Sleep Disorders in Horses Emily Douglas-Osborn (Final Year Veterinary Student)Emily Douglas-Osborn (Final Year Veterinary Student)

Physiology: Narcolepsy in humans:

Definition: A chronic neurological disorder in which dysregulation of the sleep-wake cycle occurs, characterised by excessive daytime sleepiness (EDS) and inappropriate REM sleep episodes. Other features include cataplexy, hypnagognic hallucinations and sleep paralysis(5).

There are two recognised forms of narcolepsy. Type 1, in which cataplexy (sudden muscle atonia, often triggered by emotion) is also a feature of disease, and reduced CSF hypocretin type 1 levels. Type 2 features neither of these and is diagnosed on polysomnographic findings alone(5,6,7).

Recent findings indicate that in genetically predisposed people autoimmune destruction of hypocretin(orexin)-producing neurones plays a part in the pathophysiology of narcolepsy(6,7). However this was only true of Type 1 subjects. Other genotypes such as human leukocyte antigen DQB1*0602 and T-cell receptor variations, and an association of narcolepsy with streptococcal infections, H1N1 infection and H1N1 vaccination further suggests an autoimmune aetiology(5,7).

Treatment depends on whether EDS is the only clinical sign. If it is, sodium oxybarate is the treatment of choice, despite being the only drug effective against all symptoms(13). If EDS and other symptoms occur, modafinil, or another CNS stimulant is added to the protocol(13). Behavioural modifications may also be useful, ie strategic napping or predicting when an episode may occur (5).

In horses:

-Familial cases described, 3/22 offspring of one Lippizaner stallion. No hypocretin deficiency was found but 2/3 were positive to the phystostigmine test (see later) (2012) (8). The third presented as fro a sleep-deprived horse (see later). -Familial cases described in Miniature horses, with no CSF/EEG abnormalities found (1993) (9). -An Icelandic foal, with no hypocretin deficiency, no falling, but increased NA metabolites (2009) (10).

True cataplexy (sudden and transient episodes of loss of muscle tone triggered by emotions) does not seem to occur in horses, partial cataplexy may exist(7). The familial cases all had episodes when being taken out of the stable. Episodes more often than not began as foals.

Treatment:Imipramine: Serotonin/noradrenaline reputake inhibitor.

Efficacy debated, especially with oral administration. Side effects include muscle fasciculations, tachycardia, hyper-responsiveness to sound, and haemolysis, and occur mostly at >2mg/kg dose (11). However, imipramine should work really well (see Figure 3), so why doesn’t it? This may be associated with case selection.

Sleep deprivation / primary hypersomnia:

Primary hypersomnia is a major differential for narcolepsy, and is characterised as a lack of both non-REM and REM sleep due to refusal to lie down.

Horses are otherwise normal, but whilst dozing, they appear to enter REM sleep. The head is slowly lowered to the floor, the eyelids droop, the horse may drop to his knees or enter sternal or lateral recumbency, or alternatively will suddenly return to a standing position again. This may occur several times in one episode, until the horse is otherwise distracted.

Figure 4: A YouTube search yielded 22 “narcoleptic” horses, of which only 3 did not present like this.

-One case presented for chronic weight loss and was noticed to do this, an enterolith was identified and removed. 1 hour post-operatively, the horse was noted lying in lateral recumbency for 12 hours, and was seen lying for 2-3 times a day for 10 days until discharge (2006)(12).

- One case presented for narcolepsy, having already been diagnosed with equine protozoal myeloencephalitis. It had changed hands 30 days ago, going from a farm with 100 fieldmates to being kept alone. A fieldmate was found, after which the horse was reported to be lying in the field for up to 50% of the time, and the collapsing resolved (2006)(12).

J.J. Bertone (2006) postulated that there are three reasons a horse may not lie down:

- Pain- Environmental stress and insecurity Monotony induced drowsiness, ie during grooming/plaiting.

“Help, my horse is falling over!”

Text minimum 16 ptLine spacing 1.1

Testing:

Atropine (0.04-0.8mg/kg IV) will suppress a narcoleptic attack for 12-30 hoursPhystostigmine – (0.03mg/kg IV) will induce an attack in 3-10 minutes.Neostigmine doesn’t cross the blood-brain barrier so cannot prevent it but can rule out other causes of collapse such as myasthenia and botulism.

Differentiation between EDS and sleep deprivation may be difficult.

Future options for narcolepsy:

-Polysomnography has been done in Germany, 2014, and can characterise the different sleep phases(14). - Limitations occur due to considerations for the owner’s safety. But bear in mind that narcoleptic humans are allowed to drive!

Advice for owners of horses with PH:

-Euthanasia is always an option. -Do not ride for the time being, and take care if handing.-Check rugs/bellies/tails for evidence of lying down.-Keep a diary of episodes.-Get some video of the episodes, if it fits with PH, then:

-Get a history from the previous owner as to how the horse was kept.-Deep straw bedding and larger stable size have been shown to encourage lying behaviour(15,16).-Ensure the horse has at least one if not more field-/stablemates.-These options may take weeks to months to work. -If this doesn’t work a phenylbutazone trial may be indicated. -Medication such as Zylkene, or in-feed magnesium calmers may also help. Another option is mild sedation , if indicated and sensibly used.

The sleep-wake cycle is a complex process of which the complete physiology is not yet clear. The following areas of the central nervous system have been shown to contribute to sleep control: (1) - The raphe nuclei in the lower pons and medulla. - The nucleus of the tractus solarius stimulate the above.-Diencephalic areas, such as the rostral hypothalamus -and thalamus .- The basal forebrain sleep area. - The locus coerulius.-The perifornical area. -The tegmental areas. Figure 1: Areas of the brain involved in the sleep-wake cycle.

In 1982, Alexander Borbély hypothesised that thecycle could be defined by two processes:

Process S is the homeostatic generation of a building sleep “drive”. Electroencephalogram (EEG) findings showed that slow wave activity increased exponentially as the time awake increased, and decreased during sleep. Subjects also slept for longer after having been awake for longer.(2) When this process reaches a threshold, sleep is achieved. (3)

 Process C is a mediated by circadian rhythms controlled in the suprachiasmatic nucleus (SCN) of the hypothalamus. The melatonin secreting pathway ascends to the RAS, which is responsible for alertness. This alters the threshold at which Process S causes the RAS to be inhibited. This may alter depending on external factors such as pain, stress, or environment, which increase sympathetic stimulation to the RAS. (3)

REM vs Non-REM Sleep:

There are two types of sleep, rapid eye movement “REM” or deep sleep, and Non-REM, light sleep. Non REM sleep has four stages of increasing depth, with stages 3 and 4 being referred to as slow wave sleep (SWS). Brain activity during REM sleep (low voltage, mixed frequency) resembles that during wakefulness. On average, horses spend 1 hour in 24 in REM sleep, and 3 in non-REM sleep(14). Figure 2 (right): EEG readings at different sleep stages (1).

REM and non-REM occur in repeating cycles throughout the period of sleep, with the REM type increasing in duration each time. REM sleep is mediated by noradrenaline serotonin and acetylcholine. Whereas non-REM sleep is mediated by serotonin and dopamine. (1)

Figure 3 : Neurotransmitters in the control of REM sleep (1).

Brain activity, heart and respiratory rate, blood pressure, sympathetic tone, and body temperature all drop in non-REM sleep. In REM sleep, these parameters are as in awake individuals, but muscle tone is absent, except in respiratory and ocular muscles (3).

Differentials:Consciousness lost:SeizuresSyncope

Sleep disordersOthers

Consciousness kept/ Weakness:Exertional rhabdomyolysis Atypical myopathy MetabolicShockEHVToxicity

Myasthenia gravisBotulismHyperkalaemic periodic paralysisEquine protozoal myeloencephalitis (USA) Foals Wobblers/Barkers/Metabolic

Rule out others by history, signalment, full physical examination, neurological examination, biochemistry and haemotology, imaging, EHV PCR, etc...

Look for sources of pain on clinical exam. Especially pain which may restrict lying behaviour. Check the dorsal carpi, pasterns and fetlocks for scuff marks and effusions.

Advise the owner not to ride for the time being.  

References:1. Canan, S., Physiology of Sleep (Lecture, Yildirim Beyazit University, Turkey) accessed online 17/04/2015 at http://www.ybu.edu.tr/sinancanan/contents/files/605Sleep.pdf  2. van Someren, E.J.W., (2010) “Slow Brain Oscillations of Sleep, Resting State and Vigilance” Proceedings of the 26th International Summer School of Brain Research, Held at the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands, 29 June-2 July, 2010.  3. Goel, N., Basner, M., Rao, H., Dinges, D., (2013) “Circadian Rhythms, Sleep Deprivation, and Human Performance” Progress in Molecular Biology and Translational Science 119:155-190. 4. Tae, W.K., Jong-Hyun, J., Seung-Chul, H., (2015) “The Impact of Sleep and Circadian Disturbance on Hormones and Metabolism” International Journal of Endocrinology Volume:2015, Article ID 591729. 5. Thorpy, M.J., Dauvilliers, Y., (2015) “Clinical and practical considerations in the pharmacologic management of narcolepsy” Sleep Medicine 16:1:9-18. 6. Nishino, S., Deguzman, C., Yamadera, W., Chiba, S., Kanbayashi, T., (2012) “Neurochemistry and biomarkers of narcolepsy and other primary and secondary hypersomnias” Sleep Medicine Clinics, 7:233-248. 7. Adamantidis, A.R., Zhang, F., Aravanis, A.M., Deissroth, K., de Lecea, L., (2007) “Neural substrates of awakening probed with optogenetic control of hypocretin neurons” Nature, 450:420–424.  8. Ludkova, E., Nishino, S., Sakai, N., Jahn, P., (2012) “Familial narcolepsy in the Lipizzaner horse: a report of three fillies born to the same sire” Veterinary Quarterly 32:2:99-102.  9. Lunn, D.P., Cuddon, P.A., Shaftoe, S., Archer, R.M., (1993) “Familial occurrence of narcolepsy in miniature horses” Equine Veterinary Journal 25:6:483-487. 10. Bathen-Nöthen, A., Heider, C., Fernandez, A.J., Beineke , A., Sewell, A.C., Otto, M., Tipold, A., (2009) “Hypocretin measurement in an Icelandic foal with narcolepsy” Journal of Veterinary Internal Medicine 23:6:1299-1302.  11. Peck K.E., Hines M.T., Mealey K.L., Mealey R.H., (2001) “Pharmacokinetics of imipramine in narcoleptic horses” American Journal of Veterinary Research 62:5:783-786. 12. Bertone, J., (2006) “Excessive Drowsiness Secondary to Recumbent Sleep Deprivation in Two Horses” Veterinary Clinics of North America: Equine Practice 22:1:157-162. 13. Thorpy, M., (2015) “Update on Therapy for Narcolepsy” Current Treatment Options in Neurology © Springer Science+Business Media New York 10.1007/s11940-015-0347-4

14. Magdelena, M., Kalus, N.L.B., (2014) “Schlafverhalten und Physiologie des Schlafes beimPferd auf der Basis polysomnographischer Untersuchungen” Inaugural dissertation for the attainment of the veterinary degree of the Veterinary Faculty of the Ludwig-Maximilians-University, Munich. Accessed 22/04/2015: http://edoc.ub.uni-muenchen.de/16740/1/Kalus_Magdalena.pdf 15. Greening, L., Shenton, V., Wilcockson, K., Swanson, J., (2013) “Investigating duration of nocturnal ingestive and sleep behaviours of horses bedded on straw versus shavings” Journal of Veterinary Behavior: Clinical Applications and Research 8:2:82-86. 16. Raabymagle, P., Ladewig, J., (2006)”Lying behaviour in horses in relation to box size” Journal of Equine Veterinary Science 26:1:11-17.