonia alone. No other causal variants were found in the coding sequence of the investigated candidate genes in these latter 5 dogs. CONCLUSION: The KCNJ10 c.627C>G variant, or rarely the CAPN1 c.344G>A variant, was confirmed to be the causal variant of spinocerebellar ataxia. We also report the presence of the KCNJ10 c.627C>G variant in the Dachshund breed. In dogs with myokymia and neuromyotonia alone the reported gene variants were not found. Other genetic or immune-mediated causes should be investigated to explain the clinical signs of these cases.

New insights into the treatment of meningoencephalomyelitis of unknown origin since 2009: A review of 671 cases.

"Meningoencephalomyelitis of unknown origin" (MUO)-a collective term for a group of clinically-indistinguishable (but pathologically distinct) autoimmune diseases of the CNS-has become increasingly commonly recognized throughout the world. In the 1960s-1980s the focus was primarily on the pathological description of these conditions and, largely anecdotally, their response to glucocorticoids. The subsequent availability of magnetic resonance imaging for companion animals led to a focus on imaging characteristics and response of MUO to various immunosuppressive medications. Previous reviews have not found clear evidence of superiority of any specific treatment regimen. Here, we review outcomes in a further 671 dogs treated with various combinations of glucocorticoids and immunosuppressive drugs and reported since 2009, aiming to determine whether recommendations can be drawn from the material published during more recent decades. We observe that: (i) there is more complete information on outcome of MUO-affected dogs solely receiving glucocorticoids and these reports provide evidence to undermine the dogma that MUO inevitably requires treatment with glucocorticoids plus an immunosuppressive drug; (ii) there is far more information on the pharmacokinetics of cytarabine delivered by a variety of routes, revealing that previous dosing and duration of administration in dogs with MUO may not have been optimal; and, (iii) there is a large number of cases that could be available for entry into multi-institutional randomized controlled trials. Finally, we suggest new research avenues that might aid future clinical trials in MUO through improved understanding of etiological triggers and individual patterns of immune response, such as the impact of the gut microbiome, the potential of CSF flow cytometry, and the establishment of robust clinical scores for evaluation of treatment success.

Diagnostic features of type II fibrinoid leukodystrophy (Alexander disease) in a juvenile Beagle dog.

A 3-month-old female entire Beagle presented with a progressive history of caudotentorial encephalopathy. Reactive encephalopathies were ruled out and tests for the most common infectious diseases agents were negative. Magnetic resonance imaging of the brain using a 1.5 Tesla scanner showed diffuse, bilateral, T2-weighted and T2-weighted-FLAIR hyperintense, T1-weighted hypointense, noncontrast-enhancing lesions involving the white matter of the cerebellum, brainstem, spinal cord, and forebrain to a lesser extent. There was cerebellar enlargement. Abnormalities were not detected on cerebrospinal fluid examination. Given the progressive nature of the disease and suspected poor prognosis the dog was euthanized. Histopathological analysis of the brain was consistent with fibrinoid leukodystrophy, also known as Alexander disease. Based on the classification used in humans, this is a description of MRI of a case of type II Alexander disease in veterinary medicine, with characteristics different to other described leukoencephalopathies in dogs.

Thoracolumbar Spinal Stabilization with Three Dimensional-Printed Drill Guides and Pre-Contoured Polyaxial Bone Plates.

OBJECTIVE: The aim of this study was to report new preoperative and intraoperative techniques performed for canine thoracic or lumbar spine kyphosis stabilization using three-dimensional-printed patient-specific drill guides, polyaxial titanium bone plates and drill stops, and to determine the accuracy of screw placement using these techniques. STUDY DESIGN: Retrospective study, five client-owned dogs. RESULTS: Three-dimensional-printed patient-specific drill guides and drill stops allowed safe drilling and screw placement in all of the cases, with (i) 84% of the screws graded as I (ideal placement) and 16% as IIa, IIIa or IIIb according to the modified Zdichavsky classification (partial penetration of medial pedicle wall, partial penetration of lateral pedicle wall and full penetration of lateral pedicle wall respectively), (ii) mean mediolateral deviation of ± 4.06 degrees (standard deviation: 8.21 degrees) compared to planned trajectories and (iii) variation in screw depth of ± 2.29mm (standard deviation: 3.07mm) compared to planned depth. CONCLUSION: We believe that the techniques presented here for thoracic spinal stabilization in dogs show promise; they allowed safe placement of screws along planned trajectories and depth; they also removed the need to use polymethylmethacrylate, while the use of titanium offers the possibility to repeat magnetic resonance imaging in these cases with chronic spinal conditions.

Serum anti-GM2 and anti-GalNAc-GD1a ganglioside IgG antibodies are biomarkers for immune-mediated polyneuropathies in cats.

Recent work identified anti-GM2 and anti-GalNAc-GD1a IgG ganglioside antibodies as biomarkers in dogs clinically diagnosed with acute canine polyradiculoneuritis, in turn considered a canine equivalent of Guillain-Barré syndrome. This study aims to investigate the serum prevalence of similar antibodies in cats clinically diagnosed with immune-mediated polyneuropathies. The sera from 41 cats clinically diagnosed with immune-mediated polyneuropathies (IPN), 9 cats with other neurological or neuromuscular disorders (ONM) and 46 neurologically normal cats (CTRL) were examined for the presence of IgG antibodies against glycolipids GM1, GM2, GD1a, GD1b, GalNAc-GD1a, GA1, SGPG, LM1, galactocerebroside and sulphatide. A total of 29/41 IPN-cats had either anti-GM2 or anti-GalNAc-GD1a IgG antibodies, with 24/29 cats having both. Direct comparison of anti-GM2 (sensitivity: 70.7%; specificity: 78.2%) and anti-GalNAc-GD1a (sensitivity: 70.7%; specificity: 70.9%) antibodies narrowly showed anti-GM2 IgG antibodies to be the better marker for identifying IPN-cats when compared to the combined ONM and CTRL groups (P = .049). Anti-GA1 and/or anti-sulphatide IgG antibodies were ubiquitously present across all sample groups, whereas antibodies against GM1, GD1a, GD1b, SGPG, LM1 and galactocerebroside were overall only rarely observed. Anti-GM2 and anti-GalNAc-GD1a IgG antibodies may serve as serum biomarkers for immune-mediated polyneuropathies in cats, as previously observed in dogs and humans.

A 3-Dimensional Printed Patient-Specific Surgical Guide to Facilitate Transsphenoidal Hypophysectomy in Dogs.

Objective: Hypophysectomy in dogs is a difficult surgery that requires specific learning and training. We aimed to evaluate the accuracy of a 3-dimensional printed patient-specific surgical guide to facilitate choosing the entry point in the basisphenoid bone before approaching the sella turcica during transsphenoidal hypophysectomy in dogs. Methods: Two canine cadavers and 8 dogs undergoing transsphenoidal hypophysectomy for Cushing's disease treatment, involving design and fabrication of a 3-dimensional printed guide. The ideal entry point in the basisphenoid bone outer cortical layer was determined in each dog pre-operatively; its anatomical location was described with a set of measurements then compared to post-operative computed tomography measures describing the location of the outer cortical window created in the basisphenoid bone. Results: Several guide designs were proposed, and a consensus reached based on surgeons' experience performing hypophysectomy. The device chosen could be applied to the size and shape of skulls encountered in this case series. The pre-planned measurements were comparable to post-operative measurement (there was also no statistical difference), with median of differences <0.1 mm, which we judged as clinically acceptable. Clinical Significance: Hypophysectomy in dogs is a challenging procedure that has a learning curve and needs to be performed by specialist neurosurgeons. We propose that a low-profile 3-dimensional printed surgical guide can aid the specialist neurosurgeon to locate the burring site of the outer cortical layer of the basisphenoid bone at a pre-defined location and with good accuracy. It does not alleviate the need to understand the anatomy of the region and to know how to create a slot within the basisphenoid bone, which remains essential to enter the sella turcica. This device could help specialist veterinary neurosurgeons wishing to be trained to perform hypophysectomy.

Transplantation of encapsulated autologous olfactory ensheathing cell populations expressing chondroitinase for spinal cord injury: A safety and feasibility study in companion dogs.

Spinal cord injury (SCI) can cause irreversible paralysis, with no regenerative treatment clinically available. Dogs with natural SCI present an established model and can facilitate translation of experimental findings in rodents to people. We conducted a prospective, single arm clinical safety study in companion dogs with chronic SCI to characterize the feasibility of intraspinal transplantation of hydrogel-encapsulated autologous mucosal olfactory ensheathing cell (mOEC) populations expressing chondroitinase ABC (chABC). mOECs and chABC are both promising therapies for SCI, and mOECs expressing chABC drive greater voluntary motor recovery than mOECs alone after SCI in rats. Canine mOECs encapsulated in collagen hydrogel can be matched in stiffness to canine SCI. Four dogs with complete and chronic loss of function caudal to a thoraco-lumbar lesion were recruited. After baseline measures, olfactory mucosal biopsy was performed and autologous mOECs cultured and transduced to express chABC, then hydrogel-encapsulated and percutaneously injected into the spinal cord. Dogs were monitored for 6 months with repeat clinical examinations, spinal MRI, kinematic gait and von Frey assessment. No adverse effects or significant changes on neurological examination were detected. MRI revealed large and variable lesions, with no spinal cord compression or ischemia visible after hydrogel transplantation. Owners reported increased pelvic-limb reflexes with one dog able to take 2-3 unsupported steps, but gait-scoring and kinematic analysis showed no significant improvements. This novel combination approach to regeneration after SCI is therefore feasible and safe in paraplegic dogs in a clinical setting. A randomised-controlled trial in this translational model is proposed to test efficacy.

The Design of a Low Noise, Multi-Channel Recording System for Use in Implanted Peripheral Nerve Interfaces.

In the development of implantable neural interfaces, the recording of signals from the peripheral nerves is a major challenge. Since the interference from outside the body, other biopotentials, and even random noise can be orders of magnitude larger than the neural signals, a filter network to attenuate the noise and interference is necessary. However, these networks may drastically affect the system performance, especially in recording systems with multiple electrode cuffs (MECs), where a higher number of electrodes leads to complicated circuits. This paper introduces formal analyses of the performance of two commonly used filter networks. To achieve a manageable set of design equations, the state equations of the complete system are simplified. The derived equations help the designer in the task of creating an interface network for specific applications. The noise, crosstalk and common-mode rejection ratio (CMRR) of the recording system are computed as a function of electrode impedance, filter component values and amplifier specifications. The effect of electrode mismatches as an inherent part of any multi-electrode system is also discussed, using measured data taken from a MEC implanted in a sheep. The accuracy of these analyses is then verified by simulations of the complete system. The results indicate good agreement between analytic equations and simulations. This work highlights the critical importance of understanding the effect of interface circuits on the performance of neural recording systems.

Rostral mandibulectomy for the management of trismus in a cat.

CASE SUMMARY: A 5-year-old domestic shorthair cat was evaluated for weight loss and poor coat condition due to an inability to open its mouth (trismus) following head trauma 2 months previously. Contrast CT, electromyography and temporal muscle biopsy identified findings consistent with muscle atrophy, denervation and degeneration. Conservative treatment failed to improve the trismus so a rostral mandibulectomy was performed. Following surgery, the patient resumed normal grooming behaviour and was able to eat soft food unaided. The cat re-presented 5 months postoperatively at which time its body condition had improved; however, episodes of sneezing had been noted. An oronasal fistula was diagnosed and treated successfully with a silicon nasal septum button. Follow-up at 30 months reported an excellent outcome. RELEVANCE AND NOVEL INFORMATION: Management of trismus with rostral mandibulectomy may be associated with a good return to function, including prehension and ingestion of food, and restoration of normal grooming activity. Rostral mandibulectomy could be considered for animals with trismus for other aetiologies such as masticatory myositis where other management options are not available.

Developing a predictive model for spinal shock in dogs with spinal cord injury.

BACKGROUND: Reduced pelvic limb reflexes in dogs with spinal cord injury typically suggests a lesion of the L4-S3 spinal cord segments. However, pelvic limb reflexes might also be reduced in dogs with a T3-L3 myelopathy and concurrent spinal shock. HYPOTHESIS/OBJECTIVES: We hypothesized that statistical models could be used to identify clinical variables associated with spinal shock in dogs with spinal cord injuries. ANIMALS: Cohort of 59 dogs with T3-L3 myelopathies and spinal shock and 13 dogs with L4-S3 myelopathies. METHODS: Data used for this study were prospectively entered by partner institutions into the International Canine Spinal Cord Injury observational registry between October 2016 and July 2019. Univariable logistic regression analyses were performed to assess the association between independent variables and the presence of spinal shock. Independent variables were selected for inclusion in a multivariable logistic regression model if they had a significant effect (P ≤ .1) on the odds of spinal shock in univariable logistic regression. RESULTS: The final multivariable model included the natural log of weight (kg), the natural log of duration of clinical signs (hours), severity (paresis vs paraplegia), and pelvic limb tone (normal vs decreased/absent). The odds of spinal shock decreased with increasing weight (odds ratio [OR] = 0.28, P = .09; confidence interval [CI] 0.07-1.2), increasing duration (OR = 0.44, P = .02; CI 0.21-0.9), decreased pelvic limb tone (OR = 0.04, P = .003; CI 0.01-0.36), and increased in the presence of paraplegia (OR = 7.87, P = .04; CI 1.1-56.62). CONCLUSIONS AND CLINICAL IMPORTANCE: A formula, as developed by the present study and after external validation, could be useful for assisting clinicians in determining the likelihood of spinal shock in various clinical scenarios and aid in diagnostic planning.

Delivery of chondroitinase by canine mucosal olfactory ensheathing cells alongside rehabilitation enhances recovery after spinal cord injury.

Spinal cord injury (SCI) can cause chronic paralysis and incontinence and remains a major worldwide healthcare burden, with no regenerative treatment clinically available. Intraspinal transplantation of olfactory ensheathing cells (OECs) and injection of chondroitinase ABC (chABC) are both promising therapies but limited and unpredictable responses are seen, particularly in canine clinical trials. Sustained delivery of chABC presents a challenge due to its thermal instability; we hypothesised that transplantation of canine olfactory mucosal OECs genetically modified ex vivo by lentiviral transduction to express chABC (cOEC-chABC) would provide novel delivery of chABC and synergistic therapy. Rats were randomly divided into cOEC-chABC, cOEC, or vehicle transplanted groups and received transplant immediately after dorsal column crush corticospinal tract (CST) injury. Rehabilitation for forepaw reaching and blinded behavioural testing was conducted for 8 weeks. We show that cOEC-chABC transplanted animals recover greater forepaw reaching accuracy on Whishaw testing and more normal gait than cOEC transplanted or vehicle control rats. Increased CST axon sprouting cranial to the injury and serotonergic fibres caudal to the injury suggest a mechanism for recovery. We therefore demonstrate that cOECs can deliver sufficient chABC to drive modest functional improvement, and that this genetically engineered cellular and molecular approach is a feasible combination therapy for SCI.

Bladder and Bowel Management in Dogs With Spinal Cord Injury.

Spinal cord injury in companion dogs can lead to urinary and fecal incontinence or retention, depending on the severity, and localization of the lesion along the canine nervous system. The bladder and gastrointestinal dysfunction caused by lesions of the autonomic system can be difficult to recognize, interpret and are easily overlooked. Nevertheless, it is crucial to maintain a high degree of awareness of the impact of micturition and defecation disturbances on the animal's condition, welfare and on the owner. The management of these disabilities is all the more challenging that the autonomic nervous system physiology is a complex topic. In this review, we propose to briefly remind the reader the physiology of micturition and defecation in dogs. We then present the bladder and gastrointestinal clinical signs associated with sacral lesions (i.e., the L7-S3 spinal cord segments and nerves) and supra-sacral lesions (i.e., cranial to the L7 spinal cord segment), largely in the context of intervertebral disc herniation. We summarize what is known about the natural recovery of urinary and fecal continence in dogs after spinal cord injury. In particular we review the incidence of urinary tract infection after injury. We finally explore the past and recent literature describing management of urinary and fecal dysfunction in the acute and chronic phase of spinal cord injury. This comprises medical therapies but importantly a number of surgical options, some known for decades such as sacral nerve stimulation, that might spark some interest in the field of spinal cord injury in companion dogs.

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.

Current Approaches to the Management of Acute Thoracolumbar Disc Extrusion in Dogs.

Intervertebral disc extrusion (IVDE) is one of the most common neurologic problems encountered in veterinary clinical practice. The purpose of this manuscript is to provide an overview of the literature related to treatment of acute canine thoracolumbar IVDE to help construct a framework for standard care of acute canine thoracolumbar IVDE where sufficient evidence exists and to highlight opportunities for future prospective veterinary clinical research useful to strengthen care recommendations in areas where evidence is low or non-existent. While there exist a number of gaps in the veterinary literature with respect to standards of care for dogs with acute thoracolumbar IVDE, recommendations for standard care can be made in some areas, particularly with respect to surgical decompression where the currently available evidence supports that surgery should be recommended for dogs with nonambulatory paraparesis or worse. While additional information is needed about the influence on timing of decompression on outcome in dogs that are deep pain negative for longer than 48 h duration, there is no evidence to support treatment of the 48 h time point as a cut off beyond which it becomes impossible for dogs to achieve locomotor recovery. Surgical decompression is best accomplished by either hemilaminectomy or mini-hemilaminectomy and fenestration of, at a minimum, the acutely ruptured disc. Adjacent discs easily accessed by way of the same approach should be considered for fenestration given the evidence that this substantially reduces future herniation at fenestrated sites. Currently available neuroprotective strategies such as high does MPSS and PEG are not recommended due to lack of demonstrated treatment effect in randomized controlled trials, although the role of anti-inflammatory steroids as a protective strategy against progressive myelomalacia and the question of whether anti-inflammatory steroids or NSAIDs provide superior medical therapy require further evaluation.

Long-term outcome of Miniature Schnauzers with genetically confirmed demyelinating polyneuropathy: 12 cases.

BACKGROUND: A demyelinating polyneuropathy with focally folded myelin sheaths was reported in 3 Miniature Schnauzers in France in 2008 and was predicted to represent a naturally occurring canine homologue of Charcot-Marie-Tooth (CMT) disease. A genetic variant of MTRM13/SBF2 has been identified as causative in affected Miniature Schnauzers with this polyneuropathy. OBJECTIVE: To provide data on the long-term progression in affected Miniature Schnauzers from Spain confirmed with the MTRM13/SBF2 genetic variant. ANIMALS: Twelve Miniature Schnauzers presented between March 2013 and June 2019. METHODS: Only dogs presented with consistent clinical signs and homozygous for the MTRM13/SBF2 genetic variant were included. Clinical signs, age of onset and presentation, time from onset to presentation, treatment, outcome, and time from diagnosis to final follow-up were retrospectively reviewed. RESULTS: The hallmark clinical signs at the time of presentation were regurgitation with radiologically confirmed megaesophagus (11/12) and aphonic bark (11/12) with or without obvious neuromuscular weakness despite electrodiagnostic evidence of appendicular demyelinating polyneuropathy. Age of onset and clinical presentation were 3-18 and 4-96 months, respectively. Treatment was mostly symptomatic and consisted of head elevation during meals, antacids, prokinetics, bethanechol, sildenafil, mirtazapine, or some combination of these. During the follow-up period (7-73 months), clinical signs were unchanged in (11/12) cases with aspiration pneumonia developing occasionally (6/12) and being the cause of death in 1 dog. CONCLUSIONS AND CLINICAL IMPORTANCE: Demyelinating polyneuropathy of Miniature Schnauzers tends to remain stable over the long term leading to a good prognosis with preventive feeding measures and symptomatic treatment to control aspiration pneumonia.