Cataplexy

Cataplexy is a sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror. It affects approximately 70% of people who have narcolepsy, and is caused by an autoimmune destruction of hypothalamic neurons that produce the neuropeptide hypocretin (also called orexin), which regulates arousal and has a role in stabilizing the transition between wake and sleep states. Cataplexy without narcolepsy is rare and the cause is unknown.

Etymology

The term cataplexy originates from the Greek κατά (kata, meaning "down"), and πλῆξις (plak, meaning "strike"). It was first used around 1880 in German physiology literature to describe the phenomenon of tonic immobility, also known as "playing possum." This animal is able to feign death when threatened. In the same year, French neuropsychiatrist Jean-Baptiste Gélineau coined the term "narcolepsy" and published clinical reports that contain details about two patients who have a similar condition as narcoleptic cases today. However, the onset reported by him was in adulthood, as compared to nowadays cases reported in childhood and adolescence. Even though he preferred the term "astasia" instead of "cataplexy," the case described by him remained iconic for the full narcoleptic syndrome.

Signs and Symptoms

Cataplexy manifests itself as muscular weakness, which may range from a barely perceptible slackening of the facial muscles to complete muscle paralysis with postural collapse. Attacks are brief, most lasting from a few seconds to a couple of minutes, and typically involve dropping of the jaw, neck weakness, and/or buckling of the knees. Even in a full-blown collapse, people are usually able to avoid injury because they learn to notice the feeling of the cataplectic attack approaching, and the fall is usually slow and progressive. Speech may be slurred and vision may be impaired (double vision, inability to focus), but hearing and awareness remain normal.

Cataplexy attacks are self-limiting and resolve without the need for medical intervention. If the person is reclining comfortably, he or she may transition into sleepiness, hypnagogic hallucinations, or a sleep-onset REM period. While cataplexy worsens with fatigue, it is different from narcoleptic sleep attacks and is usually, but not always, triggered by strong emotional reactions such as laughter, anger, surprise, awe, and embarrassment, or by sudden physical effort, especially if the person is caught off guard.

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Mechanism

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 arterio-venous 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. 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.

Theories for episodes

A phenomenon of REM sleep, muscular paralysis, occurs at an inappropriate time. This loss of tonus is caused by massive inhibition of motor neurons in the spinal cord. When this happens during waking, the victim of a cataplectic attack loses control of his or her muscles. As in REM sleep, the person continues to breathe and is able to control eye movements.

Hypocretin

The hypothalamus region of the brain regulates basic functions of hormone release, emotional expression, and sleep. A study in 2006 in "Tohoku Journal of Experimental Medicine" concluded that the neurochemical hypocretin, which is regulated by the hypothalamus, was significantly reduced in study participants with symptoms of cataplexy. Orexin, also known as Hypocretin, is a primary chemical important in regulating sleep as well as states of arousal. Hypocretin deficiency is further associated with decreased levels of histamine and epinephrine, which are chemicals important in promoting wakefulness, arousal, and alertness.

Diagnosis

The diagnosis of narcolepsy and cataplexy is usually made by symptom presentation. Presenting with the tetrad of symptoms (Excessive daytime sleepiness, sleep onset paralysis, hypnagogic hallucinations, cataplexy symptoms) is strong evidence of the diagnosis of narcolepsy. A Multiple Sleep Latency Test (MSLT) is often conducted in order to quantify daytime sleepiness.

Treatment

Cataplexy is treated with medications. The treatments for narcolepsy and cataplexy can be divided into treatments that act on the excessive daytime sleepiness (ESD) and those which improve the cataplexy. For most of the patients, this will represent lifelong medication. Nevertheless, most of the treatments in humans will act only symptomatically and do not target the loss of the orexin-producing neurons.

When treating cataplexy, all three systems: adrenergic, cholinergic, and dopaminergic must be considered. In the studies made both in vitro and in vivo, it was proven that the adrenergic system can be inhibited by antidepressants. In the mouse models, the cataplexy is regulated by the dopaminergic system via the D2-like receptor, which, when blocked, decreases the cataplectic attacks. The cholinergic system was also observed in animal models, and it was suggested that stimulations of this system led to severe cataplexy episodes in canine models.

There are no behavioral treatments. People with narcolepsy will often try to avoid thoughts and situations that they know are likely to evoke strong emotions because they know that these emotions are likely to trigger cataplectic attacks.

Gamma-hydroxybutyrate

Gamma-hydroxybutyrate (GHB, also known as Sodium oxybate) has been found to be effective at reducing the number of cataplexy episodes. Sodium oxybate is generally safe and is typically the recommended treatment.

Antidepressants

• If the above treatment is not possible, venlafaxine is recommended. Evidence for benefit is not as good.
• Previous treatments include tricyclic antidepressants such as imipramine, clomipramine, or protriptyline. Monoamine oxidase inhibitors may be used to manage both cataplexy and the REM sleep-onset symptoms of sleep paralysis and hypnagogic hallucinations.
• In clinical practice, venlafaxine (doses 75–225 mg daily) or clomipramine (25–100 mg daily) are the most common antidepressants used to treat cataplexy. If the patient wishes to have a sedative effect, then clomipramine is prescribed. The effect of these drugs is to suppress the REM component and to increase the brainstem monoaminergic levels. The venlafaxine is a norepinephrine and serotonin reuptake inhibitor, whereas clomipramine is a tricyclic antidepressant. Their effects can be seen within 48 hours after the drug is administered and at doses smaller than the ones used in depression. Nevertheless, the EMA and the FDA do not approve these antidepressants for the treatment of cataplexy. Frequently, tolerance is developed by the patients, and typically the risk of cataplexy rebound or "status cataplecticus" appears when their intake is abruptly interrupted.

Future treatments for cataplexy

Immune-based therapies

• Narcolepsy with cataplexy is considered an autoimmune-mediated disorder, so some therapies based on this hypothesis have been developed. The immune-based therapies developed were more or less effective and include:
• Corticosteroid: After testing in one human and one canine case, it proved to be ineffective, so it is less likely to be further used.
• Intravenous immunoglobulins (IVIgs): It may decrease the symptoms, but its effectiveness is still subjective and unconfirmed by placebo-controlled trials. It was also suggested that sometimes it might have life-threatening side effects. Nevertheless, after giving this treatment to a patient with undetectable orexin levels in the cerebrospinal fluid after only 15 days after the disease onset, the cataplexy was improved, and the orexin levels started to normalize.
• Plasmapheresis: Should be similar to IVIgs, but it is more invasive, and even less data is available for it.
• Immunoadsorption
• Alemtuzumab

Histaminergic H3 receptor inverse agonist

The histaminergic neurons have a very important role in preserving consciousness and helping maintain wakefulness during cataplexy. In narcolepsy, there seems to be an increase in these neurons, supposing to compensate for hypocretin loss. A promising therapy would be to increase the activation of histaminergic neurons by an inverse agonist of the histamine H3 receptor, which enhances histamine release in the hypothalamus. An inverse agonist of the histamine H3 is Pitolisant. Results after drug testing on animals have indicated increased wakefulness in normal animals, decreased sleepiness, and blocked abnormal transitions from REM sleep to awake state in hypocretin knock-out mice. Also, placebo-controlled studies suggest some positive effects of Pitolisant on cataplexy symptoms, increasing the levels of alertness and wakefulness.

Research

Research is being conducted on hypocretin gene therapy and hypocretin cell transplantation for narcolepsy-cataplexy.

Lifestyle modifications

In addition to pharmacological treatments, certain lifestyle modifications can help manage cataplexy symptoms and improve the quality of life for individuals with narcolepsy and cataplexy:

• Maintaining a consistent sleep schedule: Going to bed and waking up at the same time every day, including weekends, can help regulate the sleep-wake cycle and reduce the frequency of cataplexy attacks.
• Taking scheduled naps: Short naps (15-20 minutes) during the day can help alleviate excessive daytime sleepiness and decrease the risk of cataplexy attacks.
• Avoiding triggers: Identifying and avoiding situations or emotions that may trigger cataplexy attacks can help reduce their frequency.
• Practicing good sleep hygiene: Creating a comfortable sleep environment, avoiding caffeine and alcohol close to bedtime, and engaging in relaxation techniques can improve sleep quality and help manage cataplexy symptoms.
• Regular exercise: Engaging in regular physical activity can improve overall health and help regulate sleep patterns.
• Stress management: Learning stress reduction techniques, such as mindfulness, meditation, and deep breathing exercises, can help manage stress levels and potentially decrease the frequency of cataplexy attacks.
• Support groups: Joining a support group or participating in online forums can provide emotional support and practical advice from others who are also living with narcolepsy and cataplexy.

Prognosis

Cataplexy is a chronic condition that usually persists throughout an individual's lifetime. While there is no cure for cataplexy, symptoms can often be managed effectively with medications and lifestyle adjustments. Some people may experience a decrease in the frequency of cataplexy attacks over time, while others may require ongoing treatment to manage their symptoms.

Epidemiology

The prevalence of narcolepsy with cataplexy is estimated to be between 25 and 50 per 100,000 people. It affects both males and females equally and is typically diagnosed in childhood or adolescence, although some cases may not be diagnosed until adulthood. The prevalence of cataplexy without narcolepsy is rare, and the exact number of cases is unknown.

See also

• Narcolepsy
• Sleep paralysis
• Hypnagogic hallucinations
• Excessive daytime sleepiness

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