Narcolepsy-Cataplexy

Robert J. MacKay

■ Definition and Etiology Narcolepsy is a spectrum of CNS disorders characterized by episodes of excessive sleepiness or muscular weakness, or both, and REM-onset sleep.

Sleep-wakefulness regulation is normally achieved through reciprocal interplay of consciousness-arousing and consciousness­depressing regions of the brain.¹ Included in the arousal system are cholinergic and monoaminergic (histaminergic, serotonergic, dopaminergic, and noradrenergic) neurons located in the caudal hypothalamus/brainstem regions that diffusely project to the forebrain to upregulate cortical function. Conversely, gamma­aminobutyric acid (GABA)-ergic neurons of the rostral hypothalamus play a critical role in sleep by inhibiting neurons of the arousal system. Two closely related neuropeptides, orexins A and B (also known as hypocretins 1 and 2), produced exclusively by neurons in the lateral hypothalamus, are neurotransmitters critically involved in the neuronal circuitry regulating sleep and wakefulness states. Via numerous afferent connections, orexin-positive neurons sense the body's external and internal environments and regulate wakefulness accordingly, mostly by stimulating consciousness-arousing monoaminergic neurons. Multiple lines of evidence suggest that sporadic narcolepsy in humans is caused by a dysfunctional orexin system, usually as a result of degeneration of orexin neurons.

Narcolepsy has been reported in numerous horse and pony breeds, a Suffolk lamb, Spanish fighting bulls, a Guernsey bull, and a Brahman bull.^2-11 Most cases appear to be sporadic, but early-onset, probably familial occurrence has been reported in American Miniature Horse, Lipizzaner, Suffolk, Shetland pony, and Fell pony foals^2,12 and has been observed by the author in a family of Morgan horses. The collapse syndrome associated with squeezing neonatal foals traditionally has been viewed as a transient form of cataplexy; however, one study demonstrated that the associated EEG patterns were slow waves consistent with abrupt transition to non-REM sleep and thus were more characteristic of narcolepsy than of cataplexy.¹³

■ Clinical Signs The clinical signs of narcolepsy include staggering, lowered head and neck, buckling of the thoracic limbs, kneeling posture, flaccidity of the lips, closure of the eyes, loss of the menace reflex, stertorous breathing, and ataxia. During severe narcoleptic attacks (narcolepsy-cataplexy), the animal collapses into lateral recumbency and appears comatose. Only rarely is REM sleep observed after collapse. The sensorium returns to normal after seconds to minutes. In the periods between attacks, the animal appears normal, although repeated attacks result in trauma to the dorsal aspects of the fetlocks and the knees and to the face.^12,14 Cataplexy, which may occur with or without narcolepsy, is a sudden episode of paralysis of the voluntary muscles, often induced by strong emotions (usually positive) in the patient and can range from atonic, areflexic paralysis of all skeletal muscles, except those of the diaphragm and eyes, to slight transient buckling of the limbs without collapse into recumbency.

Environmental factors that can stimulate cataplectic attacks include active restraint, suckling, feeding, changing of the stall environment, grooming, or cross-tie-related activities of horses such as saddling, removal of tack, and washing. Despite this association, narcolepsy in adult horses usually occurs while horses are in stalls or at pasture without any obvious prior stimulation.¹⁴ Most cases of narcolepsy in humans are associated with cataplexy, but sleep attacks without cataplexy and cataplexy without sleep attacks also occur. Mild cataplexy and attacks of excessive sleepiness can be difficult to distinguish in adult large animals in that both may cause blank facial expression, hanging of the head and neck, and buckling of the limbs with or without collapse into recumbency.¹⁴ Sudden arousal associated with the stimulation of collapse and ground impact also could terminate either type of episode. In view of diagnostic ambigui­ties based on observations of mild sleep attacks, cataplexy that persists after collapse is the most frequently recognized mani­festation of sleep disorders in large animals.

Signs are generally stable and lifelong. The cataplexy component of juvenile cases usually improves as the animal gets older but rarely resolves completely.

■ Diagnosis Strict electroencephalographic criteria, includ­ing the early onset of waveforms typical of REM sleep at the beginning instead of in the middle of a sleep cycle, are in place for confirming the diagnosis and for distinguishing narcolepsy from narcolepsy without cataplexy. The electroencephalographic changes of narcolepsy and cataplexy have been reported in a Brahman bull.³ In horses, electroencephalographic waveforms may be normal or may reveal fast waves typical of REM activity.¹⁴ Orexin concentrations in CSF are typically low in humans and dogs with sporadic or familial narcolepsy but normal in familial forms associated with mutations in the genes for orexin receptors.^15,16 In CSF samples from a narcoleptic Icelandic foal and three related narcoleptic Lipizzaner fillies, immunoreactive orexin concentrations were comparable with those from normal horses.^2,17 It is important to evaluate this diagnostic finding in both juvenile and adult-onset forms of the disease in large animals.

Cataplexy can be induced by IV administration of the centrally acting cholinesterase inhibitor physostigmine salicylate (0.05 to 0.1 mg/kg),⁴ but attacks cannot be evoked in all animals. In one series of 3 narcoleptic horses challenged, 2 responded positively to the challenge²; in another report, only 1 of 10 affected horses had a positive response.⁹ Signs of cataplexy can be reversed for at least 24 hours by one dose of atropine sulfate (0.02 to 0.1 mg/kg IV).^9,17 Diagnostic drugs must be admin­istered with caution because of the possibility of inducing colic, especially in horses.

Syncope and seizures are included in the differential diagnosis of narcolepsy. In general, syncope is characterized by acute collapse without warning and, unlike narcolepsy, is not preceded by a gradual lowering of the head and drowsiness. Increased focal or generalized tonic-clonic muscle activity and postictal depression are typical with seizures but not with narcolepsy. In addition, excessive sleepiness can be observed in horses that have an underlying painful physical condition, environment, or social position that prevents them from lying down to sleep.¹⁸ Therefore a complete history and thorough physical examination are essential.

■ Treatment and Prevention The tricyclic antidepressant imipramine (0.5 to 1 mg/kg PO bid to qid) can be used to treat cataplexy but is ineffective in treatment of the sleepiness component of narcolepsy. This drug must be administered with caution, and oral dosages in horses should not exceed 2 mg/kg.⁶ Results of oral imipramine therapy are inconsistent; duration of effect is approximately 5 hours. Anecdotal reports indicate that tyrosine has been of benefit in some, but not all, narcoleptic horses. Its presumed mode of action is to increase dopamine neurotransmitter concentrations.¹⁴

Selective serotonin reuptake inhibitors are also used in humans for treatment of cataplexy but have not been evaluated in large animals for this purpose.¹⁹ Sodium oxybate (the sodium salt of gamma hydroxybutyrate) is widely used as a wakefulness­promoting drug in narcoleptic humans and may apply to the treatment of veterinary patients.¹⁹