How to know if you have narcolepsy and what to do about it

Causes

Experts have not established the exact causes of narcolepsy, but it is known that this pathology occurs due to a lack of orexin (a brain neurotransmitter) responsible for wakefulness. The reason why orexin production decreases is unknown.

There are also a number of factors contributing to the development of narcolepsy:

• heredity;
• traumatic brain injuries;
• infections;
• hormonal changes;
• stress, strong feelings.

Prevention

To prevent the disease, patients are recommended to:

• maintain a nightly sleep schedule;
• exercise regularly;
• avoid emotional and physical overload;
• limit the consumption of coffee, strong tea, heavy foods;
• avoid taking medications that affect sleep quality;
• promptly treat sleep disorders.

This article is posted for educational purposes only and does not constitute scientific material or professional medical advice.

Treatment

It is impossible to completely get rid of narcolepsy, but properly selected medications and lifestyle modifications can improve sleep and wakefulness.

The following medications are prescribed:

• drugs to combat daytime sleepiness;
• sleeping pills to normalize night sleep;
• antidepressants to eliminate cataplexy and hallucinations;
• Patients with narcolepsy are advised to normalize their routine and strictly adhere to it (get up and go to bed at the same time).
• This disease imposes a number of restrictions: people with narcolepsy cannot drive a car or work in hazardous industries (at heights, with machines).

Narcolepsy causes a lot of discomfort, but with proper treatment the disease can be controlled. If symptoms of the disease appear, consult a medical neurologist.

Symptoms:

• severe drowsiness during the daytime;
• cataplexy - sudden loss of muscle strength;
• hallucinations;
• sleep paralysis;
• disturbances in the nocturnal phase of sleep;
• automatic behavior;
• blurred, double vision.

The first symptoms usually appear in a previously healthy person during adolescence or young adulthood and persist throughout life. Symptoms of narcolepsy may appear all at once or develop gradually over many years:

• Irresistible daytime sleepiness plus “forced” falling asleep that occurs at any time (reading a book, watching TV, during a conversation, driving a car). Such drowsiness occurs in a person after a night's sleep. Patients often describe feeling tired, apathetic, too lazy to do anything, and lacking energy. You can resist falling asleep only for a short time, but if a person falls asleep, it is easy to wake him up. The number of such attacks per day can vary greatly, with each of them usually lasting about an hour or less. When waking up, a person may feel rested, but may fall back asleep within a few minutes and remain asleep throughout the day. With such drowsiness, it is difficult for him to work, study, the person loses concentration and memory, loses motivation, and increases irritability.
• Complete disruption of night sleep (manifested mainly by very frequent awakenings, insomnia).
• Hallucinations are unreal, frightening, in most cases, visions or sensations of an often threatening nature when falling asleep and waking up.
• Cataplexy, i.e. sudden loss of muscle tone, usually accompanied by strong emotions such as laughter, rage or excitement, surprise. During attacks, which can last from a few seconds to half an hour, a person is unable to hold his head up and feels weakness in his arms and knees, which often leads to a fall.
• Sleep paralysis, i.e. a condition in which, upon waking up, a person quite adequately assesses the surrounding situation, but at the same time has absolutely no control over his body, he is unable to move or speak.
• Automatic behavior is the patient performing normal actions without realizing what he was doing. Sometimes a person may actually fall asleep and continue an activity, but not remember it after waking up. Automatic behavior can be a symptom of narcolepsy and is dangerous if the person performs potentially dangerous activities, such as driving or cooking.

People with narcolepsy often experience symptoms such as double vision, inability to concentrate, memory loss and headaches. Children with this disease usually lag behind their peers in physical development and learning. Adults may not be able to perform the daily responsibilities of work.

If you have any of the above symptoms of narcolepsy and believe that these symptoms are affecting your ability to drive, go to school, do normal daily work, or if these symptoms are affecting your social activities and personal relationships, then you should you need to contact specialists at the Center for Neurology and Sleep Medicine to confirm the diagnosis.

At the sleep center, a specialist will carefully analyze your medical history and conduct a complete physical examination. If the doctor suspects narcolepsy, you will be offered an examination. Two tests are usually performed to confirm the diagnosis and determine the severity of the disease: polysomnography with electroencephalogram (EEG) and multiple sleep latency test (MSLT test).

Narcolepsy: modern ideas about pathophysiology and treatment methods

The term “narcolepsy” was first introduced by JB Gelineau, describing in 1880 a pathological condition characterized by irresistible short-term sleep episodes repeated throughout the day. According to the International Classification of Sleep Disorders, Third Revision (2014), narcolepsy is divided into type 1 (with cataplexy) and type 2 (without cataplexy). Cataplexy, a typical symptom of the disease, occurs in 60–70% of patients with narcolepsy. The prevalence of the latter in the general population (excluding gender differences) is 0.02–0.06%. Modern treatment options allow a differentiated approach to different types of disease. The goal of all therapeutic approaches is to optimize the control of narcolepsy symptoms, improve the quality of life, and maintain the social and professional activity of patients.

Classification of narcolepsy by severity

Introduction

As a disease, narcolepsy was first described by the French physician JB Gelineau in 1880. Individual symptoms of the condition were mentioned by the English physician T. Willis back in 1672 [1], the Irish surgeon RJ Graves in 1851, and the German psychoneurologist C. Westphal in 1871. [2]. It was T. Willis who first characterized the state of sudden falling due to decreased skeletal muscle tone and falling asleep [3].

In 1926, the English doctor W. Adie identified the disease as an independent nosological unit. Until now, among the many causes of narcolepsy, the most ridiculous and curious ones have appeared. For example, it was believed that narcolepsy could be a manifestation of schizophrenia and a psychosomatic disorder, a clinical symptom of epilepsy, hysteria or encephalitis, a consequence of sexual behavior disorder in adolescence and an imbalance in the neurochemical balance in the brain, and the result of a viral infection [4].

Epidemiology and pathophysiology

In the general population, the prevalence of narcolepsy is 0.03–0.16%. However, in a number of countries this figure varies: in America – 0.5–1 per 1000 inhabitants [5], Japan – 1 per 600 people [6], Israel – 1 per 500 thousand [7]. There is no data on the prevalence of the disease in Russia.

In 50% of patients, the disease debuts at the age of 15 years. In some cases (less than 10%), an earlier onset occurs [8].

The main cause of clinical manifestations of narcolepsy (imperative drowsiness and cataplexy) is associated with a violation of the REM sleep phase triggering system. Normally, the sleep-wake system is stable and balanced. With narcolepsy, the balance is disrupted, and sharp transitions between sleep and wakefulness appear. Spontaneous falling asleep is accompanied by physiological changes, such as decreased muscle tone and dreams. Thus, daytime manifestations of the disease are realized, namely imperative drowsiness and attacks of cataplexy. When the stability of sleep maintenance is disrupted, clinical symptoms develop at night: fragmentation and unproductiveness of night sleep.

A decrease in muscle tone is a consequence of activation of glycinergic neurons in the caudal parts of the brain stem, GABAergic neurons in the preoptic area of ​​the anterior hypothalamus and inhibition of noradrenergic neurons in the locus coeruleus [9].

With the discovery in 1989 of the orexin neuron system, the main neurotransmitter of which is considered to be orexin, or hypothalamic secretin (hypocretin), ideas about the pathophysiology of narcolepsy have changed somewhat [10, 11]. Orexinergic neurons, as well as aminergic ones, are few in number (there are only 80 thousand in the human brain), but their axons interact with neurons in various parts of the brain that release the main mediators: acetylcholine, glutamate, brain amines [12]. At the same time, orexin neurons lack reciprocal connections with GABAergic neurons of the preoptic area of ​​the anterior hypothalamus and are external regulators in relation to the sleep-wake trigger mechanism [13].

The main property of the orexin system is the additional activation of the awakening noradrenergic systems of the brain. Thus, it stabilizes the state of the “sleep-wakefulness” system, preventing aminergic neurons from suddenly “silencing”. Orexin neurons themselves receive excitatory signals from areas of the brain associated with circadian rhythms.

Closely interacting with orexin neurons are neurons that secrete a peptide called melatonin-concentrating hormone. The maximum concentration of such neurons is observed in the lateral hypothalamus and the zona incerta of the subthalamic region, the reticular formation and the caudal part of the laterodorsal tegmentum of the pons. This system is reciprocal to the orexin system and is maximally active during REM sleep [14].

There are several known causes of narcolepsy: orexin ligand deficiency, degeneration of orexin neurons, overexpression of the artificially introduced ataxin 3 gene. The pathophysiological mechanism of narcolepsy is associated with orexin ligand deficiency and degeneration of orexin neurons. Rarely, narcolepsy is caused by a mutation in the preprohypocretin (orexin precursor) gene [15].

In the absence of orexin neurons in the brain or when their number decreases, smooth and cyclical transitions in the sleep-wake system are replaced by unexpected sharp transitions (flip-flops) from one state to another.

Blood tests of patients with narcolepsy show a decrease in orexin concentration of less than 0.5 pg/ml. At the same time, in healthy individuals in a state of wakefulness, this figure is 50 pg/ml. A decrease in the level of orexin A (hypocretin 1) in the cerebrospinal fluid to less than 110 pg/ml, also characteristic of narcolepsy, indicates orexin deficiency [16].

The HLA DQB1*06:02 gene serves as a specific marker for all ethnic groups and is found in 95% of patients with type 1 narcolepsy (with cataplexy). In patients with type 2 narcolepsy (without cataplexy), the DQB1*06:02 gene is detected in only 40% of cases. In children and residents of East Asia, a connection between the disease and the DQB1*06:02 and DQB1*03:01 genes of the human histocompatibility system has been established [17].

The results of individual studies indicate the autoimmune nature of the disease, demonstrating the development of narcolepsy after immunization, as well as previous streptococcal infection of the upper respiratory tract [18]. Thus, D. Oberle et al. assessed the occurrence of narcolepsy after seasonal and pandemic influenza vaccination. Researchers found a 3.9-fold (95% confidence interval 1.8–8.5) increase in the risk of narcolepsy after vaccination [19].

Clinical manifestations and diagnosis

According to the International Classification of Sleep Disorders, Third Revision (2014), narcolepsy type 1 (with cataplexy) and narcolepsy type 2 (without cataplexy) are distinguished [20].

There is another classification of the disease, presented in the Diagnostic and Statistical Manual of Mental Disorders - DSM-5, 2013:

• narcolepsy without cataplexy with hypocretin deficiency;
• narcolepsy with cataplexy without hypocretin deficiency;
• autosomal dominant cerebellar ataxia, deafness and narcolepsy;
• autosomal dominant narcolepsy, obesity and type 2 diabetes mellitus;
• secondary narcolepsy due to other diseases [21].

Electroencephalographic recording of narcolepsy attacks shows that such conditions are the result of a sudden onset of sleep (usually the REM stage) directly during wakefulness. Narcolepsy is characterized by paroxysmal pathological drowsiness and attacks of cataplexy (decreased muscle tone).

The disease usually begins with pathological drowsiness. Subsequently, attacks of cataplexy occur. The onset of the disease with cataplexy is extremely rare. No differences in the prevalence of the disease by gender have been established. As for familial cases of the development of narcolepsy, an increase in the risk of its development by 20–40 times is observed in the first degree of relationship of the proband with a patient with narcolepsy.

Pathological drowsiness is expressed in repeated (usually every two hours) episodes of falling asleep lasting 10–20 minutes. Drowsiness increases with the patient's passive participation in what is happening during lectures, watching films in the cinema, performances in the theater. The patient cannot influence such drowsiness, unlike drowsiness during apnea or parasomnias. Attacks of paroxysmal imperative drowsiness can catch him in the most inappropriate places or when performing certain actions (eating, walking, talking, etc.).

Cataplexy is usually a bilateral decrease in muscle tone due to emotional shock or excitement. In this case, the emotional factor initiating an attack of cataplexy is key. If the decrease in muscle tone of skeletal muscles is local in nature, we should talk about a focal manifestation of cataplexy. In a classic cataplexy attack, the patient falls. The duration of such an attack is usually from several seconds to several minutes. The degree of decrease in muscle tone varies - from mild (in the form of weakness in the neck muscles, accompanied by head nodding, sagging of the lower jaw, dysarthria) to complete loss of postural muscle tone followed by a fall.

Associated symptoms of the disease include sleep paralysis, hypnagogic, hypnopompic hallucinations, automatic behavior and disturbance of night sleep.

Hypnagogic (pre-sleep) or hypnopompic (post-sleep) hallucinations can include visual, tactile and auditory modalities. These conditions also accompany vegetative manifestations of fear.

Sleep paralysis is the inability to move or speak for a short period (one or more minutes). In most patients, sleep paralysis, especially when combined with hypnagogic or hypnopompic hallucinations, causes fear.

People with narcolepsy may complain of memory lapses and involuntary behavior. Rare symptoms include ptosis and double vision.

Almost all patients indicate sleep disturbance in the form of difficulty falling asleep, maintaining sleep and frequent awakenings at night. These symptoms may create the appearance of primacy of insomnia disorders when explaining the causes of pathological paroxysmal daytime sleepiness.

The main diagnostic methods for narcolepsy are instrumental: polysomnography, multiple sleep latency test (MSLT) and wakefulness maintenance test. Polysomnography allows us to exclude the secondary genesis of daytime hypersomnia. In this case, hypersomnia can be caused by sleep-dependent respiratory disorders, insomnia, and various forms of parasomnia. Actually, polysomnographic changes in narcolepsy are not specific.

Narcolepsy can be one of the clinical symptoms of degenerative, infectious diseases of the brain, hydrocephalus, multiple sclerosis, sarcoidosis, brain injury, multisystem degeneration, Parkinson's disease, etc. [22, 23].

The mandatory diagnostic criteria for narcolepsy include excessive sleepiness occurring almost daily for at least three months, and sudden bilateral loss of muscle tone that develops in response to intense emotions (cataplexy).

Optional diagnostic features include sleep paralysis, hypnagogic and hypnopompic hallucinations, automatic behavior, and nighttime sleep disturbance.

According to MTLS, sleep latency does not exceed eight minutes, two or more episodes of falling asleep begin with the REM sleep stage. According to a polysomnographic study, REM sleep latency does not exceed 15 minutes [20].

The severity of narcolepsy is assessed by the severity of sleepiness based on the Epworth scale [24] and the MTLS. The criteria are presented in the table.

There are acute periods of the disease (duration no more than six months), subacute (up to 12 months) and chronic (over 12 months).

The Wakefulness Maintenance Test is more often used to assess the effectiveness of therapy in relation to daytime sleepiness.

Treatment

The main goal of narcolepsy treatment is to maximize the patient’s quality of life. The therapeutic algorithm involves reducing daytime sleepiness, increasing the level of daytime wakefulness, and reducing the frequency of cataplexy attacks [25–27].

The presence of three leading symptoms of the disease: excessive drowsiness and sleep attacks, cataplexy, and nighttime sleep disturbance determines the choice of therapy [28].

First-line treatments for daytime sleepiness in adults with narcolepsy are modafinil and armodafinil, which consists only of the R-enantiomer of racemic modafinil. The effect of modafinil is realized by increasing the amount of dopamine in the striatum and nucleus accumbens, norepinephrine in the hypothalamus and ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex [29]. Modafinil at a dose of 200–400 mg/day reduces daytime sleepiness, increases average sleep latency and the ability to maintain wakefulness [30].

The first-line treatment for catalepsy includes sodium hydroxybutyrate, a metabolite of gamma-aminobutyric acid [31]. The addition of sodium hydroxybutyrate to modafinil is accompanied by a decrease in subjective and objective indicators of the severity of drowsiness compared to modafinil monotherapy [32].

Second-line drugs for the treatment of excessive daytime sleepiness in narcolepsy are methylphenidate and amphetamines (a combination of dextroamphetamine or amphetamine and dextroamphetamine or amphetamine sulfate).

Second-line drugs for the treatment of cataplexy, also effective for sleep paralysis and hypnagogic hallucinations, are selective serotonin reuptake inhibitors or tricyclic antidepressants. In particular, we are talking about selective serotonin reuptake inhibitors with an activating effect - fluoxetine 20–60 mg/day and similar drugs, venlafaxine 75–300 mg/day, imipramine 25–200 mg/day, clomipramine 25–200 mg/day . It is possible to use anticonvulsants, for example carbamazepine at a dose of 200–400 mg/day.

To relieve night sleep disturbances, hypnotics are also used - imidazopyridines at a dose of 5–10 mg/day, cyclopyrrolones at a dose of 7.5 mg/day. It is possible to use melatonin preparations at a dose of 2–3 mg/day.

In narcolepsy, behavioral therapy plays a special role, providing appropriate recommendations for the patient and aimed at reducing the severity of symptoms of the disease.

Unfortunately, existing treatment methods have a number of limitations (poor tolerability, complex dosage regimen, low efficiency, etc.), which requires the search for more effective drugs [33].

The last decade has been marked by the emergence of fundamentally new drugs that affect the main symptoms of the disease. This refers to both orexin (hypocretin) and neorexin (non-hypocretin) agents.

Non-hypocretin therapy drugs include:

• histamine receptor blockers – H3 antagonists (inverse agonists);
• monoaminergic reuptake inhibitors targeting specific neurotransmitters.

Pitolisant, an H3 receptor inverse agonist, received approval in the European Union in March 2021 for the treatment of adult patients with types 1 and 2 narcolepsy. The drug is started with a dose of 9 mg/day, then over the course of a week the dose is titrated to a maximum of 36 mg/day. In some cases, pitolisant is effective at a dose of 4.5 mg/day [34].

Several other H3 receptor antagonists are currently in clinical trials (BF2.649, PF-03654746, GSK189254, GSK239512, MK-0249, MK-3134, JNJ-17216498, and ABT-286). For example, the effect of the drug JZP-110, a selective dopamine/norepinephrine reuptake inhibitor, is aimed at reducing the severity of daytime sleepiness and increasing the level of daytime wakefulness [35]. Orexin treatment, gene therapy and immunotherapy are still in the experimental stage.

Conclusion

The emergence of new classes of drugs for the treatment of narcolepsy is intended to improve the quality of life of patients. Pharmacology continues to evolve. And it is possible that in the near future fundamentally new drugs will appear, which will be created on the basis of genetic engineering (biotechnological) and medical technologies.

Types of Narcolepsy

There are two main types of narcolepsy:

1. Type 1 includes somnolence and cataplexy. Tests will show that the neurotransmitter known as hypocretin is almost completely absent. This can happen after an infection causes an autoimmune condition.
2. Type 2 is mostly associated with excessive daytime sleepiness, but the person usually does not experience sudden weakness.
3. Secondary narcolepsy can occur when damage or tumor damages the hypothalamus, the part of the brain involved in sleep.

What is narcolepsy

Narcolepsy is a neurological sleep disorder, Narcolepsy, National Sleep Foundation, in which the brain cannot control sleep and wakefulness.
The disease occurs very rarely Narcolepsy, National Sleep Foundation - in one person in 2,000–3,000, equally common in men and women. Narcolepsy develops in adolescence, but can go undetected for a long time. Sometimes it progresses quickly, over a few weeks, and sometimes it takes years after the first signs to become stable.

Causes of a special illness

Narcolepsy is a fairly rare disease (affects 1 person out of 2 thousand). It develops mainly in 20-50 year old men, but can also appear in childhood. Despite its low prevalence, this pathology is very dangerous, because an individual can suddenly fall asleep at any moment and anywhere while performing some action. Such an attack cannot be controlled and therefore interferes with normal activities - it is impossible to properly study, work, do everyday activities, or drive a car. All this negatively affects personal and social life. Children with this disease are developmentally delayed.

The sensations of those suffering from narcolepsy are similar to those experienced by people who have not slept for two days, and this reduces the quality of life.

Researchers cannot explain the exact cause of drowsiness syndrome, since it has not been studied enough due to its uniqueness. However, it turned out that psychological and psychiatric problems are not to blame.

Currently, the following factors for the development of the disease are called:

• heredity;
• lack of special genes of hypocretins (orexins) - neurotransmitters that ensure the transmission of signals to sleep and awakening in the brain;
• dysfunction of the immune system;
• overwork;
• severe infections;
• skull injuries;
• viral diseases;
• malfunctions of the endocrine glands, including the pituitary gland.

Sleepy during the day and at night, narcoleptics often have trouble falling asleep or constantly wake up. This is associated with abnormalities in the areas of the brain that regulate the main stages of sleep: the rapid phase occurs earlier than normal, and the deep phase is absent altogether.

How to treat narcolepsy?

Narcolepsy is currently incurable. Patients are given symptomatic treatment, which allows them to slightly improve their quality of life. To reduce daytime sleepiness, stimulants are prescribed, as well as drugs that reduce the manifestations of cataplexy and sleep paralysis.

Treatment of the disease should be carried out in specialized clinics. At the Sleep Medicine Center at the Rehabilitation Clinic in Khamovniki, specialists have been helping people fight a variety of sleep disorders for many years.

Intense narcolepsy and frequent attacks of cataplexy limit life in society, and episodes of cataplexy are even life-threatening. Patients are at risk when driving a car, working with moving machinery, and even when preparing food.

Causes of narcolepsy

The exact causes of narcolepsy are not understood. Its occurrence is associated with pathology of the parts of the brain that control the process of falling asleep. In particular, patients exhibit pathology in the structure of hypothalamic neurons. The hereditary nature of the disease is assumed.

Narcolepsy is much less common in children than in adults. Parents of such children complain that preschool children are lazy and inactive. Those around you should be wary of the child's desire to sleep during the day. Characterized by attacks of sudden “falling off” to sleep during monotonous actions or after eating.

With narcolepsy syndrome, parents notice attacks of cataplexy in the child. After emotions (crying, screaming, joy), the patient develops severe muscle weakness, he becomes limp and falls without losing consciousness.

It has been noted that some children with narcolepsy also suffer from sleep apnea or have symptoms of restless legs syndrome. Parents who notice these symptoms in their child should contact a somnologist for a polysomnography.