Cataplexy is the sudden loss of muscle tone that is triggered by the experience of an intense emotion. The word cataplexy comes from the Latin word “cataplessa” which means, “to strike down with fear or the like” [1]. Cataplexy is the result of an absence of the hypocretin (also known as orexin) neurotransmitter in the hypothalamus. Although it is commonly linked to the syndrome narcolepsy, it may be associated with other pathological conditions. In this review, we will specifically focus on cataplexy and describe its clinical features, its association with the neurotransmitter hypocretin and the human leukocyte antigen DQB1*0602, as well as treatment options. Secondary causes of cataplexy will also be discussed.

Contents

Clinical characteristics

The sudden loss of muscle tone in cataplexy is similar to rapid eye movement (REM)-associated muscle atonia during sleep, but it is occurring during wakefulness. Emotions that may trigger attacks include laughter, fear, anger, frustration, annoyance, nervousness, embarrassment, and sadness. Positive emotions, specifically laughter, are most predictive of triggering a cataplectic event. Data from the Stanford University Sleep Disorders Clinic of 200 patients with cataplexy showed that 100 percent of these patients reported laughter as the most common trigger, followed by a feeling of amusement, or surprise with happiness and joy [2]. A study by Anic-Labat et al. reported that emotions arising from "hearing or telling a joke," "laughing," or "when angry," were most predictive of the loss of muscle function in clear-cut cataplexy [3].

A cataplectic attack is sudden in onset and is localized to a specific muscle group or parts of the body. The subject is lucid during this attack and it is important to recognize that consciousness is always maintained at the onset of cataplexy. As the attack continues the patient may experience sleepiness, hallucinations, or sleep-onset REM period. A full-blown attack may occur and results in complete muscle paralysis with postural collapse and possible injury. However, most often patients with postural collapse have the capability to avoid injury because the fall is slow and progressive. The more commonly limited cataplectic attacks involve the head and face, neck, upper limb, and more rarely lower limb known as "knee buckling" [4]. Patients present with trembling of mesenteric muscles, rictus, dysarthria, head and upper arm drop, and may drop objects held in hands [4-6]. A study of 40 cataplectic patients (age range 13-23 years) reported that sagging of the jaw, inclined head, drooping of the shoulders, and transient buckling of the knees were the most common presentations [2]. Slurred speech may be present. However, diaphragmatic paralysis resulting in central apneas has not been reported. There is an isolated form that involves facial muscles exclusively. Cataplexy may rapidly reoccur repeatedly, giving birth to “status cataplecticus” [4], and to the “limp man syndrome” as described by Stalh et al. [7]. “Status cataplecticus” is rare and can be extremely disabling to the individual. Cataplexy also occurs more frequently in times of emotional stress and when patients are deprived of napping while sleepy.

In a 24-hour period, cataplectic attacks usually occur between the hours of 10 am and 9 pm [6]. Few attacks occur between the hours of 10 pm and 9 am. Attacks can last from a few seconds up to ten minutes, and may occur up to several times per week [4-6]. Cataplexy is considered “typical” when it is always of short duration (< 5 minutes) and triggered by laughing or joking [2]. A survey of 100 cataplectic patients from the Stanford Sleep Disorders Clinic (age range 14-24 years) reported that 93 percent of the attacks lasted less than two minutes, 6 percent reported events lasting up to five minutes, and 0.94 percent reported events lasting longer than five minutes [2]. There is a bimodal pattern of age of onset of symptoms; either at 15 or 35 years [8, 9]. It has also been reported past the age of forty. Guilleminault et al. [10] investigated 51 prepubertal children with narcolepsy; in 10 subjects (5 years and younger) cataplexy was the symptom first recognized. Cataplectic symptoms in general tend to decrease with age. A review of 100 patients with cataplexy at the Stanford Sleep Disorders Clinic (age range 12-20 years) reported that 62 of these patients stopped taking anti-cataplectic medications after 10 years [2]. However, the general decrease in cataplectic symptoms with aging may be reversed after the experience of a significant emotional upset, such as a loss of spouse in older subjects [11].

Cataplexy is rarely observed in an office visit, and even if it does occur, only a trained specialist who is familiar with the condition often notices it. The onset of cataplexy is associated with the absence of deep tendon reflexes that comes back with the return of normal muscle tone. This is a simple test that differentiates cataplexy from other drop-attacks. In cases where cataplexy is mild or triggered by unusual emotions, it can be difficult to define whether the patient's description of the experience reflected a true cataplectic episode, or rather physiological muscle weakness associated with intense laughter or other activity. Questionnaires that are specifically focused on emotional triggers and anatomical localization of attacks can significantly differentiate definitive cataplexy from other nonspecific episodes of muscle weakness [3].

HLA typing

HLA markers are crucial in the relationship between cataplexy and narcolepsy. The presence or absence of cataplexy is a critical factor in determination of a positive HLA genotype. In 1983 Honda et al. [12] from Japan found that narcolepsy is associated with two specific serologically defined HLA class II antigens, DR2 and DQ1. Several investigators have confirmed this finding across different ethnic groups. The HLA DQ1 is a more sensitive marker for narcolepsy with cataplexy than DR2 [13]. DQB1*0602 is the major HLA susceptibility allele for excessive daytime sleepiness with clear-cut cataplexy across different ethnic groups [14, 15]. Depending on the series, 88 to 98 percent of patients with clear-cut cataplexy are HLA DQB1*0602 positive independent of ethnicity. Mignot and colleagues found in 509 narcoleptic patients that the frequency of a positive DQB1*0602 haplotype was strikingly higher in patients with narcolepsy and cataplexy versus patients with narcolepsy without cataplexy (76.1% in 421 patients versus 40.9% in 88 patients, respectively) [16]. A positive allele for HLA DQB1*0602 was most frequently seen in patients with severe cataplexy (94.8%) and progressively decreased in patients with mild cataplexy (54.2%) [16].

But the relationship of HLA and narcolepsy with cataplexy is complex. The association of DQB1*0602 with DQA1*0102 is more common with narcolepsy in multi-ethnic studies [15]. In heterozygotes the alleles DQB1*0601 and DQB1*0501 are protective against narcolepsy. In cases where narcoleptic patients without cataplexy were negative for DQB1*0602, it has been shown that DQB1*0301 was the second susceptibility gene. The association of DQB1*0602 and DQB1*0301 has a higher level of susceptibility for cataplexy than other combinations. Finally, this specific marker DQB1*0602 for cataplexy in narcoleptic patients is also present in 12 to 28 percent of the general population [15, 17, 18]. Thus the test has poor sensitivity and therefore has limited value in diagnosing narcolepsy with cataplexy. However, in cases of questionable narcolepsy with atypical presentations or without cataplexy, a negative DQB1*0602 would be useful but not 100 percent reliable, to guide further diagnostic work-up and therapeutic options.

The hypocretin system

Our understanding of cataplexy has changed with the discovery of the cerebral spinal fluid (CSF) hypocretin neurotransmitter and its role in the control of wakefulness and sleep. Cataplexy in humans is most commonly related to a lesion of the hypocretin system. In a dog model cataplexy is caused by a mutation of the hypocretin receptor-2 [19]. Since this discovery, man-induced genetic manipulations involving the hypocretin-1 and hypocretin-2 receptors and the creation of knocked-out mice models have been created to investigate cataplexy [20]. Wake promoting systems in the brain include noradrenergic (located in locus coeruleus), serotonergic, and histaminergic cells [21-23]. All of these cells are influenced by hypocretin neurons, with the locus coeruleus receiving a predominant excitation signal. The loss of hypocretin results in the inhibition of the predominant wake promoting mechanism of the noradrenergic system, and to a lesser extent the other two systems. Patients with cataplexy and are positive for the HLA-DQB1*0602 allele have been found to have low CSF hypocretin-1 levels 99 percent of the time [24]. In other words, the presence of cataplexy and a positive HLA-DQB1*0602 allele are almost always associated with low levels of CSF hypocretin-1. Checking for levels of CSF hypocretin-1 is most beneficial in cases where cataplexy is atypical or doubtful.

Secondary cataplexy

Despite its primary association with narcolepsy, cataplexy is considered secondary when it is due to specific lesions in the brain that cause a depletion of the hypocretin neurotransmitter. Secondary cataplexy is associated with specific lesions located primarily in the lateral and posterior hypothalamus. Cataplexy due to brainstem lesions is uncommon particularly when seen in isolation. The lesions include tumors of the brain or brainstem and arteriovenous malformations. Some of the tumors include astrocytoma, glioblastoma, glioma, and subependymoma. These lesions can be visualized with brain imaging, however in their early stages they can be missed. In children cataplexy may alert the clinician to the presence of a tumor, particularly craniopharyngioma. This tumor accounts for 9 percent of all pediatric intracranial tumors [25]. In craniopharyngiomas, the onset of cataplectic symptoms is between 5-10 years of age, which is earlier than the peak of narcolepsy with cataplexy in children around the second decade between 12-18 years. Other conditions in which cataplexy can be seen include ischemic events, multiple sclerosis, head injury, paraneoplastic syndromes, and infections such as encephalitis. Cataplexy may also occur transiently or permanently due to lesions of the hypothalamus that were caused by surgery, especially in difficult tumor resections. These lesions or generalized processes disrupt the hypocretin neurons and their pathways. The neurological process behind the lesion impairs pathways controlling the normal inhibition of muscle tone drop, consequently resulting in muscle atonia. Several reports have documented that damage to the lateral and posterior hypothalamus resulted in a loss of hypocretin producing neurons and the subsequent development of excessive daytime sleepiness and cataplexy [26, 27].

Cataplexy can be seen in infancy in association with other neurological syndromes such as Neimann-Pick type C disease [28, 29]. This disease is an autosomal recessive and congenital neurological disorder characterized by the accumulation of cholesterol and glycosphingolipids in the peripheral tissues and glycosphingolipids in the brain. The presentation is debilitating with hepatosplenomegaly, ataxia, dystonia, and progressive dementia. Recognition of cataplexy in these rare and often rapidly fatal syndromes may improve the quality of life of affected children since cataplexy does respond well to pharmacological treatment.

Treatment

Cataplexy is treated pharmacologically. There are no behavioral treatments for cataplexy. The cholinergic and noradrenergic neurotransmitter systems are targeted in the treatment of cataplexy. The tricyclic antidepressants were first on the market in the 1960s. The main feature of tricyclics is their ability to inhibit the reuptake of norepinephrine (NE) and 5-serotonin (5-HT) at the nerve endings. Noradrenergic reuptake inhibition is the key factor involved in the anticataplectic effect [30]. The older generation tricyclics such as imipramine and protriptyline were the initial drugs of choice for treating cataplexy, but their anticholinergic side effect profile (including weight gain, sexual dysfunction, and sedation) have limit their use.

A newer class of antidepressants with selective serotonergic reuptake blocking properties known as the selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, citalopram) became popular for the treatment of cataplexy. This particular class of drugs often has an active metabolite with norepinephrine reuptake blocking properties (such as norfluoxetine). Serotonin reuptake inhibitors (SSRIs) have fewer side effects compared to the tricyclics and can be used in adults and children. A side effect worth mentioning regarding tricyclic antidepressants and SSRIs is the risk of development of REM behavior disorder (RBD) due to elimination of the normal REM sleep atonia. These drugs are known to decrease stage REM sleep. They can also decrease muscle atonia associated with REM sleep and consequently dissociate REM sleep (electroencephalographic pattern of REM sleep without muscle atonia). As a consequence, the subject may act out his or her dreams and cause harm to himself/herself or others. With all of these medications, abrupt withdrawal can cause significant rebound cataplexy and REM-related symptoms that occur around day 3 and peak near day 10. The recommended withdrawal schedule is one dose every 4 days.

The newest agent for the treatment of cataplexy is sodium oxybate (gamma-hydroxybutyrate [GHB]). Although its mechanism is unknown, it reduces cataplectic attacks and other manifestations of REM sleep [31, 32]. GHB increases slow wave sleep, decreases nighttime awakenings, and consolidates REM sleep [32, 33]. Sodium oxybate is the only medication that will improve both cataplexy and daytime sleepiness. Cataplectic symptoms are improved much faster compared to improvement in daytime sleepiness, which can take up to 6 to 12 weeks. During this time, sodium oxybate should be taken concomitantly with a stimulant such as modafinil. GHB is taken twice; at bedtime and 90 to 120 minutes later. The therapeutic dose is between 6 gm and a maximum dose of 9 gm/day. Its elimination half-life is one to two hours. A significant problem with GHB is the non-medical use to elicit a state of decreased consciousness (it is classified as a Schedule I controlled substance in United States).

Summary

Cataplexy is tightly associated with the hypocretin neurotransmitter deficiency. Patients presenting with excessive daytime sleepiness, low to absent CSF hypocretin-1 level, and positive HLA DQB1*0602 haplotype will most definitely have cataplexy. In children, it is important to rule out causes of secondary cataplexy. Cataplexy is treated with antidepressants such as tricyclics and serotonin reuptake inhibitors that enhance monoaminergic neurotransmission by inhibition of monoamine reuptake of NE and 5-HT. The newest compound in the treatment of cataplexy is sodium oxybate, but its mechanism of action is unclear. Cataplexy is commonly associated with narcolepsy. Primary cataplexy is a lifelong condition and can be disabling for the individual. Therefore, accurate diagnosis, education, and treatment are essential in order to allow the individual to have a normal and active lifestyle.