Large Animal Neurology. Joe Mayhew

      The role of sleep in mammalian biology is somewhat of an enigma.¹ Adult herbivores spend a substantial proportion of time foraging, and only a few hours daily are spent in stages of sleep, a small proportion of which is rapid eye movement (REM) sleep with accompanying somatic hypotonia or atonia and recumbency.^1–3 For adult cattle and horses, this amounts to 3–5 h per day in sleep states and about 0.5 h per day in REM sleep.^3–6 Some horses appear to be able to perform REM sleep while standing² and to tolerate weeks of being unable to lie down to sleep, whereas others experience great difficulties in being cross‐tied for several days. The latter appear to go into a deep sleep state but stagger as not being able to remain upright, and some can injure themselves. Thus, the concept of sleep deprivation in horses may well be an individual phenomenon.^3,7

Without observing episodes, it can be difficult to distinguish seizures from normal and abnormal episodes of sleep and from cardiovascular collapse or syncope in otherwise perfectly healthy patients. The last of these show multiple episodes of collapse but with apparent normalcy between is incredibly rare in our experience, but seizures and sleep disorders can be quite distinguishable if observed. In this regard, 24‐h video monitoring and recording can be useful to capture suspected episodes of sleep and seizures when they are not overt.⁸ However, intermittent paralysis or cataplexy can pose as syncope, epileptic seizures (particularly pseudocataplexy or atonic seizures), hyperekplexia, and vestibular drop attacks.⁹

      In the context of sudden and unexpected collapse, there are many systemic issues that can mediate an abrupt loss of body support,¹⁰ but the majority result in other progressive signs such as weakness and obtundation or are associated with other factors such as trauma, diarrhea, or drug usage.¹¹ In about half the cases of episodic collapse, it may be possible to arrive at a final diagnosis with most having signs other than collapse being evident. Such diagnoses include cardiac arrhythmia, right‐sided heart failure, hypoglycemia, neurocardiogenic syncope, and exercise‐induced pulmonary hemorrhage. For most other cases, there will be a strong suspicion of epilepsy (Chapter 6) and sleep disorders.¹²

Sleep disorders in humans^313–15 can be categorized into many groupings, but these usually include narcolepsy with cataplexy (narcolepsy type‐1, NT‐1) (Figure 7.1), narcolepsy without cataplexy (NT‐2), and idiopathic hypersomnia (see Chapter 31 for further readings on narcolepsy in large animals).^316–23 Narcolepsy occurs in 0.02–0.15% of the population, and patients typically demonstrate excessive diurnal sleep, flaccid paralysis with somatic areflexia that constitutes cataplexy, sleep paralysis, sleep‐onset hallucinations, and nocturnal disrupted sleep. Strict EEG and EOG criteria, including the early onset of rapid eye movement at the beginning instead of the middle of a sleep cycle, are in place for confirming the diagnosis and for distinguishing narcolepsy with cataplexy from narcolepsy without cataplexy and from idiopathic hypersomnia. A familial form of narcolepsy with cataplexy occurs in dogs and humans, and in the latter it is strongly associated with the genetic allele HLA‐DQβ1*0602. An autoimmune basis to at least some forms of narcolepsy thus seems likely.¹³ Narcolepsy without cataplexy shares the same electrophysiological abnormalities and associated signs, but there is no demonstrable cataplexy. Purely excessive daytime sleep attacks, also referred to as unwanted siestas (a well‐appreciated term!), occur in idiopathic hypersomnia.

Figure 7.1 Familial narcolepsy with cataplexy as seen in these two ponies is uncommon compared to other forms of sleep disorders in horses. These ponies would, spontaneously and particularly with pleasurable stimuli such as grooming, feeding, and playing (A), rapidly become somnolent, stagger or sway, and fall passively to the ground in a cataplectic state (B) with no spinal reflexes demonstrable, where they would remain until they slowly woke up after a minute to an hour or so.

      Two novel neuropeptides (orexins), hypocretin 1 and 2, were found to be specifically expressed in certain hypothalamic neurons, and defective hypocretin signaling was related to both familial and sporadic narcolepsy.^{3,21,22,24,25} A mutation in the hypocretin receptor‐2 gene was present in dogs with familial narcolepsy although they had normal levels of hypocretins in their CSF and hypothalamus. Neurotransmission through hypocretin‐1 was likely to be intact indicating that defective hypocretin‐2 function is more important in producing narcolepsy in that model. In contrast, dogs with sporadic narcolepsy had no expressed hypocretins in the CSF or brain tissue. Hypocretin deficiency, as shown by low or absent concentrations in CSF, has been found in 90% of patients with sporadic narcolepsy with cataplexy, and less commonly in familial narcolepsy²⁶ and in sleep deprivation, suggesting that disorders with marked cataplexy are more dependent on dysfunctional hypocretin pathways.

In the sporadic and some familial forms of the disease, various pieces of evidence indicate that there may be an autoimmune attack on hypocretin‐producing neurons and decreased hypocretin‐expressing neurons in the hypothalamus have been reported.^27–30 Attempts to identify a neural autoantibody in canine and human narcolepsy have been unsuccessful; however, evidence for the presence of a functional, IgG autoantibody in serum of narcoleptic humans and not in controls which upregulates cholinergic activity, a characteristic of narcolepsy, has been presented.³¹ Further evidence that the immune system plays a role in canine genetically dependent narcolepsy has been published. ^{One study found that immunosuppressive and anti‐inflammatory drugs delayed the onset and severity of narcolepsy and cataplexy in treated dogs compared to controls. Also, there has been an upsurge in acquired influenza vaccine‐induced narcolepsy type 1 (Pdmx‐NT1) and a loss of hypocretin‐producing neurons in this form of narcolepsy as well as in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1). Results of attempts at treating narcolepsy in dogs with prednisolone and systemic and intrathecal hypocretin‐1 have been poor, perhaps because of depleted hypothalamic neurons.34 However, using alternating periods of desipramine and yohimbine (an α‐2 antagonist to activate adrenergic transmission) therapy for the cataplexy showed promise.}

      Many normal newborn foals can be induced into a sleep‐like state by firm, whole‐body restraint or cuddling to sometimes even lie still on the ground when released.³⁵ This phenomenon wanes rapidly over a few days and it has been postulated that this is persistence of a protective mechanism that stops vigorous reflex movement occurring in utero, especially during birth.

      Astute observational studies of sleep–wake cycling in domestic animals can result in modified environments to facilitate relaxed leaning behavior, as depicted here for an elephant using a leaning fence with horizontal protuberance for support. Source: Modified from Schiffmann et al.³⁶

      Some syndromes of adult‐onset sleep attacks in large animals—especially horses—clinically resemble true narcolepsy with cataplexy; however, confirming limb atonia, limb areflexia, as well as onset of REM sleep at the onset of an episode does not appear to have been documented. Thus, it is likely that many of these cases of adult‐onset sleep attacks are examples of sporadic idiopathic hypersomnia, probably with influences of sleep deprivation as discussed above.⁷ Many factors of animal domestication, including disrupted social hierarchy, confinement, and occupational maladies, appear to be involved with lack of restful sleep, and astute observational programs can result in very useful management alterations to assist in restoring acceptable sleep–wake cycles.³⁶ A detailed understanding of sleep patterns, including the associated encephalographic patterns, and determining the roles, if any, of hypocretin pathways and their immune attack