Narcolepsy-Cataplexy Syndrome (Narcolepsy with Cataplexy)

The narcolepsy-cataplexy syndrome is a condition characterized by excessive daytime sleepiness and sudden but brief episodes of sleep accompanied by loss of muscle tone. Loss of hypothalamic neurons that secrete hypocretin is the underlying cause, but the mechanism remains unclear. The diagnosis is made through polysomnography and the multiple sleep latency test and determination of hypocretin levels in the cerebrospinal fluid. Amphetamines, methylphenidate, modafinil, and sodium-oxybate are used in therapy.

Presentation

Symptoms start usually during the second decade of life, peaking at 14 years of age, while a second peak is shown to be around age 35 [18] [20]. Additionally, patients that have a positive family history for narcolepsy have shown a significant predilection toward an early onset of the condition [20]. The first symptom is excessive daytime sleepiness accompanied by fragmented sleep during the night [26]. Cataplexy, defined as sudden and brief (ranging between 5 and 30 seconds) partial or total loss of muscle tone triggered by emotional stimuli (laughter, surprise or anger) [3], may appear together with narcolepsy, but its onset is sometimes delayed for years or even decades [18]. However, it is rarely the first symptom of this condition [18]. Cataplexy may involve isolated muscle groups or it can be generalized, resulting in falling and the collapse of the individual and in rare cases, prolonged loss of muscle tone is described, known as status cataplectic [3]. Hallucinations, both visual and auditory, are also an integral component of the clinical presentation, as both hypnagogic (at sleep onset) and hypnopompic (upon awakening) may be present [3]. A subjective sense of clumsiness, slurred speech, weakness, and muscle twitches are reported prior to the attack [3].

Entire body system
  • Excessive Daytime Sleepiness The first symptom is excessive daytime sleepiness accompanied by fragmented sleep during the night. [source] The narcolepsy-cataplexy syndrome is a condition characterized by excessive daytime sleepiness and sudden but brief episodes of sleep accompanied by loss of muscle tone. [source] Namely, drugs that act on the monoaminergic system and thus promote the activity of dopamine and noradrenaline are used for managing excessive daytime sleepiness and the two most commonly used drugs are amphetamines and methylphenidate. [source]
  • Fatigue Also physicians often misdiagnose narcolepsy, mistaking the symptoms for those of other disorders, like depression, chronic fatigue syndrome, or obstructive sleep apnoea. [source] Droogleever Fortuyn HA, Fronczek R, Smitshoek M, et al ; Severe fatigue in narcolepsy with cataplexy. [source] Excessive fatigue is a common complaint and is described by those affected as being a different symptom to sleepiness. [ 9 ] Automatism occurs in many narcolepsy patients - when affected by severe sleepiness, they may have episodes in which they appear [source]
  • Hypersomnia In case of atypical or incomplete cataplexy, other causes of sleepiness must be taken into account, such as chronic insufficient sleep, idiopathic hypersomnia (see this term) or narcolepsy without cataplexy (see this term). [source] Morgenthaler TI, Kapur VK, Brown T, et al ; Practice parameters for the treatment of narcolepsy and other hypersomnias of Sleep. 2007 Dec 1 30(12):1705-11. [source] The hypersomnia is not better explained by another condition (sleep disorder, medical or neurological condition, mental disorder, substance misuse or medication). [source]
  • Weakness Partial weakness - specifically ask patients about partial weakness (eg, mild facial or jaw weakness), which they may not report. [source] Frequency varies, from several attacks per day to less than one per year. [ 4 ] The weakness is usually bilateral but one case report describes unilateral attacks. [ 12 ] Sleep paralysis This may occur as the patient is falling asleep or awakening. [source] is pathognomonic for narcolepsy and is present in around 70% of narcolepsy patients. [ 11 ] Features of a cataplexy attack: Severity can vary - eg, from a barely susceptible slackening of the facial muscles, dropping of the jaw or the entire head, to weakness [source]
  • Weight Gain Other, non specific, clinical signs include hypnagogic hallucinations, sleep paralysis, insomnia, hypnopompic hallucinations and weight gain[source]
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neurologic
  • Clumsiness A subjective sense of clumsiness, slurred speech, weakness, and muscle twitches are reported prior to the attack. [source] Both visual and auditory hallucinations may appear, together with slurred speech and a sense of clumsiness that can precede the attack. [source]
  • Drop Attack Cataplexy - may mimic drop attacks, syncope , seizures/epilepsy , transient ischaemic attack , periodic paralysis (channelopathies), psychiatric disorder, or cataplectic-like episodes (the latter can occur in healthy people). [source]
  • Headache Dry mouth, nausea, anxiety, headaches, and insomnia are most common adverse effects, while serious drug-induced rashes - Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in rare cases. [source] Autonomic symptoms have been reported in narcoleptic patients and include pupillary abnormalities, fainting spells, erectile dysfunction, night sweats, gastric problems, low body temperature, systemic hypotension, dry mouth, heart palpitations, headache [source]
  • Sleep Attack Narcoleptic sleep attacks are thought by some authorities to be the inappropriate appearance of REM sleep. [source] Stimulants are usually prescribed to treat EDS and sleep attacks, and usually control most other symptoms. [source] Sometimes sleepiness occurs so suddenly and with such overwhelming power that it is referred to as a 'sleep attack' . [source]
  • Slurred Speech A subjective sense of clumsiness, slurred speech, weakness, and muscle twitches are reported prior to the attack. [source] Both visual and auditory hallucinations may appear, together with slurred speech and a sense of clumsiness that can precede the attack. [source] Slurred speech and visual symptoms such as blurred vision or diplopia may be experienced. [source]
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Skin
  • Night Sweats Autonomic symptoms have been reported in narcoleptic patients and include pupillary abnormalities, fainting spells, erectile dysfunction, night sweats, gastric problems, low body temperature, systemic hypotension, dry mouth, heart palpitations, headache [source]
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musculoskeletal
  • Muscle Twitch A subjective sense of clumsiness, slurred speech, weakness, and muscle twitches are reported prior to the attack. [source]
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cardiovascular
  • Palpitations Autonomic symptoms have been reported in narcoleptic patients and include pupillary abnormalities, fainting spells, erectile dysfunction, night sweats, gastric problems, low body temperature, systemic hypotension, dry mouth, heart palpitations, headache [source]
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psychiatrical
Eyes
  • Blurred Vision Slurred speech and visual symptoms such as blurred vision or diplopia may be experienced. [source]
  • Diplopia Slurred speech and visual symptoms such as blurred vision or diplopia may be experienced. [source]
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Workup

The diagnostic workup comprises a meticulous patient history that includes the onset of symptoms and their features, as well as tests that evaluate sleeping patterns. Current guidelines recommend that every patient suffering from excessive daytime sleepiness accompanied by cataplexy should conduct the multiple sleep latency test (MSLT), a diagnostic procedure composed of five scheduled 20-minutes naps every two hours during the day in hospital conditions [14]. Presence or absence of REM sleep and the time necessary to fall asleep is recorded during this time and criteria for the diagnosis are: falling asleep within eight minutes across five naps and onset of REM during the first 15 minutes of sleep (termed sleep-onset REM, or SOREM) on two separate occasions [14]. Prior to initiation of MSLT, nocturnal polysomnography is performed to assess features such as sleeping time, movements, heart rate, and breathing, while actigraphy and sleeping logs may provide useful information as well [14]. If results from sleep studies, together with clinical signs and symptoms, point to the narcolepsy-cataplexy syndrome, CSF levels of hypocretin should be determined, as they are universally reduced in these patients [21] [22]. Finally, genetic studies confirming HLA-DQB1 mutations solidify the diagnosis, but it must be kept in mind that other comorbid conditions harboring HLA-DQB1 mutations should be excluded, most importantly MS, which is why physicians must perform a detailed physical examination and all necessary diagnostic procedures to rule out other conditions that have a similar clinical presentation [14]. Major depression, obstructive sleep apnea, bipolar and mood disorders, Parkinson's and Alzheimer's diseases and schizophrenia must be ruled out on the basis of their criteria [14].

Treatment

Current therapeutic principles focus on the resolution of symptoms, which is performed by using various pharmacologic agents. Namely, drugs that act on the monoaminergic system and thus promote the activity of dopamine and noradrenaline are used for managing excessive daytime sleepiness and the two most commonly used drugs are amphetamines and methylphenidate [10] [14]. Depending on the formulation, daily doses range between 10-60 mg, but various side-effects have been documented, including hypertension, production or exacerbation of psychiatric conditions such as anxiety, mania and psychosis, weight loss and tics [14]. Addiction can be a significant issue, which is why careful assessment and monitoring of patients is necessary [14]. In addition to these agents, modafinil, approved in the United States for the treatment of excessive sleepiness related to narcolepsy, has shown to be an effective agent by promoting wakefulness, but its exact mechanism of action is unknown [15]. Dry mouth, nausea, anxiety, headaches, and insomnia are most common adverse effects, while serious drug-induced rashes - Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in rare cases [14]. Gamma-hydroxybutyric acid salt, known as sodium oxybate, may be used for cataplexy as well [10]. In lower doses, it inhibits the GABAergic system, whereas stimulation of dopamine release occurs at higher doses [14]. Because of the presumed role of serotonin, noradrenaline and dopamine in the pathogenesis of narcolepsy-cataplexy syndrome, various antidepressants including selective serotonin reuptake inhibitors (SSRIs) and tricyclics (TCAs), but also monoamine-oxidase (MAO) inhibitors have been used in therapy as well, with variable success [14].

Prognosis

Numerous complications may occur during daily life, as sudden onset of sleep can happen during driving, working with dangerous equipment at work, or during class in school, resulting in severe socio-occupational difficulties [18]. Significant adjustments are necessary to minimize the risk of adverse events, as some of them may even be life-threatening. Unfortunately, the diagnosis of the narcolepsy-cataplexy syndrome is often delayed for a significant period of time [19], which can significantly affect the quality of the patient's life.

Complications

  • Auditory Hallucination Both visual and auditory hallucinations may appear, together with slurred speech and a sense of clumsiness that can precede the attack. [source] These attacks are brief and may be triggered by an excessive emotional stimulus (anger, humor, surprise), while both visual and auditory hallucinations can appear either before or after the attack. [source]
  • Cataplexy It may also help cataplexy symptoms. [source] Narcolepsy may occur with or without cataplexy[source] Falls or injuries during cataplexy attacks. [source]
  • Erectile Dysfunction Autonomic symptoms have been reported in narcoleptic patients and include pupillary abnormalities, fainting spells, erectile dysfunction, night sweats, gastric problems, low body temperature, systemic hypotension, dry mouth, heart palpitations, headache [source]
  • Hallucinations Other, non specific, clinical signs include hypnagogic hallucinations, sleep paralysis, insomnia, hypnopompic hallucinations and weight gain. [source] This condition can be terrifying, especially if it occurs with a frightening hypnagogic hallucination[source] The principal symptoms are excessive daytime sleepiness (EDS), cataplexy (loss of muscle tone), hypnagogic hallucinations, sleep paralysis, disrupted night-time sleep and automatic behaviour (being unaware of what you are doing). [source]
  • Hypnagogic Hallucination This condition can be terrifying, especially if it occurs with a frightening hypnagogic hallucination[source] The principal symptoms are excessive daytime sleepiness (EDS), cataplexy (loss of muscle tone), hypnagogic hallucinations, sleep paralysis, disrupted night-time sleep and automatic behaviour (being unaware of what you are doing). [source] Hypnagogic hallucinations are intense, vivid dreams, sometimes ccompanied by frightening auditory, visual and tactile sensations, and usually occur just on wakening or falling asleep, but may occur at other times. [source]
  • Sleep Paralysis Sleep paralysis - can be an isolated, physiological occurence; other causes are periodic paralysis, familial sleep paralysis or upper brain stroke. [source] paralysis[source] A careful description of symptoms/attacks (if considering cataplexy, sleep paralysis or hallucinations). [source]
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Etiology

Several theories regarding the etiology of the narcolepsy-cataplexy syndrome exist, but most recent studies suggest a multifactorial model [3] [6]. The loss of a small subset of neurons that synthesize hypocretin in the postero-lateral aspect of the hypothalamus is confirmed as the principal event in narcolepsy-cataplexy syndrome [3]. Namely, hypocretin is shown to be one of the most important mediators of sleep, wakefulness, energy homeostasis and feeding behavior [15]. The mechanisms that lead to this phenomenon, however, remains to be elucidated. A strong association between HLA-DQB1*0602 mutations and this condition has been discovered throughout the past few decades [5], which supports the autoimmune origin of neuronal loss in the hypothalamus. Additional research has confirmed T-cell receptor α (the major receptor for HLA-peptide presentation) polymorphisms [7], reduced expression of purinergic receptor subtype 2Y11 (P2RY11) gene involved in modulating the activity of CD8+ T-lymphocytes and natural killer (NK) cells, but also the presence of anti-streptolysin O (ASO) antibodies, which implies that the streptococcal antigen may be the trigger of narcolepsy [9]. Furthermore, anti-tribbles homolog 2 (TRIB2) autoantibodies are detected in patients who develop cataplexy shortly after narcolepsy, suggesting that they play an important role in the pathogenesis of this syndrome as well [6] [16].

Epidemiology

Prevalence rates of the narcolepsy-cataplexy syndrome are estimated between 0.02%-0.05% in the general population [10]. In Europe, a prevalence rate of 47 per 100,000 individuals has been established (corresponding to a 0.00047%) [11]. A significant ethnic predisposition has been proposed in studies that further determined a prevalence rate of 0.59% and 0.00023% in the Japanese and Israeli Jews, respectively [12]. Reports from Hong Kong indicate that 0.034% of the local population suffers from this disorder [14]. Family history has shown to be the most important risk factor for narcolepsy-cataplexy, as prevalence rates are 10-40 times higher in families with members suffering from this condition compared to the general population [17]. At this moment, gender predilection is not established [18].

Sex distribution
Age distribution

Pathophysiology

Loss of neuronal circuits that secrete hypocretins 1 and 2 (or orexins A and B) is the hallmark of the narcolepsy-cataplexy syndrome [3]. Hypocretins are peptides secreted from the postero-lateral aspect of the hypothalamus and act through monoamine G-coupled receptors in various brain regions, including the locus coeruleus, the raphe and tuberomammillary nuclei and the tegmental areas responsive to various neurotransmitters [3]. It is hypothesized that the loss of hypocretins has a profound effect on the dopaminergic, histaminergic, serotonergic and noradrenergic systems [3], which leads to the appearance of various signs and symptoms associated with sleep and muscle tone. The most probable cause of neuronal loss is an autoimmune reaction, having in mind the fact that virtually all patients have HLA-DQB1*0602 mutations, while the roles of ASO and anti-TRIB2 antibodies, as well as increased expression of P2RY11, remain to be confirmed [6] [9] [16].

Prevention

Current preventive strategies are unknown.

Summary

Initially described almost 150 years ago [1] [2], the narcolepsy-cataplexy syndrome is a clinical entity in which sudden and brief attacks of sleep and loss of muscle tone occurs, while excessive daytime sleepiness and hallucinations appear in the clinical presentation as well [3]. The cause seems to be multifactorial, involving genetic, environmental, but also autoimmune factors [3] [4]. Current theories propose that autoimmune-mediated loss of a small group of hypothalamic neurons that produce hypocretin, a neuropeptide involved in regulation of sleep and wakefulness, is the principal cause of this syndrome, while mutations of HLA-DQB1*0602 (seen in 95% of cases), aberrations in t-cell receptors and presence of antistreptolysin O antibodies further solidify this hypothesis [5 [6] [7] [8] [9]. The overall prevalence is estimated at 0.02-0.05%, with significant differences across world [10], varying from 0.00047% in Europe to 0.54% in Japan [11] [12]. Because hypocretin is involved in numerous physiological processes regarding sleep, wakefulness and other neurological functions, its absence cause significant changes in the dopaminergic, noradrenergic and histaminergic neurotransmitter systems [3]. The appearance of narcolepsy - excessive daytime sleepiness (accompanied by fragmented nocturnal sleep and the presence of limb movements during sleep), and cataplexy - sudden but brief loss of muscle tone after severe emotional stimuli such as laughter, are consequences of hypocretin deficiency [3] [10]. Symptoms most frequently appear before age 20, but the onset may occur during the third, fourth and fifth decade of life as well [13]. Both visual and auditory hallucinations may appear, together with slurred speech and a sense of clumsiness that can precede the attack [14]. The diagnosis is made through evaluation of sleep by polysomnography and multiple sleep latency test (MSLT), while cerebrospinal fluid levels of hypocretin and genetic testing for HLA mutations further solidify the diagnosis [14]. It must be noted that other comorbid conditions, mainly of psychiatric nature, may be present concomitantly, whereas HLA mutations may be seen in multiple sclerosis (MS) [14], which suggests that the workup of patients must be thorough. The goal of therapy is to reduce the burden of symptoms in daily life and amphetamine, methylphenidate, modafinil and sodium-oxybate are used to promote wakefulness through various mechanisms [14]. Because significant adverse events may occur in daily life (falling asleep when driving or handling equipment during work), timely recognition and treatment are necessary.

Patient Information

The narcolepsy-cataplexy syndrome is a condition characterized by excessive daytime sleepiness, fragmented night sleep and attacks of sleep (narcolepsy) accompanied by sudden loss of muscle tone lasting between 5 and 30 seconds, medically termed cataplexy. The cause seems to stem from the deficiency of hypocretin, one of the most important mediators of wakefulness and sleep that are released from the brain. Most recent discoveries suggest that an autoimmune reaction to the nerves that release hypocretin occurs and causes the syndrome, but the exact mechanism remains unknown. However, almost 95% of patients possess genetic mutations of molecules involved in regulation of the immune system (known as a human leukocytic antigen, or HLA), suggesting that the disease may have a multifactorial origin. The disorder affects approximately 0.02-0.05% of the general population, but significant ethnic predilections have been established. Namely, a much higher rate of the disease is seen in Japan compared to Europe and people of Jewish ancestry and the explanation is yet to be discovered. Because hypocretin plays such an important role in regulating sleep, its deficiency leads to symptoms such as excessive daytime sleepiness, disturbed night sleep, fatigue and the eventual appearance of sleep attacks simultaneously with sudden loss of either isolated muscle groups or the whole body. These attacks are brief and may be triggered by an excessive emotional stimulus (anger, humor, surprise), while both visual and auditory hallucinations can appear either before or after the attack. To make the diagnosis, procedures that evaluate sleep are performed. Nocturnal polysomnography, which serves to assess breathing, heart rate, movement, and brain activity of the patient during sleep and multiple sleep latency test are used. Once a presumptive diagnosis is made based on the obtained results, levels of hypocretin in cerebrospinal fluid and presence of specific HLA mutations should be determined, so that appropriate treatment may be initiated. The role of therapy is to alleviate symptoms of excessive sleepiness and drugs that are recommended for narcolepsy-cataplexy syndrome are amphetamines, methylphenidate, modafinil, and sodium-oxybate, but because drugs possess various side effects (hypertension, rash, addiction, dry mouth, nausea, but also induction of psychiatric symptoms such as mania and anxiety), careful evaluation and long-term monitoring of patients is vital. This syndrome may significantly impair the quality of life of patients, primarily because these attack can occur when performing tasks that require a high level of focus (driving, working with delicate equipment, or during classes), which forces them to make major adjustments in their occupation, but also education. For this reason, early recognition of the disease is essential.

Self-assessment

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