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.

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.

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.

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.

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.

Prostaglandin E2 levels in cerebrospinal fluid of normal and narcoleptic dogs.

It has been shown that endogenous prostaglandin D2 and prostaglandin E2 (PGE2) are involved in sleep-wake regulation. Our recent experimental result that exogenously administered PGE2 significantly reduces canine cataplexy (a pathological equivalent of rapid-eye-movement sleep atonia and a symptom of narcolepsy) suggests that PGE2 is involved in the pathophysiology of canine narcolepsy. In order to further investigate the role of prostaglandins (PGs) in this disorder, PG levels in cerebrospinal fluid (CSF) of genetically homozygous narcoleptic, heterozygous (unaffected), and control Doberman pinschers were studied. PGE2 levels were measured by direct radioimmunoassay (RIA) and after high-grade purification using PG affinity columns and high-performance liquid chromatography. PGD2 and PGF2 alpha levels were measured by RIA after high-grade purification. There was no significant difference in PGE2 levels between homozygous narcoleptic and heterozygous or controls dogs, and PGD2 and PGF2 alpha levels were undetectable in most cases. Our results do not favor the hypothesis that central PGE2 levels are modified in canine narcolepsy, assuming that PGE2 levels in cisternal CSF properly reflect PGE2 production in the brain.

Cholinergic mechanisms in canine narcolepsy--II. Acetylcholine release in the pontine reticular formation is enhanced during cataplexy.

Cataplexy in the narcoleptic canine has been shown to increase after local administration of carbachol into the pontine reticular formation. Rapid eye movement sleep has also been shown to increase after local administration of carbachol in the pontine reticular formation, and furthermore, acetylcholine release in the pontine tegmentum was found to increase during rapid eye movement sleep in rats. Therefore, in the present study we have investigated acetylcholine release in the pontine reticular formation during cataplexy in narcoleptic canines. Extracellular acetylcholine levels were measured in the pontine reticular formation of freely moving narcoleptic and control Doberman pinschers using in vivo microdialysis probes. Cataplexy was induced by the Food-Elicited Cataplexy Test and monitored using recordings of electroencephalogram, electrooculogram and electromyogram. Basal levels of acetylcholine in the microdialysis perfusates were approximately 0.5 pmol/10 min in both control and narcoleptic canines. Local perfusion with tetrodotoxin (10(-5) M) or artificial cerebrospinal fluid without Ca2+ produced a decrease, while intravenous injections of physostigmine (0.05 mg/kg) produced an increase in acetylcholine levels, indicating that the levels of acetylcholine levels measured are derived from neuronal release. During cataplexy induced by the Food-Elicited Cataplexy Test, acetylcholine levels increased by approximately 50% after four consecutive tests in narcoleptic canines, but did not change after four consecutive tests in control canines. Motor activity and feeding behavior, similar to that occurring during a Food-Elicited Cataplexy Test, had no effect on acetylcholine levels in the narcoleptic canines.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholinergic mechanisms in canine narcolepsy--I. Modulation of cataplexy via local drug administration into the pontine reticular formation.

Cataplexy in the narcoleptic canine has been shown to increase after systemic administration of cholinergic agonists. Furthermore, the number of cholinergic receptors in the pontine reticular formation of narcoleptic canines is significantly elevated. In the present study we have investigated the effects of cholinergic drugs administered directly into the pontine reticular formation on cataplexy, as defined by brief episodes of hypotonia induced by emotions, in narcoleptic canines. Carbachol and atropine were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of freely moving, narcoleptic and control Doberman pinschers. Cataplexy was quantified using the Food-Elicited Cataplexy Test, and analysed using recordings of electroencephalogram, electrooculogram and electromyogram. Cataplexy was characterized by a desynchronized electroencephalogram and a drop in electromyogram and electrooculogram activity. In narcoleptic canines, both unilateral and bilateral carbachol (10(-5) to 10(-3) M) produced a dose-dependent increase in cataplexy, which resulted in complete muscle tone suppression at the highest concentration. In control canines, neither bilateral nor unilateral carbachol (10(-5) to 10(-3) M) produced cataplexy, although bilateral carbachol, did produce muscle atonia at the highest dose (10(-3)). The increase in cataplexy after bilateral carbachol (10(-4) M) was rapidly reversed when the perfusion medium was switched to one containing atropine (10(-4) M). Bilateral atropine (10(-3) to 10(-2) M) alone did not produce any significant effects on cataplexy in narcoleptic canines; however, bilateral atropine (10(-2) M) did reduce the increase in cataplexy produced by systemic administration of physostigmine (0.05 mg/kg, i.v.). These findings demonstrate that cataplexy in narcoleptic canines can be stimulated by applying cholinergic agonists directly into the pontine reticular formation. The ability of atropine to inhibit locally and systemically stimulated cataplexy indicates that the pontine reticular formation is a critical component in cholinergic stimulation of cataplexy. Therefore, it is suggested that the pontine reticular formation plays a significant role in the cholinergic regulation of narcolepsy.

Narcolepsy without unique MHC class II antigen association: studies in the canine model.

Human narcolepsy is almost exclusively associated with the major histocompatibility complex (MHC) class II antigen HLA-DR2 and is the strongest HLA-disease association described to date. Canine narcolepsy resembles the human disease in its behavioral manifestations and responses to therapeutic drugs. Therefore, mixed leukocyte culture (MLC) was used to study differences in the canine MHC class II (DLA-D) antigens present in narcoleptic dogs to determine whether an analogous, unique DLA-D antigen could be identified in canine narcolepsy. Results show at least five different DLA-D antigens appear in potential narcoleptic haplotypes among the 29 dogs studied. The data demonstrate that, unlike man, in dogs there is no unique D locus antigen associated with narcolepsy and further suggest that linkage disequilibrium with a specific MHC antigen is unlikely to be essential for the manifestation of canine narcolepsy. Because human narcolepsy is thought to be multigenic, the canine narcolepsy-MHC dissociation suggests that the dog model may help elucidate the non-MHC narcolepsy gene(s).

Effect of alpha 1-adrenoceptors blockade with prazosin in canine narcolepsy.

The role of central alpha 1-adrenergic receptors in cataplexy was investigated in 4 narcoleptic poodles and 6 genetically narcoleptic Doberman pinschers. Treatment of narcoleptic dogs with prazosin, a selective alpha 1-adrenergic receptor blocker, exacerbated cataplexy in both narcoleptic dog breeds. Control and heterozygous Dobermans were not affected by the drug. Binding studies using [3H]prazosin revealed an increase in alpha 1-receptor binding apparently limited to the amygdala. The present study suggests that central alpha 1-adrenoceptors, whose role is still mostly unknown, play a fundamental role in controlling mechanisms involved in cataplexy and REM sleep.

Familial occurrence of narcolepsy in miniature horses.

In an investigation of 2 closely related Miniature Horses with a history of excessive sleepiness, depression and episodes of collapse, a diagnosis of narcolepsy was made on the basis of neurological examination and pharmacological testing. Further investigations included electroencephalographic examination (EEG), and analysis of protein content, cell count and monoamine metabolite concentrations of lumbosacral cerebrospinal fluid (CSF). There were no abnormalities noted in the EEGs, and no consistent changes in CSF neurotransmitter metabolites in the narcoleptic horses when compared with 3 normal, unrelated Miniature Horses and 2 related, clinically unaffected animals. The breeding background of the 2 affected horses was investigated and a limited survey of Miniature Horse breeders in North America was conducted. These investigations have shown that narcolepsy is a rare but distinct syndrome in the Miniature Horse, and that the cases described here appear to represent a familial occurrence of the disease.

Inheritance of von Willebrand's disease in a colony of Doberman Pinschers.

OBJECTIVE: To determine the mode of inheritance of von Willebrand's disease (vWD) and perform linkage analysis between vWD and coat color or narcolepsy in a colony of Doberman Pinschers. ANIMALS: 159 Doberman Pinschers. PROCEDURE: von Willebrand factor antigen (vWF:Ag) concentration was measured by use of ELISA, and results were used to classify dogs as having low (< 20%), intermediate (20 to 65%), or high (> 65%) vWF:Ag concentration, compared with results of analysis of standard pooled plasma. Buccal bleeding time was measured, and mode of inheritance of vWD was assessed by pedigree analysis. RESULTS: von Willebrand's disease was transmitted as a single autosomal gene defect. Results suggested that 27.04% of dogs were homozygous for vWD, 62.26% were heterozygous, and 10.69% did not have the defect. Most homozygous and some heterozygous dogs had prolonged bleeding times. Dogs with diluted coat colors (blue and fawn) were significantly overrepresented in the homozygous group, compared with black and red dogs, but a significant link between vWD and coat color was not detected. CONCLUSIONS AND CLINICAL RELEVANCE: von Willebrand's disease is transmitted as an autosomal dominant trait with variable penetrance; most dogs in this colony (89.3%) were carriers of vWD. Homozygosity for vWD is not likely to be lethal. Some heterozygous dogs have prolonged bleeding times. An association between diluted coat colors and vWD may exist.

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.

Treatment of cataplexy in a dog with narcolepsy.

A 1-year-old female Rottweiler with a history of narcolepsy and cataplexy lost weight and became worse when given cholinergic agents and/or prednisolone over a 12-day period. The dog was then treated with imipramine HCl, and has been almost clinically normal for 2 years.

Narcolepsy in a Brahman bull.

Behavioral, electrophysiologic, and pharmacologic tests were performed on a 2 1/2-year-old Brahman bull suspected of having narcolepsy. Placement on a tilt table or electroejaculation induced apparent sleep and cataplexy. Electrophysiologic recordings during the episodes revealed the low-voltage, high-frequency electroencephalogram, reduced electromyogram amplitude, and rapid eye movements in the electrooculogram associated with rapid eye movements sleep. Physostigmine salicylate appeared to elicit and potentiate the episodes, whereas atropine sulfate and imipramine reduced or blocked them. The combined results of the tests supported the diagnosis of narcolepsy.

Narcolepsy in seven dogs.

Narcolepsy in 7 dogs was tentatively diagnosed on the onset of cataplexy, before or during young adulthood. Confirmatory polygraphic sleep recordings were done in 3 of the dogs. In 2 dogs, treatment with neostigmine did not cause the signs to disappear, thus ruling out myasthenia gravis; trials with imipramine reduced catapletic attacks. Data from case histories, polygraphic recordings, drug trials, and clinical tests were used to compare and contrast the disease in man and in the dog.