narcolepsy research paper conclusion

Narcolepsy and psychosis: A systematic review

Affiliations.

• 1 Centre de Référence des Maladies Rares à Expression Psychiatrique, Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France.
• 2 Faculté de Médecine Sorbonne Université, Groupe de Recherche Clinique n°15 - Troubles Psychiatriques et Développement (PSYDEV, Paris, France.
• 3 National Reference Center for Rare Hypersomnias, Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France.
• 4 Pediatric Sleep Center and National Reference Center for Narcolepsy and Hypersomnia, Robert Debré University Hospital, Assistance Publique-Hôpitaux de Paris, Paris VII University, Paris, France.
• 5 Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
• 6 CNRS UMR 7222, Institute for Intelligent Systems and Robotics, Sorbonne University, Paris, France.
• PMID: 33779983
• PMCID: PMC8360149
• DOI: 10.1111/acps.13300

Objective: Narcolepsy is a rare sleep disorder in which psychotic-like symptoms can present diagnostic and therapeutic challenges. We aimed to review the association between, and medical management of, narcolepsy and psychosis in children and adults.

Methods: We reviewed the full text of 100 papers from 187 identified by a PubMed search on narcolepsy plus any of these keywords: psychosis, schizophrenia, delusion, side effects, safety, and bipolar disorder.

Results: Three relevant groups are described. (i) In typical narcolepsy, psychotic-like symptoms include predominantly visual hallucinations at the sleep-wake transition (experienced as "not real") and dissociation because of intrusion of rapid eye movement (REM) sleep phenomena into wakefulness. (ii) Atypical patients ("the psychotic form of narcolepsy") experience more severe and vivid, apparently REM-related hallucinations or dream/reality confusions, which patients may rationalize in a delusion-like way. (iii) Some patients have a comorbid schizophrenia spectrum disorder with psychotic symptoms unrelated to sleep. Psychostimulants used to treat narcolepsy may trigger psychotic symptoms in all three groups. We analyzed 58 published cases from groups 2 and 3 (n = 17 and 41). Features that were reported significantly more frequently in atypical patients include visual and multimodal hallucinations, sexual and mystical delusions, and false memories. Dual diagnosis patients had more disorganized symptoms and earlier onset of narcolepsy.

Conclusion: Epidemiological studies tentatively suggest a possible association between narcolepsy and schizophrenia only for very early-onset cases, which could be related to the partially overlapping neurodevelopmental changes observed in these disorders. We propose a clinical algorithm for the management of cases with psychotic-like or psychotic features.

Keywords: delusion; hallucination; narcolepsy; psychosis; schizophrenia; side effects.

© 2021 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.

Publication types

• Systematic Review
• Hallucinations / epidemiology
• Narcolepsy* / diagnosis
• Narcolepsy* / drug therapy
• Narcolepsy* / epidemiology
• Psychotic Disorders* / epidemiology
• Schizophrenia* / epidemiology

What is narcolepsy?

Narcolepsy is a chronic neurological disorder that affects the brain's ability to control sleep-wake cycles. People with narcolepsy may feel rested after waking, but then feel very sleepy throughout much of the day. Many individuals with narcolepsy also experience uneven and interrupted sleep that can involve waking up frequently during the night.

Narcolepsy can greatly affect daily activities. People may unwillingly fall asleep even if they are in the middle of an activity like driving, eating, or talking. Other symptoms may include sudden muscle weakness while awake that makes a person go limp or unable to move (cataplexy), vivid dream-like images or hallucinations, and total paralysis just before falling asleep or just after waking up (sleep paralysis).

In a normal sleep cycle, a person enters rapid eye movement (REM) sleep after about 60 to 90 minutes. Dreams occur during REM sleep, and the brain keeps muscles limp during this sleep stage, which prevents people from acting out their dreams. People with narcolepsy frequently enter REM sleep rapidly, within 15 minutes of falling asleep. Also, the muscle weakness or dream activity of REM sleep can occur during wakefulness or be absent during sleep. This helps explain some symptoms of narcolepsy.

If left undiagnosed or untreated, narcolepsy can interfere with psychological, social, and cognitive function and development and can inhibit academic, work, and social activities.

Narcolepsy is a lifelong problem, but it does not usually worsen as the person ages. Symptoms can partially improve over time, but they will never disappear completely. The most typical symptoms are:

• Excessive daytime sleepiness (EDS)—All individuals with narcolepsy have EDS, and it is often the most obvious symptom. EDS is characterized by persistent sleepiness, regardless of how much sleep an individual gets at night. However, sleepiness in narcolepsy is more like a “sleep attack,” where an overwhelming sense of sleepiness comes on quickly. In between sleep attacks, individuals have normal levels of alertness, particularly if doing activities that keep their attention.
• Cataplexy—This sudden loss of muscle tone while a person is awake leads to weakness and a loss of voluntary muscle control. It is often triggered by sudden, strong emotions such as laughter, fear, anger, stress, or excitement. The symptoms of cataplexy may appear weeks or even years after the onset of EDS. Some people may only have one or two attacks in a lifetime, while others may experience many attacks a day. In about 10 percent of cases of narcolepsy, cataplexy is the first symptom to appear and can be misdiagnosed as a seizure disorder. Attacks may be mild and involve only a momentary sense of minor weakness in a limited number of muscles, such as a slight drooping of the eyelids. The most severe attacks result in a total body collapse during which individuals are unable to move, speak, or keep their eyes open. But even during the most severe episodes, people remain fully conscious, a characteristic that distinguishes cataplexy from fainting or seizure disorders. The loss of muscle tone during cataplexy resembles paralysis of muscle activity that naturally occurs during REM sleep. Episodes last a few minutes at most and resolve almost instantly on their own. While scary, the episodes are not dangerous as long as the individual finds a safe place in which to collapse.
• Sleep paralysis—The temporary inability to move or speak while falling asleep or waking up usually lasts only a few seconds or minutes and is similar to REM-induced inhibitions of voluntary muscle activity. Sleep paralysis resembles cataplexy except it occurs at the edges of sleep. As with cataplexy, people remain fully conscious. Even when severe, cataplexy and sleep paralysis do not result in permanent dysfunction—after episodes end, people rapidly recover their full capacity to move and speak.
• Hallucinations—Very vivid and sometimes frightening images can accompany sleep paralysis and usually occur when people are falling asleep or waking up. Most often the content is primarily visual, but any of the other senses can be involved.

Additional symptoms include:

• Fragmented sleep and insomnia—While individuals with narcolepsy are very sleepy during the day, they usually also experience difficulties staying asleep at night. Sleep may be disrupted by insomnia, vivid dreaming, sleep apnea, acting out while dreaming, and periodic leg movements.
• Automatic behaviors—Individuals with narcolepsy may experience temporary sleep episodes that can be very brief, lasting no more than seconds at a time. A person falls asleep during an activity (e.g., eating, talking) and automatically continues the activity for a few seconds or minutes without conscious awareness of what they are doing. This happens most often while people are engaged in habitual activities such as typing or driving. They cannot recall their actions, and their performance is almost always impaired. Their handwriting may, for example, degenerate into an illegible scrawl, or they may store items in bizarre locations and then forget where they placed them. If an episode occurs while driving, individuals may get lost or have an accident. People tend to awaken from these episodes feeling refreshed, finding that their drowsiness and fatigue has temporarily subsided.

There are two major types of narcolepsy:

• Type 1 narcolepsy (previously known as narcolepsy with cataplexy)—This diagnosis is based on the individual either having low levels of a brain hormone (hypocretin) or reporting cataplexy and having excessive daytime sleepiness on a special nap test.
• Type 2 narcolepsy (previously known as narcolepsy without cataplexy)—People with this condition experience excessive daytime sleepiness but usually do not have muscle weakness triggered by emotions. They usually also have less severe symptoms and have normal levels of the brain hormone hypocretin.

A condition known as secondary narcolepsy can result from an injury to the hypothalamus, a region deep in the brain that helps regulate sleep. In addition to experiencing the typical symptoms of narcolepsy, individuals may also have severe neurological problems and sleep for long periods (more than 10 hours) each night.

Who is more likely to get narcolepsy?

Narcolepsy affects both males and females equally. Symptoms often start in childhood, adolescence, or young adulthood (ages 7 to 25), but can occur at any time in life. Since people with narcolepsy are often misdiagnosed with other conditions, such as psychiatric disorders or emotional problems, it can take years for someone to get the proper diagnosis.

Narcolepsy may have several causes. Nearly all people with narcolepsy who have cataplexy have extremely low levels of the naturally occurring chemical hypocretin, which promotes wakefulness and regulates REM sleep. Hypocretin levels are usually normal in people who have narcolepsy without cataplexy.

Although the cause of narcolepsy is not completely understood, current research suggests that narcolepsy may be the result of a combination of factors working together to cause a lack of hypocretin. These factors include:

• Autoimmune disorders—When cataplexy is present, the cause is most often the loss of brain cells that produce hypocretin. Although the reason for this cell loss is unknown, it appears to be linked to abnormalities in the immune system. Autoimmune disorders occur when the body's immune system turns against itself and mistakenly attacks healthy cells or tissue. Researchers believe that in individuals with narcolepsy, the body's immune system selectively attacks the hypocretin-containing brain cells because of a combination of genetic and environmental factors.
• Family history—Most cases of narcolepsy are sporadic, meaning the disorder occurs in individuals with no known family history. However, clusters in families sometimes occur—up to 10 percent of individuals diagnosed with narcolepsy with cataplexy report having a close relative with similar symptoms.
• Brain injuries—Rarely, narcolepsy results from traumatic injury to parts of the brain that regulate wakefulness and REM sleep or from tumors and other diseases in the same regions.

In the past few decades, scientists have made considerable progress in understanding narcolepsy and identifying genes strongly associated with the disorder. Groups of neurons in several parts of the brain interact to control sleep, and the activity of these neurons is controlled by a large number of genes. The loss of hypocretin-producing neurons in the hypothalamus is the primary cause of type 1 narcolepsy. These neurons are important for stabilizing sleep and wake states.

The human leukocyte antigen (HLA) system of genes  plays an important role in regulating the immune system. This gene family provides instructions for making a group of related proteins called the HLA complex, which helps the immune system distinguish between good proteins from an individual's own body and bad ones made by foreign invaders like viruses and bacteria.

One of the genes in this family is HLA-DQB1. A variation in this gene, called HLA-DQB1*06:02, increases the chance of developing narcolepsy, particularly the type of narcolepsy with cataplexy and a loss of hypocretins (also known as orexins). HLA-DQB1*06:02 and other HLA gene variations may increase susceptibility to an immune attack on hypocretin neurons, causing these cells to die. Most people with narcolepsy have this gene variation and may also have specific versions of closely related HLA genes.

However, it is important to note that these gene variations are common in the general population and only a small portion of the people with the HLA-DQB1*06:02 variation will develop narcolepsy. This indicates that other genetic and environmental factors are important in determining if an individual will develop the disorder.

Narcolepsy follows a seasonal pattern and is more likely to develop in the spring and early summer after the winter season, a time when people are more likely to get sick. By studying people soon after they develop the disorder, scientists have discovered that individuals with narcolepsy have high levels of anti-streptolysin O antibodies, indicating an immune response to a recent bacterial infection such as strep throat. Also, the H1N1 influenza epidemic in 2009 resulted in a large increase in the number of new cases of narcolepsy. Together, this suggests that individuals with the HLA-DQB1*06:02 variation are at risk for developing narcolepsy after they are exposed to a specific trigger, like certain infections that trick the immune system to attack the body.

How is narcolepsy diagnosed and treated?

Diagnosing narcolepsy

A clinical examination and detailed medical history are essential for diagnosis and treatment of narcolepsy. Individuals may be asked by their doctor to keep a sleep journal noting the times of sleep and symptoms over a one- to two-week period. A physical exam can rule out or identify other neurological conditions that may be causing the symptoms.

Two specialized tests, which can be performed in a sleep disorders clinic, are required to establish a diagnosis of narcolepsy:

• Polysomnogram (PSG or sleep study)—The PSG is an overnight recording of brain and muscle activity, breathing, and eye movements. A PSG can help reveal whether REM sleep occurs early in the sleep cycle and if an individual's symptoms result from another condition such as sleep apnea.
• Multiple sleep latency test (MSLT)—The MSLT assesses daytime sleepiness by measuring how quickly a person falls asleep and whether they enter REM sleep.

Occasionally, it may be helpful to measure the level of hypocretin in the fluid that surrounds the brain and spinal cord. To perform this test, a doctor will withdraw a sample of the cerebrospinal fluid using a lumbar puncture (also called a spinal tap) and measure the level of hypocretin-1.

Treating narcolepsy

Although there is no cure for narcolepsy, some of the symptoms can be treated with medicines and lifestyle changes.

Medications

• Modafinil—The initial line of treatment is usually a central nervous system stimulant such as modafinil. Modafinil is usually prescribed first because it is less addictive and has fewer side effects than older stimulants. For most people these drugs are generally effective at reducing daytime drowsiness and improving alertness.
• Amphetamine-like stimulants—In cases where modafinil is not effective, doctors may prescribe amphetamine-like stimulants such as methylphenidate to alleviate EDS. However, these medications must be carefully monitored because they can have side effects.
• Antidepressants—Two classes of antidepressant drugs have proven effective in controlling cataplexy in many individuals: tricyclics (including imipramine, desipramine, clomipramine, and protriptyline) and selective serotonin and noradrenergic reuptake inhibitors (including venlafaxine, fluoxetine, and atomoxetine).
• Sodium oxybate—Sodium oxybate (also known as gamma hydroxybutyrate or GHB) has been approved by the U.S. Food and Drug Administration (FDA) to treat cataplexy and excessive daytime sleepiness in individuals with narcolepsy. Due to safety concerns associated with the use of this drug, the distribution of sodium oxybate is tightly restricted.
• Histamine 3 receptor antagonist/inverse agonist—Pitolisant was recently approved by FDA as the only non-scheduled product for treating excessive daytime sleepiness or cataplexy in adults with narcolepsy. Pitolisant, which has been commercially available in the U.S. since 2019, is thought to increase histamine levels in the brain. The most common adverse reactions to Pitolisant are insomnia, nausea, and anxiety.

Lifestyle changes

Drug therapy should accompany various lifestyle changes. Remembering the following seven tips may be helpful:

• Take short naps. Many individuals take short, regularly scheduled naps at times when they tend to feel sleepiest.
• Maintain a regular sleep schedule. Going to bed and waking up at the same time every day, even on the weekends, can help people sleep better.
• Avoid caffeine or alcohol before bed. Individuals should avoid alcohol and caffeine for several hours before bedtime.
• Avoid smoking, especially at night.
• Exercise daily. Exercising for at least 20 minutes per day at least four or five hours before bedtime also improves sleep quality and can help people with narcolepsy avoid gaining excess weight.
• Avoid large, heavy meals right before bedtime. Eating very close to bedtime can make it harder to sleep.
• Relax before bed. Relaxing activities such as a warm bath before bedtime can help promote sleepiness. Also make sure the sleep space is cool and comfortable.

Safety precautions, particularly when driving, are important for everyone with narcolepsy. Suddenly falling asleep or losing muscle control can transform actions that are ordinarily safe, such as walking down a long flight of stairs, into hazards.

The Americans with Disabilities Act (ADA) requires employers to provide reasonable accommodations for all employees with disabilities. Adults with narcolepsy can often negotiate with employers to modify their work schedules so they can take naps when necessary and perform their most demanding tasks when they are most alert.

Similarly, children and adolescents with narcolepsy may be able to work with school administrators to accommodate special needs, like taking medications during the school day, modifying class schedules to fit in a nap, and other strategies.

Additionally, support groups can be extremely beneficial for people with narcolepsy.

What are the latest updates on narcolepsy?

The mission of the National Institute of Neurological Disorders and Stroke ( NINDS ) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. The NINDS, a component of the National Institutes of Health ( NIH ), along with several other NIH Institutes and Centers, supports research on narcolepsy and other sleep disorders through grants to medical institutions across the country.

Additionally, the National Heart, Lung, and Blood Institute (NHLBI) manages the National Center on Sleep Disorders Research (NCSDR) , which coordinates federal government sleep research activities, promotes doctoral and postdoctoral training programs, and educates the public and health care professionals about sleep disorders. 

Genetics and biochemicals NINDS-sponsored researchers are conducting studies devoted to further clarifying the wide range of genetic—both HLA genes and non-HLA genes—and environmental factors that may cause narcolepsy. Other investigators are using animal models to better understand hypocretin and other chemicals such as glutamate that may play a key role in regulating sleep and wakefulness. Researchers are also investigating wake-promoting compounds to widen the range of available therapeutic options and create treatment options that reduce undesired side effects and decrease the potential for abuse. A greater understanding of the complex genetic and biochemical bases of narcolepsy will eventually lead to new therapies to control symptoms and may lead to a cure.

Immune system Abnormalities in the immune system may play an important role in the development of narcolepsy. NINDS-sponsored scientists have demonstrated the presence of unusual immune system activity in people with narcolepsy. Further, strep throat and certain varieties of influenza are now thought to be triggers in some at-risk individuals. Other NINDS researchers are also working to understand why the immune system destroys hypocretin neurons in narcolepsy in the hopes of finding a way to prevent or cure the disorder.

Sleep biology NINDS continues to support investigations into the basic biology of sleep, such as examining the brain mechanisms involved in generating and regulating REM sleep and other sleep behaviors. Since sleep and circadian rhythms are controlled by networks of neurons in the brain, NINDS researchers are also examining how neuronal circuits function in the body and contribute to sleep disorders like narcolepsy. A more comprehensive understanding of the complex biology of sleep will give scientists a better understanding of the processes that underlie narcolepsy and other sleep disorders.

How can I or my loved one help improve care for people with narcolepsy?

The NeuroBioBank serves as a central point of access to collections that span neurological, neuropsychiatric, and neurodevelopmental diseases and disorders. Tissue from individuals with narcolepsy is needed to enable scientists to study this disorder more intensely. Participating groups include brain and tissue repositories, researchers, NIH program staff, information technology experts, disease advocacy groups, and, most importantly, individuals seeking information about opportunities to donate.

Additionally, NINDS supports genetic and immunological research in narcolepsy at the Stanford University Center for Narcolepsy . Blood samples from individuals with narcolepsy can be sent by mail and are needed to enable scientists to study this disorder more intensely.

Consider participating in a clinical trial so clinicians and scientists can learn more about narcolepsy and related disorders. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.

All types of volunteers are needed— those who are healthy or may have an illness or disease— of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research visit NIH Clinical Research Trials and You . Learn about clinical trials currently looking for people with narcolepsy at Clinicaltrials.gov .

Where can I find more information about narcolepsy? Information may be available from the following organizations: Narcolepsy Network Phone: 401-667-2523 or 888-292-6522 National Heart, Lung, and Blood Institute (NHLBI) Phone: 301-592-8573 or 800-575-9355 National Library of Medicine Phone: 301-594-5983 or 888-346-3656 National Sleep Foundation Phone: 703-243-1697 Wake Up Narcolepsy Phone: 978-751-3693

Insomnia and Narcolepsy: Sleeping Disorders Research Paper

Works cited.

Humans spend approximately one-third of their life for sleeping. However, the full role of this process remains unknown. It was determined that sleep is essential for cell division, body growth and reparation, memory formation and unnecessary memory files removal, protein synthesis, immunocompetence maintenance, and metabolism regulation (Silber et al. 8). Thus, it could be stated that sleeping disorders can lead to serious health problems. Insomnia and narcolepsy are two different types of sleeping disorders. Insomnia is characterized by the reduction of quantity or quality of sleep, while narcolepsy means excessive daily sleepiness.

According to the American Academy of Sleep Medicine, insomnia could be defined as “a nightly complaint of an insufficient amount of sleep or not feeling rested after the habitual sleep episode” (23). The definition also includes adverse daytime consequences of the sleeping disorder (Sateia and Buysse 3). The problem with the definition is that there are no accepted objective criteria that could be used for the disorder diagnosis. The level of distress and, therefore, the severity of insomnia depend on the individual characteristics of a patient. Besides, it was established that people with insomnia are inclined to overestimate the negative effect of sleeping disorder and underestimate the total time of sleep. Despite all the difficulties, nowadays, the clinical diagnosis of insomnia is based on the patient’s complaints and description (Sateia and Buysse 3-5).

It was stated that insomnia affected up to 30% of American citizens (Silber et al. 184). Reasons for insomnia could be various: environmental factors that prevent healthy sleep, the irregular sleep-wake cycle and unhealthy, sedentary lifestyle, stress, a wide range of physiological, neurological, and psychiatric diseases, and others (Silber et al. 185-194). It is important to determine the cause of the sleeping disorder to provide efficient therapy. For the insomnia treatment, pharmaceutical and non-pharmaceutical approaches are used. It is required to optimize the sleep environment and regime. Cognitive-behavioral therapy is also considered to be an effective method to overcome insomnia. For pharmaceutical therapy, sedative, and hypnotic medications such as benzodiazepines, nonbenzodiazepine benzodiazepine-receptors agonists, melatonin agonists, and antidepressants are used in clinical practice (Silber et al. 200-206).

Narcolepsy could be defined as “excessive sleepiness that typically is associated with cataplexy and other REM-sleep phenomena, such as sleep paralysis and hypnagogic hallucinations” (American Academy of Sleep Medicine 38). All people who suffer from narcolepsy complain of daytime sleepiness which interferes with their activities. This disorder can lead to different accidents, difficulties with employment, and various social problems (Silber et al. 68).

Narcolepsy is a less common sleeping disorder than insomnia. It was estimated that up to 67 per 100,000 persons (0.067% of a population) are suffering from this disease (Silber et al. 72). Narcolepsy can be genetically determined (approximately 90% of people with narcolepsy have HLA DQB1*0602 antigen (Goswami et al. 5)) or caused by several factors, including brain tumors, neurotransmitters regulation malfunctioning, and autoimmune diseases (Silber et al. 72-75). It is important to determine the reason for the disorder because it could be a symptom of a serious illness.

For the narcolepsy treatment, pharmaceutical and non-pharmaceutical approaches could be proposed. Regime normalization is the first step of the therapy. It is important to develop a regular sleep-wake regime, avoid night shifts, and enhance daily activities to overcome narcolepsy. A range of stimulant medications such as modafinil, sodium oxybate, methylphenidate, pitolisant, amphetamines, and mazindol is widely used for the pharmaceutical therapy of the disorder (Barateau et al. 370-372).

Two different types of sleeping disorders were reviewed: insomnia (the lack of sleeping) and narcolepsy (the excessive sleepiness). Both disorders negatively affect patients’ work and social activities and cause significant adverse consequences. The reasons for these diseases could be various, including external and internal factors. For the insomnia treatment, sedative medicaments are used, while narcolepsy requires therapy with stimulant medications. A healthy lifestyle and regular sleep-wake daily regime are also essential for recovery.

American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic and Coding Manual . 2nd ed., American Academy of Sleep Medicine, 2005.

Barateau, Lucie, et al. “Treatment Options for Narcolepsy.” CNS Drugs vol. 30, no. 5, 2016, pp. 369-379. Web.

Goswami, Meeta, et al., editors. Narcolepsy: A Clinical Guide . 2nd ed., Springer, 2016.

Sateia, Michael J., and Daniel Buysse, editors. Insomnia: Diagnosis and Treatment . 2nd ed., CRC Press, 2016.

Silber, Michael H., et al. Sleep Medicine in Clinical Practice . 2nd ed., CRC Press, 2016.

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IvyPanda. (2020, September 26). Insomnia and Narcolepsy: Sleeping Disorders. https://ivypanda.com/essays/insomnia-and-narcolepsy-sleeping-disorders/

"Insomnia and Narcolepsy: Sleeping Disorders." IvyPanda , 26 Sept. 2020, ivypanda.com/essays/insomnia-and-narcolepsy-sleeping-disorders/.

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IvyPanda . 2020. "Insomnia and Narcolepsy: Sleeping Disorders." September 26, 2020. https://ivypanda.com/essays/insomnia-and-narcolepsy-sleeping-disorders/.

1. IvyPanda . "Insomnia and Narcolepsy: Sleeping Disorders." September 26, 2020. https://ivypanda.com/essays/insomnia-and-narcolepsy-sleeping-disorders/.

Bibliography

IvyPanda . "Insomnia and Narcolepsy: Sleeping Disorders." September 26, 2020. https://ivypanda.com/essays/insomnia-and-narcolepsy-sleeping-disorders/.

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TCM syndrome differentiation and treatment of narcolepsy based on neurobiological mechanism: A review

a Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang Province

Ruiqian Guan

b Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang Province

c The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang Province.

Narcolepsy is a relatively rare brain disorder caused by the selective loss of orexin neurons. Narcolepsy is divided into Narcolepsy Type 1 (NT1) and Narcolepsis Type 2 (NT2). The pathogenesis of NT1 has been well established due to the severe loss of orexin neurons, while NT2 is still poorly understood, and little is known about its underlying neurobiological mechanisms. human leukocyte antigen alleles have been found to strongly influence the development of narcolepsy, with more than 90% of NT1 patients carrying the human leukocyte antigen II allele DQB1*06:02. In addition to the genetic evidence for the DQBI*06:02 allele, some other evidence suggests that a T cell-mediated immune mechanism destroys the orexin neurons of NT1, with CD4 + T cells being key. For this disease, traditional Chinese medicine (TCM) therapy has its own characteristics and advantages, especially the combination of acupuncture and medicine in the treatment of this disease in TCM, which has made considerable and gratifying progress. The purpose of this review is to introduce the frontier progress of neurobiology of narcolepsy, and to explore the syndrome differentiation and treatment of narcolepsy with the combined use of TCM and Western medicine combined with TCM.

1. Introduction

Although narcolepsy was described in the literature before the 19th century, it was not until the end of the 19th century that Westphal, Gelinan and Fischer published 3 articles [ 1 ] that the 2 main manifestations of narcolepsy were first clearly proposed. One is an irresistible or compulsive excessive daytime sleepiness, and the other is a transient loss of muscle tone or control triggered by emotion and accompanied by a state of consciousness preservation. [ 2 ] These observations were confirmed by later researchers. [ 1 ] Since then, however, it has been widely accepted that narcolepsy is a rare and nonspecific manifestation of other diseases. [ 3 ] By 1960, however, the main features of narcolepsy had been accurately described in a large series of cases, and the specificity of the disease was clearly established. [ 3 ]

Classic narcolepsy, now called Narcolepsy Type 1 (NT1), is characterized by the presence of convulsive symptoms or a deficiency of orexin. [ 4 ] In contrast, narcolepsy without convulsive symptoms or orexin deficiency, now known as Narcolepsy Type 2 (NT2), remains little known. Although the presence of mild and incomplete narcolepsy manifestations (“narcolepsy borderline”) is generally accepted, their inclusion in the diagnostic spectrum remains controversial. [ 5 ]

Our understanding of the clinical presentation, etiology, pathophysiology, diagnosis, and management of narcolepsy has advanced considerably over the past 20 years. [ 3 ] In 1998, 2 groups independently discovered orexin A and orexin B, small neuropeptides produced only by neurons in the lateral hypothalamus. Soon after, researchers found that narcolepsy, caused by severe orexin neuron loss, resulted in low orexin levels in the brain and cerebrospinal fluid (CSF). [ 6 ] This discovery led to the recognition of 2 types of narcolepsy: NT1 and NT2. Typical NT1 is characterized by prolonged somnolence plus convulsions, and the CSF of this disorder has very low or barely detectable orexin levels due to severe loss of orexin neurons. The symptoms of NT2 are generally less severe, and 90% of patients have normal orexin levels in the CSF. NT2 affects up to half of narcolepsy patients [ 5 ] and may also be caused by partial loss of orexin neurons, but little is known about its underlying neuropathology. [ 5 ]

The clear association of NT1 with the selective loss of orexin neurons has triggered great progress in our understanding of narcolepsy, but major problems remain. This article aims to describe the latest research progress in the neurobiological mechanism of narcolepsy and explore the possibility of the combined use of traditional Chinese medicine (TCM) and Western medicine in the treatment of narcolepsy combined with TCM.

1.1. Cognition of narcolepsy in TCM

The earliest description of narcolepsy in TCM can be found in Miraculous Pivot: “Those who lie down suddenly…pathogenic qi stays in upper jiao pattern…Wei-defensive qi stays in Yin for long time and does not work." [ 7 ] Qi is the intangible, high-mobility nutritive substance that maintains vital activities. Pathogenic qi is opposite to healthy qi, it is a collective term for all pathogenic factors. Upper Jiao pattern is characterized by fever, sweating, coughing and panting. Unconsciousness and delirium may also be present. Wei-defensive Q is opposite to the Ying-nutrient qi. It travels outside the vessels and is transformed from the nutrients of water and food. It is worth noting that there is no name of “narcolepsy” in TCM, but modern physicians classify it into traditional pattern syndromes such as “excessive sleep,” “lethargy,” “vertigo,” and “epilepsy.”

Pattern Syndrome is a pathological summarization of the disease location, nature, severity, and prognosis in a certain stage. Five zang organs is a collective term for the 5 internal organs—the heart, liver, spleen/pancreas, lung, and kidney. Treatment based on pattern identification is the whole process of applying theories, principles, prescriptions, and medicines to clinical treatment. Pattern differentiation aims to analyze the signs and symptoms collected by the 4 examination methods according to the fundamental theories of the 8 principles, zang-fu organs, etiology, and pathogenesis.

Treatment refers to specific therapeutic methods directed at the differentiated pattern, and has not yet formed a unified understanding of the etiology and pathogenesis of this disease, but modern physicians have combined the research progress of Western medicine. Professor Wang Xuefeng holds that the basic pathogenesis of this disease is Yang deficiency with yin excess, disharmony between yin and yang, and that the main cause of this disease is dampness blocking Wei-defensive yang pattern. [ 7 ] In the view of TCM, Yin-yang is a concept defined as the opposing but complementary qualities of interrelated entities/phenomena in the natural world. Yang deficiency with yin excess is a mutual restraint between yin and Yang maintaining the relative Yin-Yang equilibrium. The failure of yang to restrain yin may cause relative yin excess. Damp phlegm pattern is characterized by cough with easy expectoration of profuse, sticky phlegm, limb heaviness, dizziness, tinnitus, chest stuffiness, and tightness, low food intake, greasy taste and foreign body sensation in the throat. Often results from the internal buildup of phlegm dampness. Dampness blocking Wei-defensive Yang pattern is characterized by fever, aversion to cold, mild sweating, headache, lassitude, chest tightness, poor appetite, and absence of thirst. The tongue coating is thin, white, or greasy. The pulse is delayed. This pattern often occurs when dampness blocks the flow of Wei-defensive qi.

Qiu Changlin believed that the basic pathogenesis of this disease is Spleen qi deficiency pattern. In TCM’s perspective, spleen system is a functional system composed of the spleen, stomach, muscle, lips, mouth, and spleen meridian. Spleen qi means that qi stored in the spleen. It is the driving force of the physiological activity of the spleen. Spleen qi deficiency pattern is characterized by low food intake, abdominal distension that aggravates after eating food, loose stools, and lassitude. The tongue is pale with a white coating. The pulse is slack and weak. The spleen governs transportation and transformation, and ascends the nutrients, and the emotion of the spleen is overthinking. Deficiency of spleen qi leads to weakness in transportation and transformation, and the spleen ascends the spleen ascends the nutrients.

If the spleen ascends the nutrients cannot ascend, the phlegm will stop gathering, which will hinder the middle jiao and brain. Deficiency of spleen qi affects the mind, and excessive thinking affects the mind, resulting in deficiency of the heart and spleen pattern. Deficiency of the heart and spleen pattern leads to lassitude and thinking of lying down, lying down without getting up, sleeping and dreaminess. [ 8 ] It should be noted that the middle jiao pattern is characterized by fever, thirst, abdominal fullness, and constipation. Alternatively, subjective feverish sensation without elevated temperature, nausea, vomiting, stomach stuffiness, and loose stools. Often occurs when pathogenic warm heat affects the spleen and stomach and transforms into dryness or dampness. The spleen ascends the nutrients, means that the spleen qi ascends and distributes nutrients to the heart and lungs, and maintains the normal position of the internal organs. Deficiency of the heart and spleen pattern is characterized by palpitations, lassitude, low food intake, abdominal distension, and loose stools. The tongue is pale. The pulse is weak. This pattern often occurs when heart, blood, and spleen (yang) qi become deficient.

In addition, Zheng Zhongqi [ 9 ] believed that the pathogenesis of this disease was the disadvantage of Shaoyang Cardinal. Shaoyang pattern is characterized by a bitter mouth, dry throat, dizziness, blurred vision, fever alternating with aversion to cold, fullness in the chest and subcostal region, no desire to eat or drink, restlessness, and vomiting. The pulse is wiry. This pattern often occurs when pathogenic factors affect the qi flow of Shaoyang meridians.

Zhang Hongbin believes that this disease is kidney essence deficiency pattern. [ 9 ] But all of which are the various visions of various physicians. Kidney system is a functional system composed of the kidney, urinary bladder, bones, hair, ears, urethra, anus, and kidney meridian. The kidney stores and secures the essence of the human body. Means that all tangible nutrients of the human body. Of essence. It can also specifically refer to the kidney essence. Kidney essence deficiency pattern is characterized by delayed growth in children, decreased reproductive function, premature aging, tinnitus, hair loss, loose teeth, and poor memory. This pattern often results from kidney essence deficiency. Marrow is an extraordinary organ. A collective term for brain marrow, spinal cord, and bone marrow. Marrow is transformed from kidney essence. Kidney marrow deficiency pattern is characterized by delayed growth and development. Delayed healing of bone fractures, low back/knee soreness and weakness, dizziness, tinnitus, poor memory, and dementia. This pattern often results from kidney essence/marrow deficiency.

However, after careful exploration, it can be considered that the deficiency pattern in essence and the excess pattern on the surface. Excess pattern is characterized by high fever, thirst, chest tightness, panting, rapid breathing, phlegm sounds in the throat, restlessness, delirium, abdominal distension/pain/tenderness, and scanty, dark-yellow urine or hesitant, painful urination. The tongue is rough with a dry, yellow coating. The pulse is replete and forceful. Contributing factors may include 6 pathogenic factors, parasites, or dysfunction of the zang–fu organs (subsequent food stagnation, retention of phlegm/fluid/water/dampness, and blood stasis). Deficiency pattern: it is characterized by general weakness, a weak pulse, and abdominal softness. Often results from insufficiency of qi, yin, yang, or blood. Therefore, under the guidance of this principle, this article explores the possibility of treating this disease by the combined use of TCM and Western medicine based on the neurobiological mechanism of Western medicine.

1.2. Neurobiological basis

1.2.1. the function of or’exin neurons..

Orexin neurons regulate many functions, chief among them the physiological functions of stabilizing wakefulness and coordinating rapid eye movement (REM) sleep. [ 10 ] In rodents, orexin neurons are active during wakefulness, especially during increased exercise or motivated behavior; in contrast, these neurons were relatively inactive during quiet wakefulness, as well as during sleep. According to related studies, intracerebroventricular injection of orexin A or orexin agonists in rodents can promote wakefulness and strongly inhibit REM sleep for several hours. [ 11 ] This is most likely done by stimulating neurons in the basal forebrain and monoaminergic nuclei to promote arousal and inhibit REM sleep. In the transition to sleep, GABAergic neurons in the lateral preoptic area and median preoptic area may inhibit orexin neurons and many other wakefulness-promoting neurons, enabling animals to maintain sleep. [ 12 ]

How Orexin a produces such a long arousal period is unknown, and little is known about orexin neurons in humans, but orexin A may be present in the extracellular space for a long time, while orexin B may have a short half-life. [ 13 ] Orexin peptide may automatically activate orexin neurons via OX2R. Therefore, once these cells fire, they may remain active for a long time, contributing to long-term maintenance of wakefulness. [ 14 ] However, this view of automatic firing is controversial, as some researchers have reported that orexin neurons do not express the orexin receptor. [ 14 ] At present, little is known about the firing pattern of orexin neurons, and more long-term recordings are needed. [ 15 ] It should be noted that the conditions triggering orexin release are not clear, and the high frequency firing of orexin neurons may trigger the release of orexin from dense core vesicles. [ 13 , 14 ] In addition, as with other spontaneously released neuropeptides, some basal levels of orexin tone may be present all time; in support of this, orexin receptor antagonists promote sleep in humans even at night, when orexin neurons might be expected to be inactive. [ 16 ]

1.2.2. Impact of orexin loss.

1.2.2.1. poor ability to stay awake..

Almost all patients with narcolepsy feel sleepy during the day and are prone to transition to Non-REM sleep. [ 17 ] However, the drowsiness of most patients can be relieved after waking up in the morning or taking a nap, indicating that the symptoms are recoverable. But drowsiness returned after just an hour or two, indicating that the system that maintains wakefulness is dysfunctional. When immobilized or encouraged to sleep, narcoleptics can fall asleep very quickly. [ 18 ] Patients were instructed to attempt sleep every 2 hours on a multiple small sleep latency test (Multiple Sleep Latency Test). On average, narcoleptics fall asleep in less than 8 minutes out of 5 20-minute sleep opportunities, and they tend to take only 1 to 2 minutes, while people without narcoleptics usually take 10 to 20 minutes. [ 19 ] Moreover according to related experiments, due to the frequent and rapid transition to non-REM, the awake time in orexin-null mice and mice lacking orexin neurons was only half that of the control group. [ 20 ]

1.2.3. REM sleep is poorly regulated.

Orexin neurons inhibit REM sleep, and patients with narcolepsy exhibit dysregulation of REM sleep as manifested by poor circadian rhythm of REM sleep, rapid transition to REM sleep and disruption of REM physiology. Normally, REM sleep occurs only during typical sleep hours, but because of the loss of the orexin signal, REM sleep can occur at any time of day. [ 21 ] In fact, this pattern is central to the diagnosis of narcolepsy. In Multiple Sleep Latency Test, narcoleptics typically enter REM sleep during 2 or more of their 5 daytime naps, whereas healthy people rarely enter REM sleep during the day. [ 22 ] In fact, REM sleep is usually preceded by at least 60 minutes of non-REM sleep at night, but in NT1, REM sleep often occurs within a few minutes of sleep onset. [ 23 ]

Mechanistically, the tendency of narcolepsy to enter REM sleep during the day may be due to uncontrolled circadian rhythms or inhibition of REM sleep. [ 10 ] REM sleep exhibits a strong circadian rhythm. It is normally inhibited during the active phase by circadian signals transmitted from the suprachiasmatic nucleus to the dorsomedial hypothalamic nucleus (Dorsomedial Hypothalamic Nucleus, DMH). [ 24 ] According to related studies, DMH neurons send signals to orexin neurons, and the absence of orexin neurons in mice reduces the amplitude of circadian sleep rhythm by half. [ 25 ] These results suggest that orexin neurons, together with additional projections from the DMH, contribute to the suppression of REM sleep [ 19 ] during the active phase.

1.2.4. Evidence of autoimmune mechanisms.

Narcolepsy is caused by the selective destruction of orexin-producing neurons, so what kills orexin-producing neurons remains a major mystery. However, according to the latest research, there is a lot of evidence that NT1 is an autoimmune disease mediated by T cells. [ 26 ] T cells can be divided into 2 categories, CD4 + helper T cells secrete cytokines to regulate or assist the active immune response. While CD8 + killer T cells use cytotoxic particles to lyse their target cells. Both reactive types of T cells are triggered through T cell receptors (TCRs) that recognize small, processed peptides presented to them by major histocompatibility complex (Major Histocompatibility Complex, MHC) molecules on antigen presenting cells; peptide fragments that bind to MHC molecules are called MHC-peptide complexes. CD4 + T cells recognize antigens [ 26 ] that bind to MHC class II molecules on the surface of antigen-presenting cells. While CD8 + T cells respond to antigens presented by MHC class I molecules, which are expressed on all nuclear cells but rarely in neurons. [ 27 ]

1.2.5. MHC class II alleles and susceptibility to narcolepsy.

human leukocyte antigen (HLA) alleles strongly influence the development of narcolepsy. More than 90% of NT1 patients carry HLA class II alleles DQB1*06:02, [ 28 , 29 ] and crystal structure modeling shows that a fragment of the pre-orexin protein closely matches the binding groove of DQB1*06:02. [ 30 ] The DQB1*06:02 allele confers a 200-fold increased risk of NT1, [ 31 ] a known association of HLA with any disease-NT1 rarely occurs in people who lack this allele. Homologues of this allele have twice the risk of NT1 compared with heterogenors. [ 32 ] The HLA allele DQAI*01:02 is in strong linkage disequilibrium with DQBI*06:02 and carries a similar risk. [ 33 ] DPBI*05:01 also increases the risk of NT1, although the results have a smaller impact. [ 34 ] In contrast, some other class II alleles had the greatest effect on narcolepsy risk, but 2 studies showed a small and independent effect of class I alleles. [ 35 ]

1.2.6. Orexin neurons may be killed by t cells.

In addition to the above genetic evidence involving the MHC class II DQBI*06:02 allele, a specific polymorphism at the locus encoding the TCR alpha chain [ 36 ] was included. Other evidence suggests that a T cell-mediated immune mechanism destroys orexin neurons in NT1 and that CD4 + cells are critical. It is important to note that CD4 + T cells may not directly destroy orexin neurons, [ 37 ] but they can release cytokines that stimulate the attack on orexin neurons by CD8 + cells, macrophages, and natural killer cells. Using a transgenic mouse model in which orexin neurons express hemagglutinin and T cells possess a hemagglutinin-specific TCR, a research team showed that CD8 + cells are capable of destroying orexin neurons. [ 38 ] However, the primary attack of CD8 + cells on orexin neurons cannot occur in NT1 because MHC class I molecules involved in CD8 + cell activation are rarely expressed in humans except during early development and after exposure to interferon-gamma. [ 39 ]

1.3. TCM treatment based on neurobiological mechanism

As mentioned above, according to the current Western medicine research, the occurrence of narcolepsy has a relatively clear link with the loss of orexin neurons, and according to the progress of TCM research, the basic pathogenesis of this disease is deficiency in origin and excess in superficiality, Yang deficiency and Yin excess. At this level, the research of Chinese and Western medicine can refer to each other and combine with each other. Therefore, the treatment of narcolepsy based on neurobiological mechanisms combined with TCM syndrome differentiation is feasible and worthy of study.

1.4. Progress of TCM research on narcolepsy

Although the basic pathogenesis is clear, the etiology and pathogenesis of narcolepsy are relatively complex, and there are relatively few studies on TCM. So far, the cognition of the etiology, pathogenesis, and syndrome types of narcolepsy has not been able to form a relatively unified cognition. [ 40 ] Professor ZHang Lei [ 41 ] divided the disease into 5 syndromes: Yang deficiency and mental stagnation, liver wind with phlegm, intertwined phlegm-blood stasis pattern, and deficiency of the spleen and kidney pattern. Professor ZHENG Zhongqi [ 42 ] divided narcolepsy into 3 stages: deficiency of the liver and kidney pattern in the early stage, damp heat in the spleen and stomach pattern in the middle stage, and disharmony between the Ying nutrients and Wei-defence pattern in the late stage. Professor Wang Xuefeng [ 43 ] treats narcolepsy from lung and spleen. In addition, Professor Qiu Changlin [ 8 ] treated narcolepsy from spleen deficiency, and divided the disease into spleen deficiency with phlegm dampness pattern, Kidney yang deficiency pattern, kidney essence deficiency pattern and blood stasis due to qi stagnation. It is gratifying that increasingly TCM research teams have begun to break through the limitations of personal experience and use modern science and technology to study this disease systematically and normatively.

Most of the TCM syndrome types divided by the above TCM experts are less important in this article. Due to the limited space of this article, if the above TCM syndrome types have little to do with the article, they will not be discussed. Consult the literature and the WHO international standard terminology on TCM.

Treatment of narcolepsy is based on syndrome differentiation of TCM (Tables ​ (Tables1 1 and ​ and2 2 ).

Frequency distribution of traditional Chinese medicine.

Frequency distribution of traditional acupoints.

The basic ways of TCM therapy of the disease are decoction, acupuncture, and massage, and the first 2 are the most important.

So far, there is no unified cognition of syndrome differentiation and typing of this disease, so this paper discusses the treatment of this disease based on syndrome differentiation and treatment according to the classification of syndrome elements and pathogenic factors on the basis of summing up the experience of predecessors. Lang Yi et al [ 44 , 45 ] searched all the journals in China Journal Full-text Database (1979–2017) and Wanfang Database (1990–2017), standardized the narcolepsy syndromes that met the requirements, extracted the syndrome elements, and studied the narcolepsy syndromes and syndrome elements based on the literature. It can provide a reference and basis for further determining the standard of TCM syndrome differentiation and classification of narcolepsy.

1.5. Deficiency syndrome

Deficiency in origin and excess in superficiality is the basic pathogenesis of this disease, so deficiency syndrome is also an important syndrome type of this disease, and the deficiency of this disease is different types such as kidney yang deficiency pattern, kidney essence deficiency pattern, deficiency of the spleen and lung pattern, and deficiency of the spleen and kidney pattern. Kidney Yang deficiency pattern is characterized by cold intolerance. Cold limbs (especially below the lower back and knee joints), a bright, pale or dark complexion, profuse, clear urine, and frequent urination at night. The tongue is pale. The pulse is weak. This pattern often occurs when kidney yang fails to warm the body. The syndrome of kidney deficiency and marrow deficiency has been discussed above. Lung system is a functional system composed of the lung, large intestine, skin, body, hair, nose, and lung meridian. Deficiency of the spleen and lung pattern is characterized by low-pitched cough with thin, clear sputum, shortness of breath, panting, low food intake, abdominal bloating, and loose stools. The tongue is pale with a white, slippery coating. The pulse is weak. This pattern often results from qi deficiency of the lung and spleen. Deficiency of the spleen and kidney pattern is characterized by low food intake, abdominal bloating, loose stools, low back soreness/pain, and tinnitus. This pattern often occurs as a result of deficiency of the spleen and kidney.

It should be noted that these syndromes are not distinct from each other, but often influence and interact with each other. Professor Zhang Lei [ 41 ] is good at treating kidney yang deficiency pattern with Cinnamon branch and cinnamon soup (cassia twig, Chinese herbaceous peony, glycyrrhiza, ginger, and jujube) and Ephedra asarum aconite soup (ephedra, herba asari, and monkshood). Decoction of Rehmanniae (prepared rehmannia root, morinda officinalis how, dogwood, dendrobe, cistanche, monkshood, fructus schizandrae, cassia twig, poria, dwarf lilyturf root, acorus tatarinowii and polygala amflra) and Sijunzi Decoction (ginseng, poria, atractylodes macrocephala koidz and liquorice) were used to treat deficiency of the spleen and kidney pattern. Professor Qiu Changlin [ 41 ] advocated that Poria & Cassia Combo Decoction should be used to treat kidney yang deficiency pattern and Dihuang Yinzi should be used to treat kidney essence deficiency pattern. Feng Fan, et al [ 46 ] created Xingshuian Prescription, which used Agrimonia Pilosa, Ephedra, Morinda officinalis, Zanthoxylum bungeanum, Chaenomeles sinensis, Curcuma aromatica and Calculus Bovis in order to tonify deficiency and strengthen, refresh and induce resuscitation. 46 patients with narcolepsy were treated with 1 dose per day. The short-term efficacy was evaluated after 6 months of treatment, and the long-term efficacy was evaluated after 6 months of withdrawal. The effective rate of symptoms after treatment was observed. The results showed that the total effective rate was 95.7%. The total effective rate was 80.4%. After treatment, the number of cases with various symptoms was reduced, and the effective rate was more than 60.0%. It is concluded that the treatment of narcolepsy with Xingshuian Prescription can significantly improve the clinical signs and symptoms and has a good effect. Professor Wang Shaojie [ 47 ] created a prescription for early administration, which was composed of Radix Astragali, Radix Pseudostellariae, Herba Ephedrae, Fructus Evodiae, Rhizoma Chuanxiong, Flos Magnoliae, Fructus Aurantii Immaturus, Rhizoma Atractylodis Macrocephalae, Poria and Radix Glycyrrhizae in order to Regulate qi and strengthen the spleen.

1.6. Qi stagnation pattern

Liver is a functional system composed of the liver, gallbladder, tendons, nails, and liver meridian. Qi stagnation pattern is characterized by migratory distension. Fullness and pain in the subcostal region and abdomen that alleviate after sighing, belching, bowel sounds, and flatus. The pulse is wiry. Often results from qi stagnation of the zang–fu organs or in the localized area.

Emotional discomfort and internal injury of the 7 emotions cause the Liver qi stagnation pattern, and cause Liver qi stagnation transforming into a fire pattern. Liver fire is generated in the middle, causing disharmony between the Ying-nutrients and Wei-defence, and causing stagnation in the upper part of the brain, resulting in drowsiness and excessive sleep. “Sheng Ji Zong Lu” [ 48 ] records: “The liver and gallbladder are both solid, and Ying-nutrients and Wei-defence are blocked, then the pure one is turbid and disturbed, so he often sleeps and lies. Professor Wang Xuefeng [ 49 ] is good at treating narcolepsy of the liver and regards “Spleen deficiency with qi stagnation pattern, and disharmony between the liver and spleen pattern" as the main pathological mechanism of the disease. She likes to use Radix Bupleuri, Radix Astragali, poria cocos, Rhizoma Atractylodis Macrocephalae, Rhizoma Dioscoreae, Radix Panacis Quinquefolii, Jiao Sanxian, Radix Curcumae, Albizzia julibrissin, Rhizoma Acori Tatarinowii. Professor Zheng Zhongqi, [ 50 ] based on the 6 meridians syndrome differentiation of Shaoyang syndrome, considered that the disease was due to the stagnation of Shaoyang and the dysfunction of the cardinal, and used Xiaochaihu Decoction (Radix Bupleuri, Rhizoma Pinelliae, Radix Ginseng, Radix Glycyrrhizae, Rhizoma Zingiberis Recens and Fructus Jujubae) to reconcile Shaoyang, and soothe the liver and promote bile flow.

1.7. Wind syndrome

“Plain Questions” [ 51 ] records: “Wind, good deeds and several changes.” Pathogenic wind is a pathogenic factor characterized by opening the skin pores, high mobility, and upward/outward movement. Paroxysmal sleep occurs suddenly, falls asleep, quickly wakes up as usual, and soon returns to sleepiness. It occurs frequently during the day, and there is no fixed number. The characteristics of this disease are similar to those of pathogenic wind. If emotional stimulation causes hyperactivity of the liver yang pattern and disturbs the spirit, it will occur during lethargy. Hyperactivity of liver yang pattern is characterized by dizziness of hyperactivity of liver Yang pattern, blurred vision, tinnitus, lower back pain, limb numbness, feverish sensations in the palms, soles and chest, flushed cheeks, restlessness, irritability, and a dry and bitter mouth. The tongue is red with a scanty coating. The pulse is thready and rapid. This pattern often occurs when liver yin fails to control liver yang. Qinggan Xingshen Decoction was prepared by Professor Zhang Lei. [ 41 ] Cornu Saigae Tataricae, Ramulus Uncariae Cum Uncis, Scorpio, Radix Scutellariae, Lapis Chloriti, Rhizoma Pinelliae Preparata, Poria, Pericarpium Citri Reticulatae, Caulis Bambusae In Taenia, Fructus Aurantii Immaturus Preparata, and Radix Glycyrrhizae are used in the prescription to Soothe the liver and extinguish wind, then clear heat and transform phlegm. Professor Wang Shaojie [ 47 ] treated the disease according to the theory of epilepsy and applied Fit-settling Pill to the treatment of the disease, which was taken in the evening with Radix Polygoni Multiflori Preparata, Radix Polygalae, Fructus Alpiniae Oxyphyllae, Plumula Nelumbinis, Rhizoma Acori Tatarinowii, Cortex Albiziae, Semen Ziziphi Spinosae, Radix Curcumae, Spica Prunellae, Fructus Gardeniae, Poria.

1.8. Damp phlegm pattern

In the treatment of this disease, pathogenic wind and phlegm dampness are closely related. It is recorded in Yi Xue Cong Zhong Lu [ 52 ] : “When the wind is born, it will carry the potential of wood and overcome the earth, and the earth disease will gather fluid and form phlegm.” Wind phlegm enters the meridians pattern, and the failure of consciousness leads to sudden lying and rapid sleep. Professor Zhang Lei [ 41 ] considered that liver wind with phlegm was one of the syndromes of this disease, and the prescription was Qinggan Xingshen Decoction. Zhu Danxi [ 53 ] believed that “all diseases are caused by phlegm,” and Song Xianyuan [ 54 ] advocated the use of Raw Jujube Powder, which was made of raw jujube, Acorus gramineus and borneol, to Open the orifices and unblock impediments. Clinical observation of 18 patients with narcolepsy showed that 12 cases were significantly effective, 4 cases were effective, and 2 cases were ineffective. The total effective rate was 88.9%. The curative effect is quite good. Professor Qiu Changlin [ 8 ] treated Phlegm dampness accumulating in the spleen pattern with Fragrant sand, 6 gentleman soup, and Shenlingbaizhu Powder based on this theory, strengthening the spleen and transform the dampness, inducing resuscitation and restoring consciousness.

1.9. Blood stasis syndrome

It is recorded in Plain Question “The heart is the ruler’s official, and the spirit comes from it.” [ 55 ] The heart governs the blood and vessels, and the heart governs the bright spirit. If Seven emotions cause internal damage, it will lead to liver qi stagnation pattern. Qi stagnation leads to blood stasis. Blood stasis due to qi stagnation leads to obstruction of the heart vessels. Heart vessel stasis pattern leads to loss of disquieted heart, spirit pattern, dizziness, headache, drowsiness, and insomnia. Heart system is a functional system composed of the heart, small intestine, blood vessels, face, tongue, and heart meridian. The view of TCM is: Blood is a red liquid that circulates within the blood vessels to moisten and nourish the body. It is an essential substance to maintain life activities. Blood stasis is a pathological state of slow, coagulated or stagnant circulation of blood.

Wang Qingren’s famous prescriptions, Tongqiao Huoxue Decoction and Xuefu Zhuyu Decoction, [ 56 ] should be used to treat this disease. Modern physicians have also made innovations on this basis. Cui yuanwu [ 57 ] modified Xuefu Zhuyu Decoction (Radix Rehmanniae, Semen Persicae, Flos Carthami, Fructus Aurantii, Radix Bupleuri, Rhizoma Chuanxiong, Radix Platycodonis, Radix Cyathulae, Radix Angelicae Sinensis, Radix Glycyrrhizae Preparata, Cortex Lycii, Radix Paeoniae Alba) to treat this disease. Qiu Changlin [ 8 ] used Zhenwu Decoction and Xuefu Zhuyu Decoction to treat narcolepsy. He liked to use Radix Aconiti Lateralis Preparata, Rhizoma Atractylodis Macrocephalae, Rhizoma Zingiberis, Ramulus Cinnamomi, Rhizoma Chuanxiong, Fructus Aurantii, Radix Angelicae Sinensis, Flos Carthami, Radix Polygalae, and Rhizoma Acori Tatarinowii. Chen Jinghe [ 58 ] used Taoren Siwu Decoction (Semen Persicae, Flos Carthami, Radix Rehmanniae, Radix Paeoniae Alba, Radix Angelicae Sinensis, and Rhizoma Chuanxiong) as the main prescription for treating systemic diseases, and proposed fifteen methods for promoting blood circulation and removing blood stasis based on syndrome differentiation and treatment.

Treatment based on pattern identification of Acupuncture and Moxibustion in TCM.

According to relevant studies, acupuncture and moxibustion treatment of narcolepsy [ 59 ] can activate the excitability of the cerebral cortex, while reducing the adverse reactions of drug treatment, combined with TCM decoction treatment, quick effect, good curative effect, can play a “simple and inexpensive” therapeutic effect.

According to the related research, the acupoint selection rule of acupuncture and moxibustion for narcolepsy, [ 60 ] the most frequently used acupoint is Baihui, and the acupoints for this disease are mostly distributed in the head, face, neck and neck. Li Shizhen’s “Compendium of Materia Medica · Magnolia · Invention” [ 61 ] says that “the brain is the house of the primordial spirit,” and acupuncture at the acupoints on the top of the head embodies the principle of “where the acupoints are, where the indications are.” Baihui is the meeting point of Yang. Acupuncture at this point can connect yin and Yang veins, run through the meridians and acupoints of the whole body, regulate the body, and achieve the state of Yin and Yang. The occurrence frequency of Neiguan is second only to Baihui. Neiguan belongs to the Pericardium Meridian of Hand-Jueyin and is a collateral point, which passes through the Yin and Wei Meridians and has the effects of calming the heart and tranquilizing the mind, regulating qi and relieving pain. Dacheng of Acupuncture and Moxibustion [ 62 ] says: “At the junction of Jueyin” leads the way to Yin and Yang, open and block. Neiguan can harmonize Yin and Yang, calm the heart and tranquilize the mind, and make Yang come out from Yin, so that patients can get rid of lethargy and drowsiness, wake up and open the mind, and treat narcolepsy.

In the analysis of the frequency of using meridians, [ 60 ] the frequency of using meridians from high to low was Governor Vessel, Bladder Meridian, Gallbladder Meridian, Stomach Meridian, and Spleen Meridian. The Governor Vessel is known as the “Sea of Yang Meridians,” which commands the Yang of the whole body and stimulates the Yang Qi of the whole body. The Classic of Difficulties: Twenty-eight Difficulties [ 63 ] says: “The Governor Vessel starts” It belongs to the brain. The governor vessel ascends into the brain. When the governor vessel is full of qi and blood, it ascends into the brain. When the sea of marrow is full, the mind is clear. Bladder meridian, gallbladder meridian, and stomach meridian are all Yang meridians, which cooperate with the governor vessel to regulate and control Yang qi in the body, to achieve the effects of stimulating Yang qi, stimulating the mind, awakening the mind and inducing resuscitation, and dispelling restlessness and tiredness.

Professor Zhuang Lixing [ 64 ] used acupuncture combined with medicine to treat narcolepsy. The main points were Sishenzhen, Shenting, Yintang, and Suliao, and the auxiliary points were Neiguan and Sanyinjiao. Radix Codonopsis, Poria, Rhizoma Atractylodis Macrocephalae, Radix Glycyrrhizae Preparata, Rhizoma Acori Tatarinowii, Radix Curcumae, Herba Menthae (added later), Radix Bupleuri, and Radix Astragali are used as TCMs. Zhao Yin [ 65 ] and Ye Chenlin [ 66 ] also advocated the combination of acupuncture and medicine for the treatment of this disease.

In addition, Zheng Hong et al [ 67 ] Collected 32 patients with this disease by using the needling method of harmonizing Ying and Wei, with Shenmai and Zhaohai as the main points and Baihui, Sishencong, Fengchi, Shenmen, Shenting and Benshen as the matching points, and the total effective rate of treating this disease reached 87.5%. Ma Lixin et al [ 68 ] selected Shenmai, Zhaohai, Baihui and Sanyinjiao by using the acupuncture method of tonifying Shenmai and purging Zhaohai. Regulating channels and collaterals, harmonizing Yin and Yang, stimulating Yang qi, refreshing, and inducing resuscitation, and treating the disease; Ci Qinren et al [ 69 ] used filiform needle to prick Fengchi, Fengfu and Tianzhu first, then the purgative method was used to prick Shuigou and Yintang horizontally, and finally needling Neiguan and Shangxing to penetrate Baihui, in order to lift Yang Qi, restore consciousness and open orifices, and cured 18 patients with narcolepsy.

1.10. Massage and other treatment methods

In addition to acupuncture and medicine, there are massage, ear acupuncture, and other methods to treat the disease. [ 40 ] However, due to their own limitations, these treatments are difficult to be used as the main treatment, more as an adjuvant treatment, combined with acupuncture and medicine, to treat narcolepsy. Ear acupuncture is a therapeutic method to stimulate points on the ear with an acupuncture needle.

Song Li [ 70 ] and others mainly used massage techniques to instruct patients to lie on the right side, start from Changqiang point, pinch up the skin and subcutaneous tissue, push along the Governor Vessel to Baihui point, then push from Zhibian point to Tianzhu point along the Bladder Meridian, and from Yangbai point to Jianjing point along the Gallbladder Meridian, then release the soft tissue along both scapulae, lateral waist and sacrum with heavy manipulation of levator muscle and shaking separation, combined with electroacupuncture. 32 patients were treated and the effective rate was 93.7%.

Zhu Huiming et al [ 71 ] treated 32 cases of narcolepsy with electroacupuncture combined with auricular point sticking, and the total effective rate was 85%. Ma Songtao [ 72 ] also treated the disease with auricular point sticking alone.

2. Discussion

In recent years, the research on narcolepsy in TCM and western medicine has made rapid progress and achieved gratifying results, such as the study of T cells. Although many achievements have been made, the pathogenesis of this disease in Western medicine has not yet been fully understood. At present, it is clear that the pathogenesis of NT1 is due to the severe loss of orexin neurons, and the CSF orexin level of this disease is very low or almost undetectable. However, the neurobiological mechanism of NT2 is not yet fully understood, and 90% of NT2 patients have normal or exin levels. NT2 affects up to half of narcoleptics, but unfortunately little is known about it.

TCM research on this disease started late, but under the guiding ideology of TCM holistic concept and syndrome differentiation and treatment, it has also made considerable progress by drawing on the valuable experience of ancient masters. However, there are still many problems in the study of this disease in TCM.

Through the collation of narcolepsy syndrome literature, it is found that there are still many problems in the study of TCM syndrome of narcolepsy. Because narcolepsy is a rare disease, the sample size is limited, most of the literature is small sample research, the syndrome type is single, which limits the quality of research, and still needs a larger sample size of high-quality syndrome research. Moreover, most of the literatures lack the description of syndrome differentiation standards, and most of them have no standards or self-made standards, and the disunity of syndrome differentiation standards also limits the reliability of research conclusions. Even though some studies have adopted clear and recognized criteria for syndrome differentiation, such as national standards, diagnostics of TCM, etc., because the above criteria are the criteria for syndrome differentiation of the whole disease domain, the 4 core symptoms of narcolepsy, namely, paroxysmal somnolence, sudden onset, sleep paralysis and hallucination, are not included in the criteria of syndrome differentiation, and only the peripheral symptoms are used as the basis for syndrome differentiation. It is easy to cause bias in syndrome differentiation. The establishment of standardized syndrome diagnostic criteria for narcolepsy is the premise and basis for in-depth study of TCM and multicenter collaborative research of this disease. This study initially reflects the distribution law of narcolepsy syndromes and syndrome elements, which can provide a reference and basis for further determining the TCM syndrome differentiation criteria of narcolepsy.

Because of the above reasons, the author of this article has to admit with regret that there are few high-quality randomized controlled trials and meta-analysis studies of narcolepsy in China and even in the world, which is one of the unsolved problems in the field of TCM so far, and this is also one of the purposes of writing this review, in order to inspire future researchers of TCM. In strict accordance with modern medical research design methods, a unified standard of TCM syndrome differentiation was formulated, to carry out high-quality randomized controlled trials and Meta-analysis studies.

Therefore, about this disease, Chinese medicine itself has advantages, can be combined with the frontier progress of Western medicine, forming TCM therapy the unique curative effect of narcolepsy, Western medicine for the pathogenesis of this disease is not yet clear, Chinese medicine can start from itself, form a diagnosis and treatment model with Chinese characteristics, combined use of TCM and Western medicine, treatment of narcolepsy.

It is believed that, with the continuous advancement of narcolepsy research, Chinese medicine will make increasingly progress, achieve increasingly gratifying success, and continue to contribute to the development of Chinese medicine.

In addition, because this article is a traditional literature review, on the one hand, based on the analysis of the literature that may include research results, the literature review article can cover a wide range of topics with different levels of completeness and comprehensiveness. But it must therefore be a very broad description. The literature review reviews the published literature, which means that the material included has some degree of permanence and has been through the peer review process. The literature review approach was designed to identify work and research that had been done previously and to build on previous work, but the literature review therefore lacked a clear intent to expand or analyze the data collected. Any conclusions that the authors themselves may draw are subject to bias, as they may inadvertently leave out important parts of the literature or fail to question the validity of the statements made. Objectively speaking, the TCM research on narcolepsy is still in a relatively scarce stage, and the content of clinical research and basic research is less, which makes the author face greater challenges in the process of comprehensive summary, and this article is bound to have some shortcomings, which is beyond doubt. However, the author hopes that this article will inspire more TCM researchers to enter this field and contribute to the research of this discipline. Therefore, the author here makes the most sincere apology to all experts and readers, and hopes that we will do better in future research.

Author contributions

Conceptualization: Zhao Liu.

Data curation: Zhao Liu, Ruiqian Guan, Limin Pan.

Formal analysis: Zhao Liu.

Funding acquisition: Zhao Liu.

Investigation: Zhao Liu.

Methodology: Zhao Liu.

Project administration: Zhao Liu.

Resources: Zhao Liu.

Software: Zhao Liu.

Supervision: Zhao Liu.

Validation: Zhao Liu.

Visualization: Zhao Liu.

Writing – original draft: Zhao Liu.

Writing – review & editing: Zhao Liu.

Abbreviations:

The datasets generated during and/or analyzed during the current study are publicly available.

Heilongjiang Provincial Key R & D Plan (No.: GZ21C001); Traditional Chinese Medicine Research Project of Heilongjiang Province: ZYW2022-128 2.

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

The authors have no conflicts of interest to disclose.

How to cite this article: Liu Z, Guan R, Pan L. TCM syndrome differentiation and treatment of narcolepsy based on neurobiological mechanism: A review. Medicine 2022;101:49(e32025).