Cataplexy
| Michelle Cao and Christian Guilleminault (2008), Scholarpedia, 3(1):3317. | doi:10.4249/scholarpedia.3317 | revision #28539 [link to/cite this article] |
Cataplexy is the sudden loss of muscle tone that is triggered by the experience of an intense emotion.
Contents |
Introduction
Cataplexy is considered pathognomonic for the diagnosis of narcolepsy, although it can be seen independently. Cataplexy has long been considered the most predictive feature of the overall syndrome. A positive history of cataplexy is a better discriminant for narcolepsy than two or more sleep-onset REM periods (SOREM) and a short sleep latency on multiple sleep latency testing (MSLT), and it is sufficient enough to diagnose narcolepsy. It is the second most common symptom reported by narcoleptic patients after excessive daytime sleepiness.
Clinical features
Cataplexy is characterized by a sudden loss of muscle tone that is triggered by intense emotion. The sudden loss of muscle tone is analogous to rapid eye movement (REM)-associated muscle atonia, but it is occurring during wakefulness. Emotions that trigger attacks include laughter, anger, frustration, annoyance, nervousness, embarrassment, sadness, and fear. Data from the Stanford University Sleep Disorders Clinic of 200 patients with cataplexy showed that 100% of these patients reported laughter as the most common trigger, followed by a feeling of amusement, and surprise with happiness/joy. In another study by Anic-Labat et al, emotions arising from "hearing or telling a joke," "laughing," or "when angry" were most predictive of the lost of muscle function in clear-cut cataplexy. It is clear that positive emotions, especially laughter, are most predictive of triggering a cataplectic event. Cataplexy also occurs more frequently in times of emotional stress, or when patients are deprived of napping when feeling sleepy. Cataplexy is easily recognizable when clinical features are typical. A cataplectic attack is sudden in onset, localizable to a specific muscle group or parts of the body, and the subject is lucid during the experience. It is important to remember that consciousness is always maintained at the onset of cataplexy. As the attack continues patients may experience sleepiness, hallucinations, or sleep-onset REM period. Full-blown attacks do occur and result in complete muscle paralysis with postural collapse and possible injury. However, most often patients with postural collapse have the capability to avoid injury, as the fall is slow and progressive. The more commonly limited cataplectic attacks involve the face and head, neck, upper limb, more rarely lower limb known as "knee buckling." The most common isolated form involves facial muscles. Patients present with trembling of mesenteric muscles, rictus, dysarthria, head and upper arm drop, and may drop objects held in hands. A study of 40 cataplectic patients (age range from 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. Slurred speech may be present. Diaphragmatic paralysis resulting in apneas has not been reported.
In a study by Gelb et al, cataplectic attacks usually occur between 10am and 9pm in a 24-hour period. Few cataplectic attacks appeared between the hours of 10pm and 9am. Attacks can last from a few seconds to 10 minutes, and may occur up to several times per week. A survey of 100 cataplectic patients from the Stanford Sleep Disorders Clinic (age range 14-24 years) showed that 93% of the attacks lasted less than two minutes, 6% reported events lasting up to five minutes, and 0.94% reported events lasting longer than five minutes. A study by Dauvilliers et al showed two peaks in the age of onset of symptoms at 15 and 35 years. Onset of cataplexy has been reported past the age of 40 years. Cataplectic symptoms tend to decrease with age. A review of 100 patients with cataplexy at the Stanford Sleep Disorders Clinic (age range 12-20 years) showed that 62 of these patients stopped taking anti-cataplectic medications after 10 years. However, the general decrease in cataplectic symptoms may reverse after experiencing a significant emotional upset such as lost of a spouse in older subjects.
Cataplexy is rarely observed in an office visit, and even if it does occur, it is often only noticed by a trained specialist whom is familiar with the condition. If, cataplexy is observed it is associated with the absence of deep tendons reflexes that comes back with return of normal muscle tone. This is a simple test that dissociates cataplexy from other drop-attacks. In many cases when cataplexy is mild or triggered by unusual emotions, it can be difficult to define whether the patient's description of the experience reflects a true cataplectic episode, or rather physiological muscle weakness associated with intense laughter or athletic activity. Results from a study by Mignot et al (Validation of a Cataplexy Questionnaire in 983 Sleep-Disorders Patients at the Stanford University Center for Narcolepsy) showed that several questions specifically focused on emotional triggers and anatomical localization of attacks can significantly differentiate definitive cataplexy from other nonspecific episodes of muscle weakness.
HLA typing
In 1983 a study by Honda et al from Japan found that narcolepsy is associated with two specific serologically defined HLA class II antigens, DR2 and DQ1. Since then, several investigators have confirmed this finding across different ethnic groups. The presence or absence of cataplexy is a critical factor in determining HLA genotype positivity. The HLA DQ1 is a more sensitive marker for narcolepsy with cataplexy than the DR2. Mignot et al showed that the major HLA susceptibility allele for narcolepsy with clear-cut cataplexy is HLA-DRB1*0602 across different ethnic groups. Depending on the series, 88 to 98% of patients with clear-cut cataplexy are HLA DQB1*0602 positive independent of ethnicity. The frequency of DQB1*0602 being positive was strikingly higher in patients with cataplexy versus patients without cataplexy but with narcolepsy (76.1% in 421 patients versus 40.9% in 88 patients) in a study of 509 narcoleptic patients by Mignot et al. Positivity of the allele was highest in patients with severe cataplexy (94.8%) and progressively decreased to 54.2% in patients with mildest cataplexy. HLA-DQB1*0602 homozygotes have two to four times higher risks of developing cataplexy with narcolepsy than heterozygotes. But the story of HLA and narcolepsy-cataplexy is complex; the association of DQB1*0602 with DQA1*0102 is more common with narcolepsy in multi-ethnic studies. But in heterozygote alleles DQB1*0601 and DQB1*0501 are protective for narcolepsy. Familial narcoleptics exceptionally present with DQB1*0602. Also in cases negative for DQB1*0602 and presence of clear narcolepsy-cataplexy, it was shown that DQB1*0301 was a second susceptibility gene and the association of DQB1*0602/DQB1*0301 had a higher level of susceptibility than many other combinations. Finally, this specific marker for cataplexy in narcoleptic patients is also present in 12% to 28% of the general population. Thus the test has poor sensitivity and therefore has limited value in diagnosing narcolepsy. However, in cases of narcolepsy with atypical or without cataplexy, a negative DQB1*0602 would be useful to guide further diagnostic work up and therapeutic options.
Hypocretin/orexin system
The pathophysiology of narcolepsy with cataplexy for a long time has remained a mystery until the discovery of the role of hypocretin/orexin system in the control of sleep and wakefulness. Hypocretin-1 level in cerebral spinal fluid (CSF) is considered diagnostic for cataplexy if levels are below 110 pg/mL and no other pathology is present. The accepted standard for normal and abnormal values were done at the Stanford Center for Narcolepsy; normal > 200 pg/mL, low-abnormal < 110 pg/mL, and intermediate level > 110 < 200 pg/mL. Hypocretin-1 sensitivity and specificity are 91.7% and 100% respectively, for cataplexy with narcolepsy. In comparison, Hublin et al found that in patients with cataplexy and excessive daytime sleepiness, the presence of two or more sleep-onset REM (SOREM) during MSLT has a sensitivity of 78.5% and a specificity of 62%. Patients with cataplexy and positive HLA-DQB1*0602 have been found to have low CSF hypocretin-1 levels in 99% of the cases. In other words, the presence of cataplexy and positive HLA-DQB1*0602 is almost always associated with low levels of CSF hypocretin-1. Checking for levels of CSF hypocretin-1 can be done in cases where cataplexy is atypical or doubtful.
Secondary cataplexy
Although cataplexy is primarily associated with narcolepsy, there are secondary causes of cataplexy. Secondary cataplexy is associated with specific lesions located in the lateral and posterior hypothalamus, and the brainstem less commonly. These lesions disrupt the hypocretin/orexin neurons and their pathways. Secondary causes include tumors of the brain or brainstem, arterio-venous malformations, ischemic events, multiple sclerosis, head injury, and infections such as encephalitis. Some of the tumors include astrocytoma, glioblastoma, glioma, subependynoma, and even paraneoplastic syndromes. These lesions can be seen with brain imaging, however in their early stages they can be missed. In children cataplexy may reveal the presence of a tumor, particularly craniopharyngioma. This tumor accounts for 9% of all pediatric intra-cranial tumors. The onset of symptoms is between 5-10 years of age, which is earlier than the most common age of narcolepsy-cataplexy that peaks during the second decade usually between 12 and 18 years of age. Cataplexy may also be seen transiently or permanently due to lesions of the hypothalamus created at time of surgery, especially in difficult resections. Cataplexy due to brainstem lesions is uncommon particularly when noted in isolation. The neurological process behind the lesion impairs relays or pathways controlling the normal inhibition of muscle tone drop. During REM sleep there is a lifting of this active inhibition and development of muscle atonia that blocks the acting out of active dreaming. There are several relays and neuro-transmitters that are involved in this descending pathway that impinge on the spinal motor neurons except those controlling the diaphragm. When present cataplexy may rapidly re-occur in time, giving birth to the “limp man syndrome” as described by Stalh et al.
Cataplexy may be seen in infancy in association with other neurological syndromes such as Neimann-Pick type C disease. It is an autosomal recessive and congenital neurological disorder characterized by the accumulation of cholesterol and glycosphingolipids in the peripheral tissues and of glycosphingolipids in the brain. The presentation is florid with hepato-splenomegaly, ataxia, dystonia, and progressive dementia. Recognition of the cataplexy in these rare and often rapidly fatal syndromes may improve quality of life of affected children as their cataplexy responds to the selective serotonin reuptake inhibitor venlafaxine.
Treatment
The goal of treatment in cataplexy is to control cataplectic symptoms to allow the patient to have a productive personal and professional life. Most of the medications used to treat cataplexy have major side effect profiles including addiction potential and tolerance issues. It is important to remember that cataplaxy with narcolepsy is a lifelong disease. Therefore, the treatment of cataplexy is a fine balance between the side effect profile of medications and allowing the patient to have a productive lifestyle. First and foremost, education, counseling, and referral to support groups are important because the disease is not common and patients as well as those around them must be aware of its consequences and know what to expect. Career counseling is important for the patient and the employer. Both parties should know which jobs to avoid, shift-work or on-call scheduling, transportation, or jobs that demand long hours without breaks. Regarding behavioral treatment, scheduled naps are very important in narcoleptics with cataplexy. These naps are short 15-20 minutes in duration about every four hours during daytime. Regular sleep-wake schedule, avoidance of frequent time zone changes, and good sleep hygience are also essential.
Several neurotransmitter systems have been identified that affect the inhibitory pathways involving lower motorneurons, mainly the muscarinic, cholinergic, and the noradrenergic systems. This finding has allowed for pharmacologic treatment options for cataplexy. Most medications used for cataplexy have a noradrenergic reuptake blocker action. Tricyclic antidepressants such as protriptyline and clomipramine were the initial drugs of choice for treating cataplexy, but their anticholinergic side effect profile (particularly impact on erection and ejaculation) has limit their use. A newer class of drugs known as selective serotonin reuptake inhibitors such as fluoxetine and venlafaxine has active noradrenergic reuptake blocker metabolites. This class of drugs has fewer side effects compared to the tricyclics and can be used in adults and children. A side effect worth mentioning regarding tricyclic antidepressants and selective serotonin reuptake inhibitors is the development of REM behavior disorder. These drugs are known to decrease REM sleep, therefore they can decrease muscle atonia of REM sleep and as a consequence dissociate REM sleep (electroencephalographic pattern of REM sleep without muscle atonia). As a consequence, the subject may act out his or her dreams. The newest agent used to treat cataplexy is sodium oxybate (gamma-hydroxybutyrate [GHB]). Although its mechanism is unknown, it is thought to consolidate REM sleep, and therefore decreases cataplectic symptoms and improves daytime sleepiness. Sodium oxybate is the only medication that will improve both cataplexy and daytime sleepiness of narcolepsy. Cataplexy will be improved faster and it will take 6 to 12 weeks to see improvement in daytime sleepiness. Sodium oxybate will have to be taken with a stimulant such as modafinil during that time. In some patients modafinil will slightly increase the risk of cataplexy. Sodium oxybate however has a serious side effect profile including respiratory depression at higher dosage than recommended (maximum dose is 9g/day), as well as abuse potential. As with all of these medications, abrupt withdrawal can cause significant rebound cataplexy and REM-related symptoms which occur around day 3 and peaks near day 10. The recommended withdrawal schedule is one dose every 4 days.
Summary
The presence of cataplexy is diagnostic of narcolepsy. Its absence does not rule out narcolepsy, but a more comprehensive approach to diagnosis and evaluation of the syndrome should be conducted. HLA typing for the specific allele DQB1*0602 and low CSF hypocretin-1 level can aide in cases of atypical or doubtful narcolepsy with cataplexy.
References
Guilleminault C, Pelayo R: Narcolepsy in Prepubertal Children. Ann Neurology 1998, 43:145-52.
Nevsimalova S, Vankova S, Preztl M, Bruck D: Narcolepsy in Children and Adolescents. Clinical and Psychosocial Aspect. (in Czech) CeskaSlov. Neurol Neurochir 2002, 65:169-74.
Dalal MA, Schuld A, Pollmacher T: Undetectable CSF Level of Orexin A (hypocretin-1) in HLA DR2 Negative Patients With Narcolepsy Cataplexy. J Sleep Res 2002, 11:273.
Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, Vankova J, Black J, Harsh J, Bassetti C, Schrader H, Nishino S: The Role of Cerebrospinal Fluid Hypocretin Measurement in the Diagnosis of Narcolepsy and Other Hypersomnias. Arch Neurology 2002, 59:1553-62.
Mignot E, Lin L, Rogers W, Honda Y, Qiu X, Lin X, Okun M, Hohjoh H, Miki T, Hsu S, Leffell M, Grumet F, Fernandez-Vina M, Honda M, Risch N. Complex HLA DR and DQ Interactions Confer Risk For Narcolepsy in Three Ethnic Groups. Am J Human Genet 2001, 68:686-89.
Martinez-Rodriguez J, Lin L, Iranzo A: Decrease Hypocretin-1 (Orexin-A) Levels in Cerebrospinal Fluid of Patients With Myotonic Dystrophy and Excessive Daytime Sleepiness. Sleep 2003, 26:287-90.
Vankova J, Stepanova I, Jech R: Sleep Disturbances and Hypocretin Deficiency in Niemann-Pick Disease Type C. Sleep 2003, 26:427-30.
Kambayashi T, Abe M, Fujimoto: Hypocretin Deficiency in Niemann-Pick Disease With Cataplexy. Neuro pediatrics 2003, 34:52-3.
Arii J, Kambayashi T, Tanabe Y: CSF Hypocretin-1 (Orexin-A) in Childhood Narcolepsy and Neurologic Disorders. Neurology 2004, 63(12):2440-2.
Kubota H, Kambayashi T, Tanabe Y: Decrease Cerebrospinal Fluid Hypocretin-1 (Orexin-A) Near the Onset of Narcolepsy in Two Prepubertal Children. Sleep 2003, 26:555-57.
Gelb M, Guilleminault C, Kraemer H, Lin S, Moon S, Dement W, Mignot E: Stability of Cataplexy Over Several Months- Information for the Design of Therapeutic Trials. Sleep 1994, 17(3):265-273.
Guilleminault C, Fromherz S: Narcolepsy: Diagnosis and Management. In Principles and Practice of Sleep Medicine, edn 4. 2007.
Mignot E: Narcolepsy: Pharmacology, Pathophysiology, and Genetics. In Principles and Practice of Sleep Medicine, edn 4. 2007.
Longstreth WT, Koepsell TD, Ton TG, Hendrickson A, Van Belle G: The Epidemiology of Narcolepsy. Sleep 2007, 30(1):13-26.
Mignot E, Nishino S: Emerging Therapies in Narcolepsy-Cataplexy. Sleep 2005, 28(6):754-763.
Okun M, Lin L, Pelin Z, Hong S, Mignot E: Clinical Aspects of Narcolepsy-Cataplexy Across Ethnic Groups. Sleep 2002, 25(1):27-35.
Hong SC, Lin L, Jeong JH, Shin YK, Han JH, Lee JH, Lee SP, Zhang J, Einen M, Mignot E: A Study of the Diagnostic Utility of HLA Typing, CSF Hypocretin-1 Measurements, and MSLT Testing for the Diagnosis of Narcolepsy in 163 Korean Patients With Unexplained Excessive Daytime Sleepiness. Sleep 2006, 29(11):1429-1438.
Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C: HLA DQB1*0602 is Associated With Cataplexy in 509 Narcoleptic Patients. Sleep 1997, 20(11):1012-1020.
Labat SA, Guilleminault C, Kraemer H, Meehan J, Arrigoni J, Mignot E: Validation of a Cataplexy Questionaire in 983 Sleep-Disorders Patients. Sleep 1999, 22(1):77-87.
See also
Narcolepsy, Neurobiology of Sleep and Wakefulness, Parasomnias, Sleep,
