What is narcolepsy?

Etiology and pathogenesis of narcolepsy

Scientists have not yet been able to establish the exact causes of narcolepsy. For a long time, it was believed that the etiology of the disease was closely related to mental disorders. However, this theory was not confirmed. Nowadays, a theory is being actively researched that proves that the disease occurs due to a lack of a neurotransmitter, which is responsible for maintaining wakefulness. Namely, a biologically active substance, the deficiency of which leads to narcolepsy, may be hypocretin. This deficiency may be genetically determined or occur in cases of severe fatigue, severe infection, pregnancy, or traumatic brain injury.

Another theory proves the autoimmune mechanism of pathology. Proof of this theory is that abnormal T lymphocytes are found in patients with narcolepsy. In addition, the autoimmune origin of the pathology is evidenced by the onset of its development after vaccination or the detection of infectious diseases (measles, influenza). No more is known about the pathogenesis of the pathology than about its origin. Scientists suggest that the main problem of the disease is the untimeliness of the REM sleep phase - it is introduced both during the waking period and the slow-wave sleep phase.

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Narcolepsy is a mysterious, unusual condition of the body that leads to increased sleepiness during the day, up to sudden falling asleep and so-called cataplexy - an instant loss of muscle tone as a result of strong emotions. Narcolepsy was first described by the German physician Karl Westphal in 1877. Three years later, the French physician Edouard Gelineau first used this term in his article “De la narcolepsia”:

I propose the term “narcolepsy” (from the Greek “narcosis” - drowsiness, and “lambanein” - to grasp) as one of the few little-known neuroses that is characterized by a sudden short-term irresistible desire to sleep, occurring periodically at different intervals. The term "narcolepsy" is a dual analogy with somnolence and cataplexy

In his article, Gelineau mentions a case from the practice of Dr. Caffe. Dr. Caffe saw a patient for a year with intractable sleepiness that caused him to quit his job. He was a 47-year-old man who led a healthy lifestyle and never complained about anything. However, over the course of four years, he began to notice heaviness of the eyelids, drowsiness, and drowsiness; he could fall asleep while sitting or standing, and such a state depended on certain circumstances.

Gelineau described the second clinical case based on his own observations:

...If he experiences a strong emotion, pain or joy, the desire to sleep intensifies and becomes irresistible. So, for example, if he makes a good deal, sees friends, talks to a stranger, or gets lucky at cards, he collapses and falls asleep.

Mr. G., against the backdrop of emotional upsurge, felt an irresistible craving for sleep, weakness and numbness in his legs and arms, to the point of immobility. He could fall asleep during a business meeting if everything went well, during a game of cards when he had a trump card in his hands, and even while laughing he could completely lose control and fall asleep. Even an elementary feeling of affection and gratitude for his friends put him in a similar state. When he walked down the street, struggling with drowsiness, it seemed to the people nearby that he was drunk and their reaction was accordingly. Such situations had an extremely adverse psychological effect on him.

Based on his own observations and descriptions of other authors, Gelineau identified episodes of increased daytime sleepiness and sudden attacks of muscle weakness (later called catapexy) in the clinical picture of narcolepsy. However, subsequently the clinical characteristics of narcolepsy were supplemented by other signs: hypnagogic hallucinations, sleep paralysis and microsleep. As a result, at the 5th International Symposium on Narcolepsy, a new formulation of this disease was proposed:

“Narcolepsy is a disease of unknown etiology, characterized by excessive daytime sleepiness, poor quality sleep at night, cataplexy and pathological manifestations of REM (Rapid Eye Movement) sleep, such as the appearance of short-term episodes of rapid eye movement sleep in an awake person or “sleep attacks,” microsleep", sleep paralysis, hypnagogic hallucinations"

Currently, the clinical signs of the disease constitute a “narcoleptic pentad”, which includes: 1) excessive drowsiness, manifested by periodic episodes of microsleep; 2) cataplexy (sudden short-term attacks of skeletal muscle weakness of varying severity, provoked by an emotional background); 3) hypnagogic, or less commonly hypnapompic hallucinations; 4) cataplexy of falling asleep and waking up (“sleep paralysis”), manifested by the inability to carry out any movement and utter a word before falling asleep or after waking up; 5) disturbance of night sleep (frequent awakenings, frightening dreams, difficulty falling asleep after waking up.

Also, according to modern concepts, narcolepsy is divided into several subtypes. Narcolepsy type 1 involves cataplexy, which is characterized by a brief episode of sudden loss of muscle tone while maintaining consciousness. Such attacks are triggered by strong, usually positive, emotions. They can manifest themselves as weakness in the limbs or a total loss of tone. Cataplexy is not typical for type 2 narcolepsy. Such patients can sleep for several hours during the day (with a full night's rest), but within a short time after waking up they will again feel tired. Type 2 most often occurs in association with other diseases of the nervous system: tumors, neurosarcoidosis, autoimmune or paraneoplastic syndromes, multiple sclerosis, myotonic dystrophy, Parkinson's disease, etc. It must be remembered that the absence of cataplexy does not exclude type 1 narcolepsy, therefore the main criterion for the differential diagnosis of these two forms of the disease is the absence of hypocretin-1 deficiency in patients with type 2 narcolepsy.

“To understand the nature of these lesions, it is necessary to have an experimental model of narcolepsy. It was discovered by accident: one day in the mid-1960s, the famous American somnologist William Dement..., in a conversation with friends, talked about narcoleptic patients with whom he worked in the clinic at that time. Suddenly one of my acquaintances exclaimed: “Excuse me, but what you describe so colorfully is very similar to the attacks that I sometimes observe in my Doberman!”

It turned out that cataplexy attacks are occasionally observed in domestic animals (dogs, cows, horses). In this connection, for two decades scientists have been trying to find out the nature of this disease using dogs as an example. It turned out that during cataplexy attacks in dogs, the aminergic, serotonergic and histaminergic systems, which normally become completely silent during REM sleep, “turn off.” These systems are maximally active during wakefulness, but for some reason, during the period of emotional upsurge, they “turn off”, and other systems that govern our sleep turn on - as if someone is playing with a switch...

In 1998, in the USA, scientists were able to discover two peptides of similar structure, which they subsequently named hypocretins (HYPOTHALAMIC SECRETINS), since they were initially mistaken for representatives of intestinal hormones. At the same time, a group of Japanese scientists working at the University of Texas in the USA discovered two peptides with similar structures, which they named orexin A and B. Later it turned out that hypocretins 1 and 2 and orexins A and B are one and the same.

Imagine that there is a certain switch that automatically switches from the “sleep” position to the “awake” position, and vice versa. But in order to fix this or that state, another mechanism is needed; its role in the regulation of sleep and wakefulness is performed by the orexin system. Now imagine the same switch, but only with a broken locking mechanism; it will randomly “dangle” from end to end. This is exactly what happens in narcolepsy. Thus, smooth rhythmic transitions in the sleep-wake cycle are replaced by sharp, untimely “jumps” from one state to another

To better understand how this works, I suggest taking a look at Fig. 1. We see that with narcolepsy (with orexin deficiency), the sleep and wakefulness centers inhibit each other (blunt arrows), thereby balancing them. However, in this state, these “swings” are extremely unstable, which is what determines the inadequate transitions between states of sleep and wakefulness. Now imagine another situation, say not a deficiency, but an excess of orexin (B), then “wakefulness” will “outweigh” and such a person will experience insomnia. That is, as soon as one of the parties gains an advantage, the system switches to the appropriate state - this is called the flip-flop mechanism. With narcolepsy, there are no advantages for either side, the regulatory system is “lost” and the result of this breakdown is known to us.

Rice. 1. Flip-Flop mechanism

To confirm this concept, in 2007, Stanford University professor Karl Deisseroth (founder of optogenetics) conducted an interesting experiment. Karl Deisseroth's team inserted channelrhodopsin-2 into the orexin neurons of the hypothalamus of mice, then they stimulated the rodents' brains with light while they slept, causing the orexin neurons to fire, with their activity depending on the intensity and frequency of the light stimulation. During photostimulation, mice awoke from both slow-wave sleep and REM sleep. This was the proof that the release of orexin in sufficient quantities actually ensures the maintenance of wakefulness.

Rice. 2. Orexin, produced by neurons of the lateral part of the hypothalamus, activates neurons of the cortex, midline nuclei and all excitatory systems of the brain.

Orexinergic neurons are quite few in number, but they are highly branched, reaching all activating systems of the brain. By activating aminergic, cholinergic and glutamatergic “wakefulness centers”, orexin causes awakening and wakefulness. This is why orexin is also called the “activator of activators.” The orexin neurons themselves are activated by cholinergic projections of the basal forebrain and glutamatergic neurons of the hypothalamus and inhibited by GABAergic hypothalamic and serotonergic neurons of the medial raphe nuclei.

It is also worth mentioning the cells that resemble orexic neurons in morphology and produce MCH hormone (Melanin-Concentrating Hormone). MCH cell receptors correspond to the distribution of orexin receptors. The MCG system is inhibitory: it is active in REM sleep and inhibited during wakefulness. However, MCG cells remain unaffected in patients with narcolepsy (the destruction of these cells is considered as one of the possible causes of the development of Parkinson's disease).

It turned out that in patients with narcolepsy only the orexinergic neurons of the hypothalamus were destroyed. The reason for their destruction is still not clear, but research in this direction is still underway. It turned out that the human gene ataxin-3 plays a role in the destruction of orexin neurons. Model experiments have shown that its overexpression leads to apoptosis of orexin neurons. In 1999-2000 A hypothesis has emerged postulating that the destruction of orexinergic neurons is autoimmune in nature. In 2009, evidence emerged to support this theory. And at the moment there are a lot of research works explaining this mechanism. However, the question of what exactly the immune system “revolts” against and why it does not affect MCH neurons similar to orex neurons remains open.

It should be added that the autoimmune theory of the disease can explain narclepsy type 1, but even less is known about narcolepsy type 2.

Prepared by: Ashirova V. G.

Sources:

• V.M. Kovalzon “Fundamentals of Somnology”, ed. BINOM, 2012, 239 p.
• Carlos H. Schenck, MD1; Claudio L. Bassetti, MD2; Isabelle Arnulf, MD, Ph.D.3,4; Emmanuel Mignot, MD, Ph.D.3 “English Translations Of The First Clinical Reports On Narcolepsy And Cataplexy By Westphal And Gélineau In The Late 19th Century, With Commentary” – SCSM, Vol. 3, No. 3, 2007, pages 301-311
• Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. “Neural substrates of awakening probed with optogenetic control of hypocretin neurons”–Nature, 450, 15 November 2020, pages 420–424
• Scammell TE, Arrigoni E, Lipton JO “Neural Circuitry of Wakefulness and Sleep” – Neuron, 22 February 2020, pages 747-765
• E. A. Korabelnikova, K. N. Strygin “Narcolepsy in a teenager” - Journal of Neurology and Psychiatry named after. S.S. Korsakova, ed. "Media Sphere" 2016, 83-87 pp.

Symptoms of Narcolepsy

The clinical picture of the disease includes four main symptoms: daytime sleepiness, cataplexy, hypnagogic hallucinations and insomnia. Typically, patients experience several of these symptoms at the same time; all four symptoms are diagnosed at once in 10% of cases.

1. Daytime sleepiness

A patient with narcolepsy experiences several bouts of irresistible drowsiness throughout the day. Such attacks can be either single or multiple. The duration of attacks ranges from several minutes to a couple of hours. The patient is practically unable to resist sudden falling asleep, but he can be woken up in the same way as during normal sleep. In most cases, attacks occur in a monotonous environment, which can cause drowsiness in a healthy person (reading, watching TV).

The patient can also fall asleep in critical situations that require increased attention (while eating, talking, driving a car). After waking up, the patient often feels rested and alert, but after a couple of minutes he may fall asleep again. Night sleep in patients with narcolepsy is often fragmented and accompanied by nightmares, resulting in low productivity and performance during the day. Patients experience decreased motivation, poor concentration, and may experience depression. Patients with narcolepsy are susceptible to increased trauma.

2. Cataplexy

This condition is characterized by sudden muscle weakness and paralysis caused by emotional reactions such as joy, fear, anger, surprise. Weakness can manifest itself in one limb or be generalized. In the latter case, after emotional impact, the patient suddenly collapses. Cataplexy is observed in a third of all patients with narcolepsy.

3. Hypnagogic hallucinations

People with narcolepsy may experience unusual visual and auditory hallucinations while falling asleep. They resemble overly vivid dreams that occur during REM sleep. Most often, such illusions bother children. In adult patients, hallucinations are diagnosed extremely rarely.

4. Sleep paralysis

A quarter of all patients with narcolepsy suffer from sleep paralysis. This is a transient muscle weakness that occurs when falling asleep or waking up. It does not allow the patient to make voluntary movements. Patients usually feel intense fear due to the inability to move.

What is narcolepsy

Narcolepsy is a pathological condition of the nervous system of a neuralgic nature. This pathology is also called Gelineau's disease. It should not be confused with psycho-emotional disorders.

Refers to hypersomnia, and is characterized by increased daytime sleepiness, which cannot be avoided.

The violation is dangerous because sleep can occur at any moment - during work, while driving a car, on the street.

Narcolepsy syndrome is a rare disease that occurs in a young percentage of the population. It most often manifests itself in people aged 15-30 years. It is very rare in women and children.

How does an attack proceed?

The essence of the pathology lies in spontaneous daytime falling asleep. There is a strong desire to fall asleep that is impossible to cope with.

Any ways to cheer yourself up become ineffective. Exercise, washing, smoking, patting yourself on the cheeks only bring you to your senses for a short time. The patient “switches off” in different places and in different positions.

A sudden dream can last either half an hour or a second.

Usually a narcoleptic person wakes up on his own and feels a surge of strength and energy.

After a short time, the attack resumes again. During an important meeting, driving a car, even during an emotional conversation.

This behavior occurs many times a day and can be life-threatening for the patient and those around him.

Situations are possible when a person, arriving in a state of sleep, does not stop his actions.

For example, a person sleeping while driving continues to drive the car. At the same time, nacroleptics understand that they were sleeping, but they cannot do anything.

There is another type of narcolepsy - cataplexy.

In this attack state, muscle tone is lost. The patient loses the ability to move and speak.

Often aimed at a separate muscle group, then only certain parts of the body lose activity - legs bend, arms sag, head falls. At the same time, understanding is not lost; the narcoleptic is aware of what is happening to him.

This lasts for several seconds, sometimes repeated many times, almost without interruption.

A third of patients suffering from this illness have hallucinations. They can be gustatory, auditory, visual and even tactile.

Diagnosis of narcolepsy

It is not possible to diagnose a patient with narcolepsy immediately; on average, the diagnosis is made 10 years after the onset of the disease. Patients who complain of symptoms characteristic of narcolepsy are examined by a neurologist. It must be taken into account that the disease is similar in its clinical manifestations to many other neurological pathologies. That is why, for the most accurate diagnosis, consultations with such specialists as a psychiatrist, endocrinologist, epileptologist, infectious disease specialist, and gastroenterologist may be required.

Differential diagnosis

It is necessary to differentiate narcolepsy first of all from epilepsy. The symptoms of the pathology are also similar to the clinical picture of other types of hypersomnia: psychophysiological, post-traumatic (provoked by a traumatic brain injury, the presence of an intracerebral hematoma), psychopathic (occurs against the background of mental disorders such as schizophrenia or hysteria), associated with inflammatory, tumor or vascular, cerebral diseases, caused by somatic pathologies (diabetes mellitus, pernicious anemia, hypothyroidism, liver failure).

Polysomnography

The disease can be diagnosed using polysomnography, which is accompanied by EEG recording and MSLT test. An in-depth and most accurate study of pathology is carried out by a somnologist in the laboratory. The polysomnography technique involves a thorough study of the patient's night sleep. To do this, you need to spend the whole night in a specially designed room under the supervision of a doctor. Using this technique, it is possible to detect a violation of the alternation of sleep phases: an increase in the duration and frequency of the REM sleep phase. The technique also allows you to eliminate similar sleep disorders.

Causes of narcolepsy

The causes of narcolepsy remained unknown and mysterious for a long time. There were many varied and fanciful theories. Thus, according to one German researcher, narcolepsy occurs as a result of masturbation in adolescence. There were speculations about the connection of the disease with schizophrenia and neurochemical disorders of the brain.

The mystery of the cause of narcolepsy was revealed only at the end of the twentieth century. The brain structures responsible for the change between fast and slow sleep phases are to blame. Thousands of chemical reactions take place in our brain every second. Neurotransmitters are substances that ensure the transmission of nerve impulses from one cell to another. If the functioning of this well-coordinated mechanism is disrupted and the passage of a nerve impulse becomes difficult, drowsiness occurs. The neurotransmitter responsible for wakefulness was named orexin . It is the lack of orexin that provokes narcolepsy.

Scientists have yet to figure out the true reasons for the decrease in orexin levels. Currently, the most plausible theory is an autoimmune response. There are diseases of the immune system in which the defense mechanisms mistakenly attack the cells of one’s own body, destroying them.

Other causes of decreased orexin include:

• diabetes;
• brain injuries;
• infectious diseases of the nervous system;
• stress disorders, exhaustion;
• genetic predisposition.

MSLT test

The day after the polysomnography, the doctor may prescribe an MSLT test for the patient. Namely, the patient will need to try to fall asleep five times during the day. The interval between periods of short-term sleep should be about 2-3 hours. After conducting an MSLT test, a doctor can make a diagnosis if at least two sleep episodes are confirmed. For a more accurate study of the disease, the doctor may prescribe periods of hidden drowsiness. Differential diagnosis of narcolepsy involves the following diagnostic measures: ophthalmoscopy, duplex scanning, MRI of the brain, ultrasound of cerebral vessels.

Sleeping mode

Treatment of patients with narcolepsy should begin with normalizing their sleep and wakefulness patterns. It is strongly recommended that you go to bed and wake up at the same time. Almost all patients are shown the following sleep regimen: 7-8 hours of night sleep and two periods of daytime sleep from 15 minutes to half an hour. It is also important to take care of the quality of your sleep. To do this, you should avoid overeating, eating heavy food, and drinking alcohol in the evening.

In addition, patients should change their lifestyle: reduce the impact of stressful situations, significantly reduce the use of stimulants (coffee or nicotine), and begin to actively engage in sports. Often, people with narcolepsy experience a disruption in their biological clock, so they are active at night and feel sleepy during the day. For them, choosing a job that coincides with their natural sleep cycle would be ideal. Such a regime will allow you to get rid of the need to force your body to adhere to a standard operating mode and take stimulant drugs to eliminate drowsiness.

Patients with narcolepsy are advised to take short naps during the day. It is very important to plan your day so that you can take a 10-15 minute nap at least twice. Such sleep cannot fully replace nighttime sleep, but it will help overcome daytime sleepiness.

Symptoms

If we talk about the symptoms of narcolepsy, then daytime sleep is not the only manifestation that complicates the patient’s normal functioning; in addition, symptoms include:

1. Cataplexy.
2. Hallucinations.
3. Sleep paralysis.
4. Night sleep disturbance.

Daytime nap

A similar state can occur in a person at any time and he is unable to resist the wild desire to close his eyes and indulge in Morpheus. The danger lies in the fact that you can never predict where this desire will find the patient. At a lecture at the institute or while driving a bus, or perhaps during a football match.

Falling asleep is preceded by a depressed state, a decrease in the ability to soberly assess what is happening, foggy consciousness and fatigue of the body. A person is unable to fight sleep.

It is possible to wake up a sleeping person, but, as a rule, within a short period (a few minutes) the patient will fall asleep again. Depending on the severity, sleep time differs. If at the initial stage the patient only needs a few minutes, then at more advanced stages this condition can last several hours. In some cases, a person, while in a state of sleep, initially continues to perform some mechanical tasks that he performed before falling asleep (driving a car, writing on paper, etc.).

As a rule, awakening occurs suddenly and the patient feels alert and rested, even if he slept for only 10 minutes. In addition, the patient is fully aware of his condition, but cannot do anything about it on his own. Interestingly, falling asleep during the day is absolutely not affected by how much the patient slept at night.

Cataplexy

Narcolepsy and cataplexy are two inextricably linked diseases, with the second being a symptom of the first. Cataplexy is when a person loses the ability to control their muscles. Under the influence of this phenomenon, a kind of “limp” of the patient occurs, he becomes as if he were made of cotton and physically cannot raise his head, which has fallen on his chest, or rise from the floor if a fall has occurred. Cataplexy attacks do not always occur in conjunction with daytime sleep; sometimes there are spontaneous attacks that are not aggravated by falling asleep.

Daytime falling asleep in combination with cataplexy is a serious illness, since if, while driving a car, the patient begins to experience an irresistible desire to sleep, he will have time to pull over to the side of the road and avoid serious consequences, then in the event of cataplexy, injuries cannot be avoided. The muscles will refuse to obey the patient and he will not be able to do anything about it.

Cataplexy attacks do not last a long time, usually lasting up to 1–2 minutes. In rare cases, it is possible to develop cataplistic status (a condition in which attacks of cataplexy occur one after another with an interval of several seconds).

Sincere feelings (laughter, crying, rage, etc.) can provoke an attack, but often cataplexy occurs for no reason.

The characteristic features of the attack are:

• redness or paleness of the skin;
• slowing heart rate;
• increased sweating;
• difficulty breathing (if the head is thrown back).

Cataplexy almost never appears at the very beginning of the development of the disease, only after a certain period of time (from two months or more).

Hallucinations

This phenomenon develops immediately before a person falls asleep and, according to the available evidence, they are quite bright. A person can observe bright pictures, hear loud sounds, feel some smells and even touches. Usually, hallucinations occur before going to normal, nighttime sleep, agitate the patient’s consciousness and prevent sleep.

Hallucinations occur in one third of patients and are hypnogogic and hypnopompic in nature.

Hypnogic - occurring before going to bed

Hypnopompic - occurring after waking up

Sleep paralysis

What is sleep paralysis? This is cataplexy that occurs immediately after waking up or before going to bed. Sleep paralysis is a slightly worse version of cataplexy, since during the development of attacks a person is only able to blink, and all other functions are lost. Incoherent speech is often completely absent.

In 90% of cases, sleep paralysis develops at night.

Drug treatment

Drug treatment of patients with mild or moderate drowsiness begins with the administration of modafinil, which stimulates wakefulness. At the same time, the drug does not cause a feeling of euphoria or addiction syndrome. It is recommended to take it in the morning in an amount of 100-200 mg orally. If this amount of the drug is not enough to relieve the symptoms of the disease, then the doctor will additionally prescribe another 100 mg. In the most difficult situations, according to indications, the daily dose can be increased to 400 mg.

If narcolepsy does not respond to treatment with modafinil, then the patient is prescribed amphetamine derivatives: methylphenidate or dextroamphetamine. However, it must be remembered that these medications have serious side effects: addiction with a high risk of addiction, tachycardia, arterial hypertension. To reduce the incidence of cataplexy, patients with narcolepsy are prescribed the following drugs: serotonin reuptake inhibitors (Prozac), tricyclic antidepressants (anafranil and tofranil).

Treatment

Unfortunately, at the moment there is no treatment for this disease and it will not be possible to get rid of it completely; it is only possible to remove some unpleasant symptoms that interfere with normal life, in particular, cataplexy, hallucinations, sleep problems and minimize the consequences of daytime sleep.

Thus, a doctor may prescribe the following groups of medications:

• antidepressants;
• hypnotic;
• drugs to combat daytime sleep.

Medicines from the antidepressant group (imipramime, clomipramime) are used to treat cataplexy and hallucinations. Take once in the morning in the dosage prescribed by your doctor.

To combat night sleep disturbances, potent sleeping pills are used, however, their use is not always justified. In turn, to eliminate the symptoms of daytime sleep, the doctor prescribes Modafinil, Indopan, Sidnocarb or Meridil. These drugs are taken only on the recommendation of a doctor and exclusively in the morning, no later than one o’clock in the afternoon. A later intake may negatively affect night's sleep.

About a year ago, American scientists announced the development and start of testing a special spray that helps increase orexin and, if tested successfully, they will launch its mass production, which is good news.

Forecast and prevention of narcolepsy

To date, narcolepsy has no cure. As for the prognosis for the patient’s life, the disease does not affect its duration, but significantly reduces its quality. Patients who suffer from narcolepsy are prescribed symptomatic therapy. With the help of properly selected drug therapy, you can get rid of the most pronounced symptoms of the pathology. However, it is worth remembering that taking such drugs sometimes leads to side effects. There is no specific prevention of the disease, since the exact causes of its occurrence have not yet been identified.