Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis.

Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.

Effect of phenylpropanolamine and pseudoephedrine on the urethral pressure profile and continence scores of incontinent female dogs.

BACKGROUND: Traditionally, treatment of urinary incontinence in spayed female dogs has been to increase urethral sphincter tone with estrogen compounds or alpha-agonists. Phenylpropanolamine (PPA) is the most frequently used alpha-agonist for this condition, but increased cost and decreased availability of PPA as an over-the-counter medication have prompted interest in alternative therapies that may provide the same degree of efficacy. Pseudoephedrine (PD), an alpha-agonist and stereoisomer of ephedrine, is more cost-effective and available without a prescription. HYPOTHESIS: PD will not differ from PPA in its effects on urodynamic variables and owner-reported continence scores or in observed adverse effects. ANIMALS: Nine spayed female dogs with a history of urinary incontinence drawn from the clinical patient population at the Veterinary Teaching Hospital at The Ohio State University. METHODS: A randomized, double-blind crossover study evaluating changes in urodynamic variables, owner-reported continence score, and adverse effects in dogs treated with 1.5 mg/kg PO q8h PPA or PD. RESULTS: Changes in maximum urethral closure pressure and functional area after PPA therapy were significantly higher than after PD therapy. There was no change in the functional profile length after either treatment. There was a significant increase in the continence score after PPA therapy, but not after PD therapy. More adverse effects were observed in dogs treated with PD than with PPA. CONCLUSIONS AND CLINICAL IMPORTANCE: Although some dogs clinically improved, lack of statistically significant changes in urodynamic variables and owner perception of continence as well as the increased incidence of adverse effects make PD a less satisfactory alternative to PPA for the treatment of urinary incontinence in female dogs.

Clinical characterization of a familial degenerative myelopathy in Pembroke Welsh Corgi dogs.

BACKGROUND: Adult dogs with degenerative myelopathy (DM) have progressive ataxia and paresis of the pelvic limbs, leading to paraplegia and euthanasia. Although most commonly reported in German Shepherd dogs, high disease prevalence exists in other breeds. OBJECTIVE: Our aim was the clinical and histopathologic characterization of familial degenerative myelopathy (FDM) in Pembroke Welsh Corgi (PWC) dogs. ANIMALS: Twenty-one PWCs were prospectively studied from initial diagnosis until euthanasia. METHODS: Neurologic examination, blood tests, cerebrospinal fluid (CSF) analysis, electrodiagnostic testing, and spinal imaging were performed. Concentrations of 8-iso-prostaglandin F2alpha (8-isoprostane) were measured in CSF. Routine histochemistry was used for neuropathology. Deoxyribonucleic acid and pedigrees were collected from 110 dogs. RESULTS: Median duration of clinical signs before euthanasia was 19 months. Median age at euthanasia was 13 years. All dogs were nonambulatory paraparetic or paraplegic, and 15 dogs had thoracic limb weakness at euthanasia. Electrodiagnostic testing and spinal imaging were consistent with noncompressive myelopathy. No significant difference was detected in 8-isoprostane concentrations between normal and FDM-affected dogs. Axonal and myelin degeneration of the spinal cord was most severe in the dorsal portion of the lateral funiculus. Pedigree analysis suggested a familial disease. CONCLUSIONS AND CLINICAL IMPORTANCE: Clinical progression of FDM in PWC dogs was similar to that observed in other breeds but characterized by a longer duration. Spinal cord pathology predominates as noninflammatory axonal degeneration. Oxidative stress injury associated with 8-isoprostane production is not involved in the pathogenesis of FDM-affected PWC dogs. A familial disease is suspected.

Use of a disposable real-time CT stereotactic navigator device for minimally invasive dog brain biopsy through a mini-burr hole.

We assessed the feasibility, accuracy, and safety of securing site-selective brain biopsy specimens by using a real-time CT-guided stereotactic navigation system through a mini-burr hole in the skulls of two dogs. Two beagle dogs each underwent two biopsy procedures. Our results indicated that the navigation system was accurate, safe, fast, and reliable for performing real-time brain biopsy in dogs and eliminated the need or risk of a standard-flap craniotomy.

Vertebral malformation, syringomyelia, and ventricular septal defect in a dromedary camel (Camelius dromedarius).

An occipitoatlantoaxial malformation and ventricular septal defect (VSD) were diagnosed in a 36-hour-old female camel. Physical examination revealed a firm protrusion of the dorsal aspect of the atlas and axis, tilting of the head to the left, and a grade V/VI systolic murmur. Neurological examination revealed proprioceptive deficits and ataxia of all 4 limbs. Radiographic examination and necropsy demonstrated malformation, fusion of the atlas to the occiput and hypoplasia of the dens of the axis, and subluxation of the atlantoaxial joint. Dorsoventral laxity of the atlantoaxial joint was also present, with compression of the cervical spinal cord. A 1.5-cm-diameter VSD was observed also. Histopathologic examination of the cervical spinal cord revealed a cavity extending from the level of the first to fourth cervical segment, dorsal to the central canal, 5 cm long and 1-2 mm in diameter. The cells around the cavity were positive for glial fibrillary acidic protein and sporadically positive for vimentin. This cavitary structure was consistent with syringomyelia, which was lined by glial cells, surrounded by edematous white matter with Wallerian-like degeneration and with neuronal necrosis in the adjacent dorsal horns.

Superficial necrolytic dermatitis in 11 dogs with a history of phenobarbital administration (1995-2002).

The clinical records of 11 dogs with histologically confirmed superficial necrolytic dermatitis (SND) and a history of phenobarbital (PB) administration (SND/PB) were evaluated retrospectively (1995-2002). Historical, clinical, clinicopathologic, ultrasonographic, and pathologic findings were compared with those in dogs with SND without prior PB exposure (SND/No PB; n = 9) and with those dogs with PB-associated hepatotoxicity without skin disease (PB/hepatotoxicity). Dogs in the SND/PB group accounted for 44% of all histologically confirmed cases of SND that were evaluated at The Ohio State University Veterinary Teaching Hospital between 1995 and 2002. Median age of dogs in the SND/PB group was 10 years, and median duration of PB therapy was 6 years. Mean alanine aminotransferase (ALT) activity was 239 U/L, and median duration of abnormally high ALT activity was 6.25 months before SND diagnosis. Plasma amino acid concentrations measured in 1 dog were severely decreased. Ultrasonographic findings of hypoechoic nodules with hyperechoic borders corresponded to pathologic findings of nodular areas of normal hepatic tissue surrounded by zones of collapsed parenchyma with vacuolated hepatocytes. Clinical, clinicopathologic, ultrasonographic, and pathologic features of SND/PB and SND/No PB were similar. PB-associated cirrhosis and overt hepatic failure were not features of SND/PB. Different pathogenic mechanisms might induce SND in dogs. Chronic administration of PB requires further examination as a potential risk factor for the development of SND.

Minimum alveolar concentration measures of central nervous system activation in cats anesthetized with isoflurane.

OBJECTIVE: To compare the minimum alveolar concentration (MAC) of isoflurane required to prevent corticocerebral activation, autonomic responses, and purposeful movements after somatic or visceral stimulation in cats anesthetized with isoflurane. ANIMALS: 17 healthy spayed female cats. PROCEDURE: Bispectral index (BIS), autonomic parameters, and purposeful movements were monitored before and after somatic or visceral stimuli in cats anesthetized with isoflurane. End-tidal (ET) isoflurane concentration was varied to determine MAC values for cortical arousal (MAC(BIS)), autonomic responsiveness (MAC(BAR)), and purposeful movement (MAC). Bispectral index values > or = 60 were considered to represent corticocerebral activation. RESULTS: Minimum alveolar concentration for purposeful movement was significantly less than MAC(BIS) and MAC(BAR) for both somatic and visceral stimulation. Individual MAC values for somatic stimulation were not significantly different from respective MAC values for visceral stimulation. The percentage of cats that had a BIS response > or = 60 was inversely related to the end-tidal isoflurane concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Corticocerebral arousal and subcortical autonomic reflexes occured at isoflurane anesthetic concentrations at which reflexive or purposeful movements were absent. These results suggested that isoflurane had a preferential effect on voluntary motor output at low end-tidal isoflurane concentrations, and that sensory pathways, subcortical sympathetic output, and cortical responsiveness are less susceptible to the anesthetic effects of isoflurane. Bispectral index values obtained after somatic or visceral stimulation were sensitive for the detection of early changes in cortical excitability.

Use of the bispectral index as a monitor of anesthetic depth in cats anesthetized with isoflurane.

OBJECTIVE: To determine whether the prestimulation bispectral index (BIS) value or relative change in BIS after noxious stimulation can be used to assess the depth of isoflurane anesthesia in cats. ANIMALS: 17 healthy female cats. PROCEDURE: Electroencephalogram (EEG) patterns and BIS values were examined in cats that received increasing end-tidal (ET) isoflurane concentrations. Subsequently, BIS values were determined before and after either a noxious somatic or visceral stimulus in cats that received ET isoflurane concentrations ranging from 1.8% to 2.4%. Electrical stimuli of the tail base and bladder distension to 50 cm of water were the somatic and visceral stimuli, respectively. RESULTS: The resting BIS at ET isoflurane concentrations from 1.4% to 1.9% steadily decreased concurrently with increasing degrees of EEG suppression. Prestimulation BIS values, however, were not related to 1.8% to 2.4% ET isoflurane concentrations and not useful for prediction of BIS values or hemodynamic and movement responses after a noxious stimulus. The poststimulation BIS value and the difference between mean BIS values before and after stimulation were inversely correlated with increasing ET isoflurane concentrations. Poststimulation BIS values > 60 were observed at ET isoflurane concentrations greater than those associated with a movement response after a stimulus. CONCLUSIONS AND CLINICAL RELEVANCE: The prestimulation BIS value has limited use in assessing anesthetic depth in cats during isoflurane anesthesia. The change in BIS values after a noxious somatic or visceral stimulus was a reliable measure of anesthetic depth and may be a useful measure of early arousal from the hypnotic state.

Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane.

OBJECTIVE: To determine the effects of constant rate infusion of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine (MLK) combination on end-tidal isoflurane concentration (ET-Iso) and minimum alveolar concentration (MAC) in dogs anesthetized with isoflurane and monitor depth of anesthesia by use of the bispectral index (BIS). ANIMALS: 6 adult dogs. PROCEDURE: Each dog was anesthetized with isoflurane on 5 occasions, separated by a minimum of 7 to 10 days. Individual isoflurane MAC values were determined for each dog. Reduction in isoflurane MAC, induced by administration of morphine (3.3 microg/kg/min), lidocaine (50 microg/kg/min), ketamine (10 microg/kg/min), and MLK, was determined. Heart rate, mean arterial blood pressure, oxygen saturation as measured by pulse oximetry (Spo2), core body temperature, and BIS were monitored. RESULTS: Mean +/- SD isoflurane MAC was 1.38 +/- 0.08%. Morphine, lidocaine, ketamine, and MLK significantly lowered isoflurane MAC by 48, 29, 25, and 45%, respectively. The percentage reductions in isoflurane MAC for morphine and MLK were not significantly different but were significantly greater than for lidocaine and ketamine. The Spo2, mean arterial pressure, and core body temperature were not different among groups. Heart rate was significantly decreased at isoflurane MAC during infusion of morphine and MLK. The BIS was inversely related to the ET-Iso and was significantly increased at isoflurane MAC during infusions of morphine and ketamine, compared with isoflurane alone. CONCLUSIONS AND CLINICAL RELEVANCE: Low infusion doses of morphine, lidocaine, ketamine, and MLK decreased isoflurane MAC in dogs and were not associated with adverse hemodynamic effects. The BIS can be used to monitor depth of anesthesia.

Comparison of the effect of propofol and sevoflurane on the urethral pressure profile in healthy female dogs.

OBJECTIVE: To compare the effects of propofol and sevoflurane on the urethral pressure profile in female dogs. ANIMALS: 10 healthy female dogs. PROCEDURE: Urethral pressure profilometry was performed in awake dogs, during anesthesia with sevoflurane at 1.5, 2.0, and 3.0% end-tidal concentration, and during infusion of propofol at rates of 0.4, 0.8, and 1.2 mg/kg/min. A consistent plane of anesthesia was maintained for each anesthetic protocol. Maximum urethral pressure, maximum urethral closure pressure, functional profile length, and functional area were measured. RESULTS: Mean maximum urethral closure pressure of awake dogs was not significantly different than that of dogs anesthetized with propofol at all infusion rates or with sevoflurane at 1.5 and 2.0% end-tidal concentration. Functional area in awake dogs was significantly higher than in anesthetized dogs. Functional area of dogs during anesthesia with sevoflurane at 3.0% end-tidal concentration was significantly lower than functional area for other anesthetic protocols. Individual differences in the magnitude of effects of propofol and sevoflurane on urethral pressures were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Sevoflurane is an alternative to propofol for anesthesia in female dogs undergoing urethral pressure profilometry. Use of these anesthetics at appropriate administration rates should reliably distinguish normal from abnormal maximum urethral closure pressures and functional areas. Titration of anesthetic depth is a critical component of urodynamic testing.

Recurrent vestibular paroxysms associated with systemic hypertension in a dog.

CASE DESCRIPTION: A 9-year-old 19.7-kg (43.3-lb) spayed female Australian Shepherd was examined for an increase in frequency of episodic neurologic signs, often occurring upon exercise. CLINICAL FINDINGS: Between episodes of neurologic signs, the dog was considered clinically normal on the basis of findings on physical and neurologic examinations. An episode of ataxia with central vestibular signs was induced by exercising the patient in the hospital. All clinicopathologic values were within reference ranges, as were findings on magnetic resonance imaging of the brain and peripheral vestibular system. Systolic blood pressures of 180 to 200 mm Hg were recorded, and systemic hypertension was diagnosed. TREATMENT AND OUTCOME: While the dog received amlodipine and enalapril, blood pressure returned to within reference range, and episodes of neurologic signs no longer occurred. When clinical signs later recurred, systolic blood pressure was again found to be high. Following an increase in medication dosage, blood pressure normalized, and only 4 further episodes of neurologic signs were observed during a follow-up period totaling 30 months. CLINICAL RELEVANCE: Transient ischemic attack is a common diagnosis in humans but has not been described for dogs. In humans, it is defined as focal brain dysfunction caused by vascular disease that resolves completely in less than 24 hours and is often recurrent. Systemic hypertension is one of the most common preexisting conditions. We propose that the dog in the present report had clinical signs and diagnostic test results supportive of a diagnosis of transient ischemic attack.

Bispectral analysis of the electroencephalogram: a review of its development and use in anesthesia.

OBJECTIVE: To evaluate the different methodologies used to monitor anesthetic depth and to review the principles and potential applications of bispectral index (BIS) monitoring in veterinary anesthesia. DATABASES USED: Medline (1966 to present); Pubmed (mid-1960s to present); personal files. CONCLUSIONS: Current anesthetic monitoring techniques rely on indirect measures of corticocerebral arousal after a noxious stimulus. Some anesthetics and pre-anesthetics suppress responses that are used to gauge adequate hypnosis and analgesia. The BIS is a direct measure of corticocerebral activation and is inversely related to the degree of hypnosis. Dynamic changes in the BIS after a noxious stimulus may signify early nociceptive activation of the cerebral cortex and may be a useful marker of inadequate analgesia. However, application of this technique during the use of various drug combinations (i.e. clinical anesthesia) will require further research and understanding.