Cataplexy

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Cataplexy
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Specialty Neurology, Psychiatry

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. [1] Cataplexy affects approximately 20% of people who have narcolepsy, [2] 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 stabilization of the transition between wake and sleep states. [3] Cataplexy without narcolepsy is rare and the cause is unknown.

Contents

The term cataplexy originates from the Greek 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 the opossum's behavior of feigning death when threatened). [4] In the same year the French neuropsychiatrist Jean-Baptiste Gélineau coined the term 'narcolepsy' and published some clinical reports that contain details about two patients who have similar condition as the narcoleptic cases nowadays. [5] Nevertheless, the onset reported by him was in adulthood as compared to the nowadays cases reported in childhood and adolescence. [6] Even if he preferred the term 'astasia' instead of 'cataplexy' the case described by him remained iconic for the full narcoleptic syndrome. [4]

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. [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 and vision may be impaired (double vision, inability to focus), but hearing and awareness 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 of REM sleep. 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. [9] One well-known example of this was the reaction of 1968 Olympic long jump medalist Bob 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]

Mechanism

In this simplified brain circuit, damage to orexin-secreting neurons in the hypothalamus can lead to inhibition of motor neurons, thus lowering muscle tone. Simplified brain motor circuit.jpg
In this simplified brain circuit, damage to orexin-secreting neurons in the hypothalamus can lead to inhibition of motor neurons, thus lowering muscle tone.

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, infections such as encephalitis, and more rarely Niemann 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 in muscle atonia. [12]

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 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]

Hypocretin

The hypothalamus region of the brain regulates basic functions of hormone release, emotional expression and sleep. One study concluded that the neurochemical hypocretin, 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 of histamine and epinephrine, chemicals important in promoting wakefulness, arousal and alertness. [13]

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, 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]

Treatment

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 and dopaminergic—must be considered. The adrenergic system can be inhibited by antidepressants. In mouse models, cataplexy is regulated by the dopaminergic system via the D2-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 with narcolepsy 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

Gamma-hydroxybutyrate, also known as sodium 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 the EMA to treat the whole disease in adults, and by the FDA to treat patients who have cataplexy with the indication to be used for combating excessive daytime sleepiness. [4] [20] This drug helps to normalise sleep architecture and inhibits the intrusion REM sleep elements like paralysis during the day. [4]

Antidepressants

If the above treatment is not possible, venlafaxine is recommended. [20] Evidence for benefit is not as good.[ clarification needed ] [20]

Previous treatments include tricyclic antidepressants such as imipramine, clomipramine or protriptyline. [8] Monoamine oxidase inhibitors may be used to manage both cataplexy and the REM sleep-onset symptoms of sleep paralysis and hypnagogic hallucinations. [21]

In clinical practice, venlafaxine and clomipramine 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]

Future treatments

Immune-based therapies

Narcolepsy with cataplexy is considered an autoimmune-mediated disorder, so some therapies based on this hypothesis have been developed. Immunological therapies developed include: [20]

  • Corticosteroids: after testing in 1 human and 1 canine case it proved to be ineffective so is less likely to be further used.
  • Intravenous immunoglobulins (IVIgs): it may decrease the symptoms but its effectiveness is still subjective and unconfirmed by the placebo-controlled trials. It was suggested that sometimes it might have life-threatening side effects. [16] 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 normalise. [17]
  • Plasmapheresis: should be similar with IVIgs but it is more invasive and for it even less data is available. [16]
  • Immunoadsorption
  • Alemtuzumab

Histaminergic H3 receptor inverse agonist

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 is Pitolisant. [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 of Pitolisant on cataplexy symptoms increasing the levels of alertness and wakefulness. [4]

Protective devices

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

Research is being conducted on hypocretin gene therapy and hypocretin cell transplantation for narcolepsy-cataplexy. [27] [28]

See also

Related Research Articles

<span class="mw-page-title-main">Sleep disorder</span> Medical disorder of a persons sleep patterns

A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Sleep disorders are frequent and can have serious consequences on patients’ health and quality of life. Polysomnography and actigraphy are tests commonly ordered for diagnosing sleep disorders.

<span class="mw-page-title-main">Orexin</span> Neuropeptide that regulates arousal, wakefulness, and appetite.

Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone, is caused by a lack of orexin in the brain due to destruction of the cells that produce it. It exists in the forms of orexin-A and orexin-B.

Wakefulness is a daily recurring brain state and state of consciousness in which an individual is conscious and engages in coherent cognitive and behavioral responses to the external world.

Hypersomnia is a neurological disorder of excessive time spent sleeping or excessive sleepiness. It can have many possible causes and can cause distress and problems with functioning. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), hypersomnolence, of which there are several subtypes, appears under sleep-wake disorders.

<span class="mw-page-title-main">Reticular formation</span> Spinal trigeminal nucleus

The reticular formation is a set of interconnected nuclei that are located throughout the brainstem. It is not anatomically well defined, because it includes neurons located in different parts of the brain. The neurons of the reticular formation make up a complex set of networks in the core of the brainstem that extend from the upper part of the midbrain to the lower part of the medulla oblongata. The reticular formation includes ascending pathways to the cortex in the ascending reticular activating system (ARAS) and descending pathways to the spinal cord via the reticulospinal tracts.

<span class="mw-page-title-main">Ventrolateral preoptic nucleus</span> Nucleus of the anterior hypothalamus

The ventrolateral preoptic nucleus (VLPO), also known as the intermediate nucleus of the preoptic area (IPA), is a small cluster of neurons situated in the anterior hypothalamus, sitting just above and to the side of the optic chiasm in the brain of humans and other animals. The brain's sleep-promoting nuclei, together with the ascending arousal system which includes components in the brainstem, hypothalamus and basal forebrain, are the interconnected neural systems which control states of arousal, sleep, and transitions between these two states. The VLPO is active during sleep, particularly during non-rapid eye movement sleep, and releases inhibitory neurotransmitters, mainly GABA and galanin, which inhibit neurons of the ascending arousal system that are involved in wakefulness and arousal. The VLPO is in turn innervated by neurons from several components of the ascending arousal system. The VLPO is activated by the endogenous sleep-promoting substances adenosine and prostaglandin D2. The VLPO is inhibited during wakefulness by the arousal-inducing neurotransmitters norepinephrine and acetylcholine. The role of the VLPO in sleep and wakefulness, and its association with sleep disorders – particularly insomnia and narcolepsy – is a growing area of neuroscience research.

<span class="mw-page-title-main">Sodium oxybate</span> Medication to treat symptoms of narcolepsy

Sodium oxybate, sold under the brand name Xyrem among others, is a medication used to treat symptoms of narcolepsy: sudden muscle weakness and excessive daytime sleepiness. It is used sometimes in France and Italy as an anesthetic given intravenously; it is also approved and used in Italy and in Austria to treat alcohol dependence and alcohol withdrawal syndrome.

<span class="mw-page-title-main">Dorsal raphe nucleus</span>

The dorsal raphe nucleus is one of the raphe nuclei. It is situated in the brainstem at the midline. It has rostral and caudal subdivisions:

<span class="mw-page-title-main">Lateral hypothalamus</span>

The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.

Orexin-A, also known as hypocretin-1, is a naturally occurring neuropeptide and orexin isoform. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain.

An H3 receptor antagonist is a type of antihistaminic drug used to block the action of histamine at H3 receptors.

<span class="mw-page-title-main">Narcolepsy</span> Human sleep disorder that involves an excessive urge to sleep and other neurological features

Narcolepsy is a chronic neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. Narcolepsy paired with cataplexy is evidenced to be an autoimmune disorder. These experiences of cataplexy can be brought on by strong emotions. Less commonly, there may be vivid hallucinations or an inability to move while falling asleep or waking up. People with narcolepsy tend to sleep about the same number of hours per day as people without it, but the quality of sleep tends to be lessened.

Pitolisant, sold under the brand name Wakix among others, is a medication used for the treatment of excessive daytime sleepiness in adults with narcolepsy. It is a histamine 3 (H3) receptor antagonist/inverse agonist (an antihistamine drug specific to that kind of receptors). It represents the first commercially available medication in its class, so that the US Food and Drug Administration (FDA) declares it a first-in-class medication. Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness.

<span class="mw-page-title-main">Eugeroic</span> Drugs for wakefulness and alertness

Eugeroics, also known as wakefulness-promoting agents and wakefulness-promoting drugs, are a class of drugs that promote wakefulness and alertness. They are medically indicated for the treatment of certain sleep disorders including excessive daytime sleepiness (EDS) in narcolepsy or obstructive sleep apnea (OSA). Eugeroics are also often prescribed off-label for the treatment of EDS in idiopathic hypersomnia. In contrast to classical psychostimulants, such as methylphenidate and amphetamine, which are also used in the treatment of these disorders, eugeroics typically do not produce marked euphoria, and, consequently, have a lower addictive potential.

Idiopathic hypersomnia(IH) is a neurological disorder which is characterized primarily by excessive sleep and excessive daytime sleepiness (EDS). The condition typically becomes evident in early adulthood and most patients diagnosed with IH will have had the disorder for many years prior to their diagnosis. As of August 2021, an FDA-approved medication exists for IH called Xywav, which is oral solution of calcium, magnesium, potassium, and sodium oxybates; in addition to several off-label treatments (primarily FDA-approved narcolepsy medications).

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<span class="mw-page-title-main">Clinical neurochemistry</span>

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<span class="mw-page-title-main">Suvorexant</span> Medication used to treat insomnia

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References

  1. ↑ Seigal, Jerome (January 2001). "Narcolepsy". Scientific American: 77.
  2. ↑ "Narcolepsy Fact Sheet". Archived from the original on 2016-07-27. Retrieved 2011-06-23.
  3. ↑ Elphick, Heather; Staniforth, Teya; Blackwell, Jane; Kingshott, Ruth (2017). "Narcolepsy and cataplexy – a practical approach to diagnosis and managing the impact of this chronic condition on children and their families" (PDF). Paediatrics and Child Health. 272 (7): 343–347. doi:10.1016/j.paed.2017.02.007.
  4. 1 2 3 4 5 6 7 Reading, Paul (2019). "Cataplexy". Practical Neurology. 19 (1): 21–27. doi:10.1136/practneurol-2018-002001. PMID   30355740. S2CID   219207393.
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  6. ↑ Mignot, Emmanuel J.M. (2014). "History of narcolepsy at Stanford University". Immunologic Research. 58 (2–3): 315–339. doi:10.1007/s12026-014-8513-4. PMC   4028550 . PMID   24825774.
  7. ↑ Bourgoin, Jean-Maxime. "Il s'endort au volant de sa voiture" (in French). Sun Media. Le Journal de Montréal. Retrieved 11 May 2015.
  8. 1 2 Michelle Cao; Christian Guilleminault (2008). "Cataplexy". Scholarpedia. 3 (1): 3317. Bibcode:2008SchpJ...3.3317C. doi: 10.4249/scholarpedia.3317 .
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  10. ↑ Great Olympic Moments - Sir Steve Redgrave, 2011
  11. ↑ van Nues SJ, van der Zande WL, Donjacour CE, van Mierlo P, Jan Lammers G (2011). "The clinical features of cataplexy: A questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency". Sleep Medicine. 12 (1): 12–18. doi:10.1016/j.sleep.2010.05.010. PMID   21145280.
  12. ↑ Dauvilliers, Yves; Isabelle Arnulf; Emmanuel Mignot (10 February 2007). "Narcolepsy with Cataplexy". The Lancet. 39 (9560): 499–511. doi:10.1016/S0140-6736(07)60237-2. PMID   17292770. S2CID   11041392 . Retrieved April 30, 2012.
  13. ↑ Walding, Aureau. "Causes of Cataplexy". Demand Media, Inc. Retrieved April 30, 2012.
  14. ↑ Carskadon, Mary A. (1986). "Guidelines for the Multiple Sleep Latency Test (MSLT): A Standard Measure of Sleepiness". Sleep. 9 (4): 519–524. doi: 10.1093/sleep/9.4.519 . PMID   3809866.
  15. ↑ Elphick, Heather; Staniforth, Teya; Blackwell, Jane; et, al. (2017). "Narcolepsy and cataplexy – a practical approach to diagnosis and managing the impact of this chronic condition on children and their families" (PDF). Paediatrics and Child Health. 27 (7): 343–347. doi:10.1016/j.paed.2017.02.007. ISSN   1751-7222.
  16. 1 2 3 Mignot, Emmanuel; Nishino, Seiji (2005). "Emerging Therapies in Narcolepsy-Cataplexy". Sleep. 28 (6): 754–763. doi:10.1093/sleep/28.6.754. PMID   16477963.
  17. 1 2 3 4 5 6 7 Dauvilliers, Yves; Siegel, Jerry M.; Lopez, Regies; Torontali, Zoltan A.; Peever, John H. (2014). "Cataplexy – clinical aspects, pathophysiology and management strategy". Nature Reviews Neurology. 10 (7): 386–395. doi:10.1038/nrneurol.2014.97. PMC   8788644 . PMID   24890646. S2CID   2369989.
  18. ↑ Boscolo-Berto, R; Viel, G; Montagnese, S; Raduazzo, DI; Ferrara, SD; Dauvilliers, Y (October 2012). "Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): a systematic review and meta-analysis of randomized controlled trials". Sleep Medicine Reviews. 16 (5): 431–443. doi:10.1016/j.smrv.2011.09.001. PMID   22055895.
  19. 1 2 Alshaikh, MK; Tricco, AC; Tashkandi, M; Mamdani, M; Straus, SE; BaHammam, AS (15 August 2012). "Sodium oxybate for narcolepsy with cataplexy: systematic review and meta-analysis". Journal of Clinical Sleep Medicine. 8 (4): 451–458. doi:10.5664/jcsm.2048. PMC   3407266 . PMID   22893778.
  20. 1 2 3 4 5 6 Lopez, R; Dauvilliers, Y (May 2013). "Pharmacotherapy options for cataplexy". Expert Opinion on Pharmacotherapy. 14 (7): 895–903. doi:10.1517/14656566.2013.783021. PMID   23521426. S2CID   7219704.
  21. ↑ Thomas F. Anders, MD (2006). "Narcolepsy". Childhood Sleep Disorders. Armenian Medical Network. Retrieved 2007-09-19.
  22. ↑ "Clomipramine 10 mg Capsules, Hard". Medicines.org.uk. Retrieved 19 April 2021.
  23. ↑ "Anafranil Tablets". NPS MedicineWise. 8 April 2015. Retrieved 19 April 2021.
  24. ↑ "Ficha Tecnica Anafranil 75 Mg Comprimidos de Liberación Prolongada". AEMPS. Retrieved 19 April 2021.
  25. ↑ Elliott, Linnea; Swick, Todd (2015). "Treatment paradigms for cataplexy in narcolepsy: past, present, and future". Nature and Science of Sleep. 7: 159–169. doi: 10.2147/NSS.S92140 . PMC   4686331 . PMID   26715865.
  26. ↑ Schwartz, Jean-Charles (2011). "The histamine H3 receptor: from discovery to clinical trials with pitolisant: H3 Receptor: from discovery to clinical trials". British Journal of Pharmacology. 163 (4): 713–721. doi:10.1111/j.1476-5381.2011.01286.x. PMC   3111674 . PMID   21615387.
  27. ↑ "Emerging Therapies in Narcolepsy-Cataplexy" (PDF). Archived from the original (PDF) on 2012-12-03. Retrieved 2011-06-23.
  28. ↑ Weidong, W.; Fang, W.; Yang, Z.; Menghan, L.; Xueyu, L. (2009). "Two patients with narcolepsy treated by hypnotic psychotherapy". Sleep Medicine. 10 (10): 1167. doi:10.1016/j.sleep.2009.07.011. PMID   19766057.
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