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Consultant in Sleep Disorders Medicine
University Hospitals of Leicester NHS Trust
Conflicts of interest:
Dr Hanning has received grants in support of research from and has acted as a paid consultant to Cephalon Inc and Orphan Medical Inc
Cataplexy is a bilateral muscle weakness precipitated by emotion or by the anticipation of the emotion, classically laughter. It is one of the principal symptoms of narcolepsy, together with irresistible sleep attacks, hypnagogic hallucinations and sleep paralysis. The degree of muscle weakness varies between individuals, ranging from complete loss with collapse to the ground, through unsteadiness (“jelly legs”) to transient drooping of the face. The respiratory and extraocular muscles are unaffected and the sufferer is fully aware throughout, which distinguishes it from epilepsy or sudden collapse from a transient cardiac event. An episode of cataplexy typically lasts from a few seconds to approximately one minute. Recovery is generally rapid and complete. The frequency of attack varies from a few per month to multiple attacks each day. Rarely, attacks may be so frequent as to merge together (status cataplecticus). This may be precipitated by sudden withdrawal of anticataplectic medication, for example tricycli antidepressants.
In rapid eye movement (REM) sleep, pontine cholinergic neurons inhibit motor neurons in the medulla and the descending alpha motor neurons, producing the characteristic atonia of REM sleep. During wakefulness, aminergic neurons in the locus coeruleus and raphe nuclei inhibit the pontine centres and directly activate the spinal motor neurons, allowing movement. Hypocretin-/orexin- producing neurons, which are strong activators of regions such as the locus coeruleus during wakefulness, project widely throughout the brain and will thus contribute to the maintenance of muscle tone and movement. Recent evidence has suggested that narcolepsy is the result of the autoimmune destruction of hypothalamic hypocretin- producing neurons in susceptible individuals, which leads to the development of cataplexy and sleep paralysis. The amygdala, which is activated by emotion, has links to the pontine centres and may be the trigger for cataplexy. This link is probably present and active to a degree in normal subjects, perhaps giving rise to the expression “weak with laughter”.(1)
In many patients with narcolepsy, the cataplexy is mild, infrequent and does not interfere with daily living. Others are able to anticipate the symptom and suppress the emotional response. Treatment is appropriate if these conditions are not met. Several classes of drugs are effective.(2,3)
Amphetamines and similar stimulants
Amphetamines and similar stimulants, such as methylphenidate and pemoline, tend to suppress cataplexy by stimulating dopaminergic transmission. Their main indication is for the treatment of the excessive daytime sleepiness associated with narcolepsy. In this role, they have largely been supplanted by modafinil, which is preferred for its longer duration of action, lack of abuse potential and tolerance. Modafinil has no effect on cataplexy. The amphetamines are now generally used to supplement the alerting action of modafinil rather than as sole agents.
Tricyclic antidepressants (TCAs) block the reuptake of endogenous amines into presynaptic neurons, thus increasing their activity. Most are relatively selective for norepinephrine, although some, including clomipramine, also affect serotonin reuptake. All have a degree of anticholinergic activity through muscarinic receptors, which will tend to suppress REM sleep, a predominantly cholinergic activity. They should be used with caution in conjunction with amphetamines, as an exaggerated catecholamine response may occur. Most TCAs have been used for treating cataplexy, but clomipramine, at a dose of 25–75mg daily, has been widely preferred. Apart from the usual anticholinergic side-effects such as dry mouth, increased sleepiness has been reported by some subjects. These drugs have generally been supplanted by selective serotonin reuptake inhibitors (SSRIs). TCAs should not be stopped abruptly, as status cataplecticus may develop.
Monoamine oxidase inhibitors
Several monoamine oxidase inhibitors (MAOIs) have been investigated in narcolepsy/cataplexy. Selegiline, the MAO-B inhibitor which has been studied most intensively, has been shown to be effective. However, side-effect profiles and the range of interactions with other drugs and food stuffs have limited use.
Selective serotonin reuptake inhibitors
SSRIs increase the activity of endogenous amines and catecholamines, especially serotonin, by inhibiting their reuptake into presynaptic neurons. Fluvoxamine, fluoxetine, femoxetine, zimeldine and citalopram have all been shown to be effective. They are generally regarded as second-line therapy for cataplexy but are preferred to TCAs and MAOIs because of their better side-effect profiles. SSRIs should not be used concurrently with TCAs and MAOIs. A more recently introduced class of SSRIs also blocks the reuptake of norepinephrine. Venlafaxine, which has been the most studied drug for the management of cataplexy, is regarded as the agent of choice by many authorities in a dose of 37.5–75mg daily. Viloxazine and reboxetine have also been shown to be effective. This class of drugs is reported to cause less sedation and to be more alerting than TCAs. Insomnia has been reported, especially if the drug is taken in the evening.
Sodium oxybate, or γ-hydroxybutyrate (GHB), is an endogenous neurotransmitter acting on specific receptors within the central nervous system (CNS) and, at higher concentrations, on the γ-amino butyric acid (GABA)(B) receptor. GHB interacts with serotonergic, endogenous opioid and dopaminergic systems. GHB was first investigated as a sedative and anaesthetic in the 1960s but proved difficult to use and was superseded by other agents. It has been used in the management of alcohol withdrawal. Its effect in increasing slow-wave sleep (SWS) and, thus, growth hormone release led to its abuse by bodybuilders and, as it is water-soluble, tasteless and odourless, to its misuse as a “date rape” drug. Sleep is severely fragmented in narcolepsy, and early investigators hypothesised that sodium oxybate, by increasing SWS, might improve the excessive daytime sleepiness and other symptoms, including cataplexy. Orphan drug status for sodium oxybate was granted to Orphan Medical, and several clinical trials have recently been undertaken, demonstrating significant and maintained reductions in cataplexy and excessive daytime sleepiness. A licence for the management of cataplexy was granted by the FDA in 2002 and by the Committee for Medicinal Products for Human Use (CHMP) in 2005. In the USA, a postmarketing evaluation was imposed by the FDA and a risk management programme instituted in view of concerns regarding the potential for dependence and diversion of the drug for illicit use. Thus far, no significant problems have emerged in these respects.
Sodium oxybate is administered as an oral solution in a dose of 4.5–9g per night, half the dose being taken just before the desired sleep onset and the remainder four hours later. Onset is rapid, and patients are advised to take the drug when in bed and ready to sleep. The mode of action is not entirely clear, as the duration of action of the drug is much shorter than its half-life of 40–60 minutes would suggest. In addition, the maximum improvement in cataplexy and excessive daytime sleepiness takes several weeks to develop, suggesting a longer-term modulation in neuronal and receptor function. Many of the side-effects are as expected from the increase in SWS, including parasomnias (sleepwalking), enuresis and confusion, if woken shortly after dosing. Residual morning sedation, dizziness, confusion and headache have been reported. Serious potentiation of sodium oxybate by alcohol and other CNS sedatives may occur. Most authorities currently regard sodium oxybate as a second-line drug, but further experience may well lead to its increasing use as a first-line agent.
The efficacy of sodium oxybate is likely to lead to the development of other drugs active at the GHB receptor. Narcolepsy/cataplexy is the result of a presumed autoimmune destruction of hypocretin-producing cells in the hypothalamus, and immunosuppressive drugs can be administered to children in the early stages of the disease. As there is generally a considerable delay, often of several years, between first symptom and diagnosis, this approach, while interesting, is unlikely to be used widely. Analogues of hypocretin are of considerable interest for both narcolepsy/ cataplexy and appetite control.