| Cataplexy | |
|---|---|
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| Organization ofskeletal muscle; in cataplexy, the skeletal muscles are often affected. | |
| Pronunciation | |
| Specialty | Neurology,psychiatry |
| Symptoms | Muscle weakness |
| Causes | Trauma, narcolepsy |
Cataplexy is a sudden and transient episode ofmuscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror.[1] Cataplexy is the first symptom to appear in about 10% of cases ofnarcolepsy,[2] caused by an autoimmune destruction ofhypothalamicneurons that produce theneuropeptidehypocretin (also called orexin), which regulatesarousal and has a role in stabilization of the transition between wake and sleep states.[3] Cataplexy without narcolepsy is rare and the cause is unknown.
The term cataplexy originates from theGreek κατά (kata, meaning "down"), and πλῆξις (plēxis, meaning "strike")[4] and it was first used around 1880 in German physiology literature to describe the phenomenon of tonic immobility also known as "playing possum" (in reference to theopossum's behavior of feigning death when threatened).[4] In the same year the Frenchneuropsychiatrist Jean-Baptiste Gélineau coined the term 'narcolepsy' and published some clinical reports that contained details about two patients who had similar conditions to those of current narcoleptic cases.[5] Nevertheless, the onset that he reported was in adulthood, as compared to current cases reported in childhood and adolescence.[6] Even if he preferred the term 'astasia' instead of 'cataplexy', the case that he described remains iconic for the diagnosis of full narcolepticsyndrome.[4]
Cataplexy manifests itself as muscularweakness which may range from a barely perceptible slackening of the facialmuscles to complete muscleparalysis with postural collapse.[7] 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.[8] Speech may be slurred andvision may be impaired (double vision, inability to focus), but hearing andawareness remain normal.[citation needed]
Cataplexy attacks are self-limiting and resolve without the need for medical intervention. If the person is reclining comfortably, they may transition into sleepiness,hypnagogic hallucinations, or a period ofREM sleep. While cataplexy worsens with fatigue, it is different fromnarcoleptic sleep attacks and is usually, but not always, triggered by strong emotional reactions such aslaughter,anger,surprise,awe, andembarrassment, or by sudden physical effort, especially if the person is caught off guard.[9] One well-known example of this was the reaction of1968 Olympiclong jump medalistBob Beamon on learning that he had broken the previous world record by over 0.5 meters (almost 2 feet).[10][additional citation(s) needed][medical citation needed] Cataplectic attacks may occasionally occur spontaneously, with no identifiable emotional trigger.[11]
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 tobrainstem 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 includeastrocytoma,glioblastoma,glioma, andsubependymoma. 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 includeischemic events,multiple sclerosis,head injury,paraneoplastic syndromes, infections such asencephalitis, and more rarelyNiemann Pick disease. 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 inmuscle atonia.[12]
A phenomenon ofREM sleep, muscular paralysis, occurs at an inappropriate time. This loss oftonus is caused by massive inhibition ofmotor neurons in the spinal cord. When this happens during waking, the patient who had a cataplectic attack loses muscular control. As in REM sleep, the person continues to breathe and is able to control eye movements.[9]
The hypothalamus region of the brain regulates basic functions of hormone release, emotional expression and sleep. One study concluded that the neurochemicalhypocretin, also known as orexin, which is regulated by the hypothalamus, was significantly reduced in study participants with symptoms of cataplexy. Hypocretin regulates sleep and states of arousal. Hypocretin deficiency is further associated with decreased levels ofhistamine andepinephrine, chemicals important in promoting wakefulness, arousal and alertness.[13]
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, and cataplexy symptoms) is strong evidence of the diagnosis of narcolepsy. A multiple sleep latency test[clarification needed] is often conducted to quantify daytime sleepiness.[14]
Cataplexy can sometimes be misdiagnosed as aseizure disorder, and people with narcolepsy are often misdiagnosed with other conditions such aspsychiatric disorders oremotional problems, it can take years for someone to get the proper diagnosis.[2]
Cataplexy is treated with medications. Treatment for narcolepsy and cataplexy can be divided to those that act on the excessive daytime sleepiness (EDS) and those that improve cataplexy. Most patients require lifelong use of medications.[15] Most treatments in humans will act only symptomatically and do not target the loss of the orexin-producing neurons.[16]
When treating cataplexy, all three systems—adrenergic,cholinergic anddopaminergic—must be considered. The adrenergic system can be inhibited by antidepressants. In mouse models, cataplexy is regulated by the dopaminergic system via theD2-like receptor, which when blocked decreases cataplectic attacks.[clarification needed] The role of the cholinergic system has been observed in canine models, where stimulation of this system may lead to severe cataplexy episodes.[17]
There are no behavioral treatments. People withnarcolepsy will often try to avoid thoughts and situations that they know are likely to evoke strong emotions and thereby trigger cataplectic attacks.[9]
Gamma-hydroxybutyrate, also known assodium oxybate, has been found to be effective at reducing the number of cataplexy episodes.[18][19] Sodium oxybate is generally safe[19] and is typically the recommended treatment.[20]
Sodium oxybate is a natural metabolite of GABA. Its main target is the dopaminergic system because at pharmacological concentrations it acts as an agonist and modulates the dopamine neurotransmitters and dopaminergic signalling.[17] It is the only drug authorised by theEMA to treat the whole disease in adults, and by theFDA to treat patients who have cataplexy with the indication to be used for combating excessive daytime sleepiness.[4][20] This drug helps to normalisesleep architecture and inhibits the intrusion REM sleep elements like paralysis during the day.[4]
If the above treatment is not possible,venlafaxine is recommended.[20] Evidence supporting its effectiveness is primarily based on clinical experience rather than extensive clinical trials.
Previous treatments includetricyclic antidepressants such asimipramine,clomipramine orprotriptyline.[8]Monoamine oxidase inhibitors may be used to manage both cataplexy and the REM sleep-onset symptoms of sleep paralysis andhypnagogic hallucinations.[21]
In clinical practice, venlafaxine andclomipramine 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.[4] Improvement can be seen within 48 hours after the drug is administered and at doses smaller than the ones used in depression.[17] Nonetheless, antidepressants are not approved by the FDA for the treatment of cataplexy;[20] some jurisdictions have approved clomipramine for this use, however.[22][23][24] Frequently, tolerance is developed by the patients and typically the risk of cataplexy rebound or "status cataplecticus" appears when their intake is abruptly interrupted.[17]
Narcolepsy with cataplexy is considered an autoimmune-mediated disorder, so some therapies based on this hypothesis have been developed. Immunological therapies developed include:[20]
The histaminergic neurons have a very important role in preserving consciousness and in helping maintain wakefulness and remain active during cataplexy. In narcolepsy, there seems to be an increase in these neurons, possibly to compensate for hypocretin loss.[25] 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 hypothalamus.[17] An inverse agonist of the histamine H3 isPitolisant.[26] Results after testing on animals have indicated increased wakefulness in normal animals, decreased sleepiness and blocked the abnormal transitions from REM sleep to awake state in the hypocretin knock-out mice.[17] Also placebo-controlled studies suggest some positive effects ofPitolisant on cataplexy symptoms increasing the levels of alertness and wakefulness.[4]
There are several protective devices used that can help to manage the dangers as a results of falls due to cataplexies:
It is important for people with narcolepsy and cataplexy to work with their healthcare team to determine the best protective devices for their specific needs and to ensure their safety and well-being.
Research is being conducted on hypocretin gene therapy and hypocretin cell transplantation for narcolepsy-cataplexy.[27][28]