17 Aug 2015
Johnny (Ioannis) Plessas
Job Title
Sleep disorders are infrequently encountered in small animal practice, but can mimic common conditions, such as syncope or seizures, and can lead to misdiagnosis. Several sleep disorders have been reported in people, but narcolepsy/cataplexy and rapied eye movement (REM) sleep behaviour disorder are the most common in animals. Narcolepsy is characterised by the tendency to fall asleep during the day, disturbed night sleep and cataplexy.
Cataplexy is an exaggerated manifestation of narcolepsy in which sudden collapse occurs from complete atonia of the skeletal muscles. Cataplectic episodes, if frequent, are not difficult to diagnose, but some cases are more challenging. Furthermore, REM sleep behaviour disorder is characterised by involuntary, sometimes violent, muscle contractions during the REM phase of sleep, which cease as soon as the animal is aroused. This article discusses clinical features, diagnostic investigation, the most common differential diagnoses and treatment options for these disorders. Finally, the common physiological phenomenon of hypnic jerks is also mentioned, so it can be differentiated from other pathological conditions.
Sleep disorders in small animals are uncommon neurological conditions that can have a significant impact on a pet’s quality of life, and can also disturb the bond between the pet and its owner.
Several sleep disorders have been described in people, but the most common ones in small animals include narcolepsy/cataplexy and rapid eye movement (REM) sleep behaviour disorder. Despite their complex names, these conditions should not be a reason to lose sleep.
To understand the pathophysiology of these conditions, it is important to explain the normal physiology of sleep. In general, sleep is divided into two phases – the non-REM or slow wave phase and the REM phase.
Non-REM sleep is the first phase in which temperature, heart and respiratory rate decreases, animals are immobile, but retain normal resting muscle tone. This is followed by the REM phase in which temperature, heart and respiratory rate increases, flaccid paralysis predominates (via inhibition of the lower motor neurons), and it can be accompanied with eye movement (hence the name REM). Other normal movements seen in this phase include facial twitching, paddling and even vocalisation. These two phases alternate in animals every 15 minutes to 20 minutes during sleep. People experience dreams during the REM phase.
The state of wakefulness and sleep is regulated by an ill-defined mesh of neurons, called the ascending reticular activating system, which is spread throughout the brainstem.
Within this mesh there are neurons with more specific functions (hypothalamic and dorsal raphe nuclei, locus coeruleus and other centres; Figure 1) that release specific neurotransmitters (that is, hypocretin, norepinephrine, serotonin and acetylcholine) and control the function of neurons innervating postural muscles (lower motor neurons). The end result of this regulation is inhibition of the lower motor neurons and flaccid paralysis1.
Narcolepsy is a sleep disorder characterised by the tendency to fall asleep during the day, disturbed night sleep and cataplexy. Cataplexy is an exaggerated manifestation of narcolepsy in which sudden collapse occurs from complete atonia of the skeletal muscles. Narcolepsy is less noticeable in animals, whereas cataplexy, due to its dramatic presentation, is much more obvious.
Two forms of narcolepsy/cataplexy have been described in dogs: the inherited/genetic form and the acquired form1.
Inherited form: the inherited form has been reported in Dobermann Pinschers, Labrador retrievers and dachshunds, and has been associated with a mutation in the hypocretin receptor-2 gene in the brainstem2. Hypocretin levels are normal in this form, but the malfunction of its receptors leads to disregulation of the normal REM phase. An autosomal recessive mode of inheritance has been found and the onset of the clinical signs start approximately in puppies two to four months old. The clinical signs may resolve in some dogs as they reach the age of four to five years.
Acquired form: this form can occur in any breed and is associated with decreased levels of hypocretin in the cerebrospinal fluid (CSF). In people, autoimmunity has been associated with this form, but this has not been shown in dogs. Other causes of acquired narcolepsy/cataplexy include general anaesthesia, head trauma and mass lesions affecting the brainstem.
The main clinical sign is cataplexy, but increased daytime sleeping and inconsistent night sleep patterns have also been reported in dogs and cats. The cataplectic episodes are characterised by paroxysmal episodes of flaccid paralysis with abrupt return to normality. Usually, these episodes are induced by excitement such as food, greeting owners or playing.
Clinicians should be mindful narcolepsy/cataplexy in small animals is an uncommon condition and they should differentiate it from other more common conditions such as syncope, brachycephalic obstructive airway syndrome, epileptic seizures or neuromuscular weakness (Table 1).
In cases where the cataplectic episodes are frequent, diagnosis is easier based on observation of the episodes once other major differentials have been ruled out. Pharmacological testing with anticholinergic drugs such as imipramine (0.5mg/kg IV) or atropine (0.1mg/kg IV) can prevent the episodes for 45 minutes (from imipramine) up to three hours (for atropine) and support the initial suspicion3.
Diagnosis becomes more problematic in cases where the episodes are infrequent. Observation of video recordings and provocative testing can be very helpful. Food stimulation can be used, with 10 small portions of food placed about one metre apart in a row. Most normal dogs will consume the food in less than 45 seconds, whereas narcoleptic dogs take two minutes or more.
Physostigmine (0.05mg/kg to 0.1mg/kg IV) can also be used to provoke cataplexy in narcoleptic dogs1. It is important to note the mentioned drugs used for pharmacological testing are not licensed in small animals and owners should be informed about the risks associated with their use.
Genetic testing for the mutation in the hypocretin receptor-2 gene is also available for Dobermann Pinschers, Labrador retrievers and dachshunds (www.optigen.com).
A thorough general physical and neurological examination should be performed in every patient with suspected narcolepsy. If neurological deficits are present on the examination then advanced imaging (MRI) of the localised area and CSF analysis should be performed.
No specific treatment is required, apart from avoidance of triggering factors, in cases where the episode frequency is low and the patient’s quality of life is not affected. If the frequency is high enough to affect the patient’s quality of life, medical treatment should be considered.
Tricyclic antidepressants, such as imipramine hydrochloride (0.5mg/kg to 1.5mg/kg PO q 8-12h), clomipramine (3mg/kg to 6mg/kg PO q 24hr) or desipramine (3mg/kg PO q 12h) are recommended based on their ability to inhibit noradrenaline reuptake in the brain. Methylphenidate hydrochloride (0.25mg/kg PO q 24h), venlafaxine (2.5mg/kg PO q 24h), yohimbine (0.05mg/kg to 0.3mg/kg PO q 12hr) or selegeline (2mg/kg PO q 24h) have also been reported to be effective on isolated cases1,4,5,6. Hypocretin supplementation has not been shown to be successful in dogs with the acquired form.
To date, no medication can provide complete resolution of the clinical signs. The aim of treatment is to reduce the frequency of the episodes without the patient experiencing adverse effects. Anecdotally, functional tolerance can develop in patients treated chronically and regular changes in medication may be required. Spontaneous resolution of the clinical signs may occur in cases of inherited narcolepsy/cataplexy.
As aforementioned, the REM phase of sleep is characterised by flaccid paralysis, which is achieved by inhibition of the lower motor neurons from brainstem centres. Respiratory muscles escape this inhibition to maintain breathing during sleep, but sometimes other isolated muscles also escape and their contraction causes signs such as facial twitching, paddling and even vocalisation (contraction of laryngeal muscles during expiration). These movements are very brisk, last only a few seconds and are very commonly seen in small animals.
Problems arise when the degree of activity during the REM phase is so severe it leads to injuries of the animal or destruction of the house furniture – this is called REM sleep behaviour disorder.
REM sleep behaviour disorder has been reported in dogs and cats. Several breeds have been reported, including golden retriever, Australian cattle dog, Dalmatian, German shepherd dog and other breeds. In one study7, 64% of the cases were younger than one year old at the time of the onset, although the age ranged from two months to 7.5 years.
Violent limb movements, howling, barking, growling, chewing or biting during sleep were seen in the majority of the affected dogs. A characteristic feature of this disorder is affected animals can be easily aroused and the movements cease immediately.
Diagnosis can be made based on history of violent movements during sleep that can cease when the animal is aroused, but confirmation depends on electromyography and electroencephalography studies during the event, which is quite impractical in veterinary patients. Observation of videos of the episodes can be very beneficial in supporting the diagnosis.
One major differential for this disorder is epileptic seizures, but with the latter the patients cannot be easily aroused and a seizure is expected to have postictal behavioural changes after the event. Epileptic seizures may also be accompanied, although not exclusively, by autonomic signs like urination or defaecation.
There is very limited information about effective treatment for this condition. In one study6, potassium bromide at a dose of 40mg/kg/day reduced the severity and frequency in 78% of dogs. Anecdotal data also suggests clonazepam, amitriptyline or gabapentin may be beneficial in isolated cases.
Spontaneous recovery has not been reported and in some cases the clinical signs can be progressive. Extreme cases sometimes are euthanised due to the house disruption at night and repeated self-inflicted injuries.
Hypnic jerks, or sleep starts, is a very common phenomenon in people and is also presumed in animals. Although it is mentioned here, it is not a pathological disorder. Hypnic jerks are involuntary twitches that occur as the individual falls asleep and in people are also associated with a feeling of falling from height. This is a normal phenomenon that occurs during the non-REM sleep and its pathophysiology is not clear.
Presumably these jerks arise from sudden descending volleys that originate from the reticular system in the brainstem and may be activated by the instability between the states of wakefulness and sleep8.
Clinicians should be aware of these hypnic jerks and REM sleep behavioural disorders so they can be differentiated from epileptic seizures.
Sleep disorders, although uncommon, should be included on the list of differentials of dogs and cats that present with “collapsing” episodes or with sleep-associated involuntary movements. Clinicians should have a step-by-step approach in ruling out other more common differentials before diagnosing a patient with a sleep disorder and a specialist’s opinion should be sought for complex cases.
