Suspected acquired narcolepsy in 8 dogs.

BACKGROUND: Acquired narcolepsy has rarely been reported in veterinary medicine. OBJECTIVE: To describe the presentation, clinicopathological features, diagnostic imaging findings, and management of dogs with suspected-acquired narcolepsy. ANIMALS: Eight dogs with clinical features consistent with acquired narcolepsy. METHODS: A call for suspected cases of acquired narcolepsy was made online, followed by a retrospective review of detailed medical records of potential cases. Dogs were included if episodes consistent with cataplexy were present during examination by a board-certified veterinary neurologist and diagnostic work-up included magnetic resonance imaging of the brain and analysis of cerebrospinal fluid. RESULTS: Seven French Bulldogs and 1 Chihuahua (age range, 9-66 months) were included. Meningoencephalitis of unknown origin was diagnosed in 2 dogs, extracranial foci of inflammation were identified in 2 dogs (aspiration pneumonia, esophagitis, otitis media), and no abnormalities were found on diagnostic investigations in 4 dogs. Prednisolone was used in the management of all dogs, 6 dogs received imipramine, and 2 received cytosine arabinoside. An initial remission of signs was observed in all dogs, but a subsequent relapse of clinical signs was recorded for 4 dogs, of which 3 responded to adjustment or resumption of treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: The presence of cataplexy episodes should prompt a thorough diagnostic work-up to exclude the presence of intracranial (and extracranial) pathology. The potential for both remission and relapse of signs in suspected acquired cases is important for clinicians and owners to be aware of.

Sleep Disorders in dogs: A Pathophysiological and Clinical Review.

Sleep is a fundamental process in mammals, including domestic dogs. Disturbances in sleep affect physiological functions like cognitive and physical performance, immune response, pain sensation and increase the risk of diseases. In dogs, sleep can be affected by several conditions, with narcolepsy, REM sleep behavior disorder and sleep breathing disorders being the most frequent causes. Furthermore, sleep disturbances can be a symptom of other primary diseases where they can contribute to the worsening of clinical signs. This review describes reciprocally interacting sleep and wakefulness promoting systems and how their dysfunction can explain the pathophysiological mechanisms of sleep disorders. Additionally, this work discusses the clinical characteristics, diagnostic tools and available treatments for these disorders while highlighting areas in where further studies are needed so as to improve their treatment and prevention.

Symptomatic Narcolepsy/Cataplexy in a Dog with Brainstem Meningoencephalitis of Unknown Origin.

A 4 yr old, intact female cocker spaniel was presented for investigation of acute, progressive lethargy/hypersomnia; vestibular signs; and cataplexy. A narcolepsy-cataplexy episode with associated hypertension and bradycardia was triggered during examination. There was no evidence of arrhythmia on electrocardiography during the episode. Hematology, serum biochemistry, and thoracic and abdominal imaging were unremarkable. MRI of the brain and cerebrospinal fluid analysis were compatible with meningoencephalitis of unknown origin affecting the mesencephalon, pons and rostral medulla oblongata. The dog was started on immunosuppressive treatment with prednisolone and cytosine arabinoside, which was subsequently switched to cyclosporine. Narcolepsy-cataplexy episodes could initially still be triggered by offering food; however, they gradually became shorter and less frequent until they completely subsided along with all other clinical signs after 3 wk. No relapse occurred over a 32 mo follow-up period from the diagnosis. Repeated MRI revealed marked reduction in the lesion size; cerebrospinal fluid analysis revealed no abnormalities. Although very rare, symptomatic narcolepsy/cataplexy can occur in dogs and can be secondary to brainstem encephalitis. Cardiovascular changes can occur in association with narcolepsy/cataplexy and should be considered when dealing with patients presenting with these specific clinical signs.

Pituitary Macrotumor Causing Narcolepsy-Cataplexy in a Dachshund.

Familial narcolepsy secondary to breed-specific mutations in the hypocretin receptor 2 gene and sporadic narcolepsy associated with hypocretin ligand deficiencies occur in dogs. In this report, a pituitary mass is described as a unique cause of narcolepsy-cataplexy in a dog. A 6-year-old male neutered Dachshund had presented for acute onset of feeding-induced cataplexy and was found to have a pituitary macrotumor on magnetic resonance imaging (MRI). Cerebral spinal fluid hypocretin-1 levels were normal, indicating that tumor effect on the ventral lateral nucleus of the hypothalamus was not the cause of the dog's narcolepsy-cataplexy. The dog was also negative for the hypocretin receptor 2 gene mutation associated with narcolepsy in Dachshunds, ruling out familial narcolepsy. The Dachshund underwent stereotactic radiotherapy (SRT), which resulted in reduction in the mass and coincident resolution of the cataplectic attacks. Nine months after SRT, the dog developed clinical hyperadrenocorticism, which was successfully managed with trilostane. These findings suggest that disruptions in downstream signaling of hypocretin secondary to an intracranial mass effect might result in narcolepsy-cataplexy in dogs and that brain MRI should be strongly considered in sporadic cases of narcolepsy-cataplexy.

Narcolepsia y olor: resultados preliminares / Narcolepsy and odour: preliminary report

Objetivo. El propósito de este estudio es probar la hipótesis de un olor corporal característico en narcolépticos como indicador de diagnóstico. Métodos. Se testan muestras de sudor de 12 narcolépticos y 22 controles sanos de forma independiente por 2 perros entrenados. Su detección, positiva o negativa, se compara con el diagnostico gold standard de narcolepsia. Ni adiestrador ni perros conocían el tipo de muestra seleccionada o su emplazamiento en el dispositivo de búsqueda. Doce pacientes con narcolepsia, de ambos sexos y distintas edades, reclutados entre abril de 2011 y junio de 2012 y diagnosticados según criterios estándar mediante su historia clínica y la polisomnografía nocturna seguida de test de latencia múltiple del sueño, conforman el grupo de pacientes. El grupo control está formado por 22 voluntarios sanos, de ambos sexos y distintas edades, sin trastorno del sueño. Las muestras de sudor, tanto de pacientes como de controles, se recogieron siguiendo el mismo protocolo para evitar contaminación y fueron testadas de forma independiente por 2 perros entrenados. Resultados. Once narcolépticos son detectados positivamente por los perros frente a solo 3 controles sanos. Conclusión. Parece que los pacientes con narcolepsia tienen un olor corporal típico que los perros entrenados pueden detectar. El desarrollo de un test de olfato para el diagnóstico de narcolepsia abre nuevas áreas de investigación (AU)

Objectives: This study has been carried out to test the clinical hypothesis of personal smell as a hint to the diagnosis of narcoleptic patients. Methods: Sweat samples from narcoleptic and healthy controls were tested independently by two trained dogs and their positive or negative detection compared to the gold standard diagnosis for narcolepsy. Neither trainer nor dog knew the source of the sample selected or its placement in the search device. Twelve narcoleptic patient, both sexes and various ages, recruited from April 2011 to June 2012 and diagnosed according to standard criteria, through their clinical records and nocturnal polysomnography plus multiple sleep latency test, made up the patient group. The control group was made up of 22 healthy volunteer without sleep disorders, both sexes and various ages. Sweat samples from both patients and controls were collected following the same protocol to avoid contamination, and tested independently for two trained dogs. Results: Eleven narcoleptic were detected positive by the dogs while only three controls. Conclusion: It seems that narcoleptic patients have a distinct typical odour that trained dogs can detect. The development of olfactory test could be a useful method in the screening of narcolepsy while opens a new research area (AU)

Familial narcolepsy in the Lipizzaner horse: a report of three fillies born to the same sire.

The occurrence of sleep disorder in three half sibling Lipizzaner is described. Sleepiness, swaying, stumbling, carpal joints buckling and falling down onto the carpal joints had been present since early foal age in all of them. Clinical signs had gradually reduced since the age of 2 years in cases 1 and 3. Sleepiness was induced by going out from the stable in adulthood. A physostigmine test was performed in all three affected horses and produced positive results in cases 1 and 3. The result of the test in case 2 was unclear due to the almost continuous sleepiness of the foal. Hypocretin-1 concentration in the cerebrospinal fluid was established using a standardised radioimmunoassay in case 1 (317.85 pg/mL), case 2 (303.43 pg/mL) and five adult control horses (275.2 ± 47.9 [SD] pg/mL) and was considered as normal in all horses. The sire of the affected horses has had 19 other registered offspring who did not show clinical signs of sleep disorder and also dams of all three cases produced healthy foals. Based on the demographic and clinical data together with the responses to the physostigmine challenges, the diagnosis of familial equine narcolepsy was made.

Roles of the hypocretin/orexins in the regulation of sleep and wakefulness.

Hypocretin/orexin is produced exclusively in the dorsal and lateral hypothalamus but its projection is widespread within the brain and plays important roles. In this paper, we review the independent discoveries of the hypocretin/orexin peptides, the neuroanatomy of this system, and the link to the sleep disorder narcolepsy that has led to the idea that this system plays a crucial role in the regulation of sleep and wakefulness.

Review of pathophysiology and clinical management of narcolepsy in dogs.

Narcolepsy is a chronic sleep disorder that affects human beings and animals. Up to 17 breeds of dogs are affected sporadically, and familial forms occur in dobermanns, labrador retrievers and dachshunds. These dogs display characteristics strikingly similar to those of human narcolepsy, including cataplexy (a sudden loss of muscle tone in response to emotional stimulation) and a shorter sleep latency. It has recently been shown that the aetiology of both the familial form (receptor null mutation) and the sporadic form (loss of ligand production) of canine narcolepsy is associated with a deficit in hypocretin/orexin neurotransmission. Hypocretin deficiency can be detected by the measurement of hypocretin-1 in cerebrospinal fluid, and this could be used to diagnose hypocretin ligand deficient cases in clinical practice. Narcolepsy is neither progressive nor life-threatening, but the clinical signs persist throughout life, and lifelong treatment and care are required. This article reviews the recent progress in narcolepsy research in dogs, and describes the diagnosis and treatment of the disease.

[Neurodegenerative, autoimmune and genetic processes of human and animal narcolepsy]. / Aspects neurodégénératifs, autoimmunes et génétiques de la narcolepsie humaine et animale.

Narcolepsy is a rare disabling sleep disorder whose main features are excessive daytime sleepiness and cataplexy. Human narcolepsy is most frequently a sporadic disorder with both genetic and environmental factors playing a role in its pathophysiology. Implication of the hypocretin system is well-established: as mutations in both canine and murine narcolepsies and as a consistent reduction in hypocretin neuron in human narcolepsy. The cause of human narcolepsy remains unknown. However degenerative, autoimmune and/or genetic processes are the most probable causes of the hypocretin neurons loss. Acting on a specific genetic background, an autoimmune process with hypocretin neuron degeneration, in response to environmental factors, is the most probable hypothesis for most cases of human narcolepsy with cataplexy. Although narcolepsy presents one of the tightest association with a specific HLA antigen (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility. Monoaminergic, immune (TNF alpha) and hypocretinergic systems seem to be involved and may interfere with the phenotype. Treatment has not evolved significantly over the last few years. However, new drugs, such as hypocretin agonists, are currently being developed.

Narcolepsy in a hypocretin/orexin-deficient chihuahua.

A two-year-old male chihuahua suffered attacks of muscle weakness and immobility, although it had no family history of paroxysmal attacks. No neurological or blood biochemical abnormalities were recorded when it was first examined. The attacks were typically elicited by stimulation, such as feeding, and a case of sporadic narcolepsy-cataplexy was therefore suspected. Treatment orally three times a day with 1 mg/kg imipramine, was effective in reducing the attacks. The concentration of hypocretin-1/orexin A in the dog's cerebrospinal fluid was less than 80 pg/ml (22.5 pmol/litre), compared with normal canine levels of 250 to 350 pg/ml (70.0 to 98.3 pmol/litre), supporting a diagnosis of hypocretin-deficient narcolepsy.

Pharmacokinetics of imipramine in narcoleptic horses.

OBJECTIVE: To validate use of high-performance liquid chromatography (HPLC) in determining imipramine concentrations in equine serum and to determine pharmacokinetics of imipramine in narcoleptic horses. ANIMALS: 5 horses with adult-onset narcolepsy. PROCEDURE: Blood samples were collected before (time 0) and 3, 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 3, 4, 6, 8, 12, and 24 hours after IV administration of imipramine hydrochloride (2 or 4 mg/kg of body weight). Serum was analyzed, using HPLC, to determine imipramine concentration. The serum concentration-versus-time curve for each horse was analyzed separately to estimate pharmacokinetic values. RESULTS: Adverse effects (muscle fasciculations, tachycardia, hyperresponsiveness to sound, and hemolysis) were detected in most horses when serum imipramine concentrations were high, and these effects were most severe in horses receiving 4 mg of imipramine/kg. Residual adverse effects were not apparent. Value (mean +/- SD) for area under the curve was 3.9 +/- 0.7 h X microg/ml, whereas volume of distribution was 584 +/- 161.7 ml/kg, total body clearance was 522 +/- 102 ml/kg/h, and mean residence time was 1.8 +/- 0.6 hours. One horse had signs of narcolepsy 6 and 12 hours after imipramine administration; corrresponding serum imipramine concentrations were less than the therapeutic range. CONCLUSIONS AND CLINICAL RELEVANCE: Potentially serious adverse effects may be seen in horses administered doses of imipramine that exceed a dosage of 2 mg/kg. Total body clearance of imipramine in horses is slower than that in humans; thus, the interval between subsequent doses should be longer in horses.

Identification and functional analysis of mutations in the hypocretin (orexin) genes of narcoleptic canines.

Narcolepsy is a sleep disorder affecting animals and humans. Exon skipping mutations of the Hypocretin/Orexin-receptor-2 (Hcrtr2) gene were identified as the cause of narcolepsy in Dobermans and Labradors. Preprohypocretin (Hcrt) knockout mice have symptoms similar to human and canine narcolepsy. In this study, 11 sporadic cases of canine narcolepsy and two additional multiplex families were investigated for possible Hcrt and Hcrtr2 mutations. Sporadic cases have been shown to have more variable disease onset, increased disease severity, and undetectable Hypocretin-1 levels in cerebrospinal fluid. The canine Hcrt locus was isolated and characterized for this project. Only one novel mutation was identified in these two loci. This alteration results in a single amino acid substitution (E54K) in the N-terminal region of the Hcrtr2 receptor and autosomal recessive transmission in a Dachshund family. Functional analysis of previously-described exon-skipping mutations and of the E54K substitution were also performed using HEK-293 cell lines transfected with wild-type and mutated constructs. Results indicate a truncated Hcrtr2 protein, an absence of proper membrane localization, and undetectable binding and signal transduction for exon-skipping mutated constructs. In contrast, the E54K abnormality was associated with proper membrane localization, loss of ligand binding, and dramatically diminished calcium mobilization on activation of the receptor. These results are consistent with a loss of function for all three mutations. The absence of mutation in sporadic cases also indicates genetic heterogeneity in canine narcolepsy, as reported previously in humans.

[Genetics of human narcolepsy]. / Génétique de la narcolepsie humaine.

Narcolepsy is known to be a complex disorder; both genetic and environmental factors play a role in its pathophysiology. Although narcolepsy presents one of the tightest association with a specific HLA antigen (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility, both monoaminergic and hypocretinergic systems seem to be involved and may interfere with the phenotype. Implication of the hypocretin system is well-established in both canine and murine narcolepsy (caused by mutation) and a consistent reduction in hypocretin neuron seems to be the cause of human narcolepsy. An autoimmune process is probable.