Narcolepsy – Symptoms – Cataplexy – Sleep Paralysis – Hypnagogic and Hypnopompic Hallucinations – Diagnosis – Cause – Treatment – Prognosis
Narcolepsy is a disorder of REM sleep. Humans have 3 states of consciousness: wakefulness, REM sleep, and NREM sleep. Under normal conditions REM sleep is tightly controlled. REM sleep is like a wild animal – it creates lots of trouble once it is set free. Narcolepsy is caused by loss of brain control over REM sleep. REM intrusion into NREM sleep causes poor sleep quality at night. REM sleep fragments during the state of wakefulness lead to daytime sleepiness, episodic confusion, hallucinations, cataplexy, and sleep paralysis. Daytime sleepiness is usually the first complaint. Other symptoms may come later. Cataplexy typically develops within 10 years after the onset of daytime sleepiness.
Symptoms of Narcolepsy
Excessive daytime sleepiness
Excessive daytime sleepiness and sleep attacks are cardinal features of narcolepsy. A sleep attack is an irresistible sudden urge to sleep. A quiet environment or a boring activity may provoke a sleep attack, which may last from seconds to minutes. A short nap may delay the next sleep attacks for a few hours. An excessive daytime sleepiness has a severe adverse effect on the quality of life.
Disturbed nighttime sleep
Even though it is often ignored, a disturbed nighttime sleep is typical for narcolepsy. The majority of narcolepsy sufferers experience vivid dreams, fragmented sleep with frequent awakenings, and lack of refreshment in the morning. Nighttime sleep in narcopepsy is disrupted by multiple REM sleep episodes invading NREM phase.
Cataplexy is a sudden partial or complete loss of muscle tone associated with preservation of consciousness. During the attack a person may literally collapse to the ground. Sudden loss of muscle tone may be dramatic and injuries due to cataplexy do occur. Cataplexy is often misdiagnosed as an epilepsy or a fainting spell. Cataplectic attacks are usually very brief – from seconds to minutes. An abrupt discontinuation of medications for cataplexy may cause prolonged attacks. Mild cataplexy may be hard to recognize – jaw dropping, slurred speech, buckling of the knees or head nodding. Cataplexy is commonly brought up by laughter, intense positive emotions or surprise.
Sleep paralysis occurs in about two thirds of patients with narcolepsy. It is characterized by inability to move for a few seconds or a few minutes while being awake. Sleep paralysis more commonly occurs upon awakening and less commonly while falling asleep. Sleep paralysis in narcolepsy is a REM sleep phenomenon that occurs due to uncoupling of sleep paralysis and REM sleep itself. This phenomenon is not unique for narcolepsy. It may happen in an absolutely healthy person especially after sleep deprivation. There are familial forms of isolated sleep paralysis without any other symptoms of narcolepsy.
A variety of different hallucinations are experienced by two thirds of patients with narcolepsy. They occur either during transition from wakefulness to sleep (hypnagogic) or from sleep to wakefulness (hypnopompic). This type of hallucinations may be experienced by healthy people as well.
Episodes of automatic behavior are experienced by a half of narcolepsy sufferers. The person may look either normal or detached from reality while performing an apparently normal activity but there is no recollection about the activity afterwards. Automatic behavior is probably caused by the episodes of “micro-sleep”. An automatic behavior may be observed in normal individuals due to sleep deprivation.
Other Associated Symptoms
Many other sleep disorders and parasomnias are more common in patients with narcolepsy than in general population. REM sleep behavior disorder, restless legs syndrome, sleepwalking, sleep talking and obstructive sleep apnea are some of them.
Epidemiology and Genetics of Narcolepsy
Narcolepsy is a relatively uncommon disorder. It affects about 0.04% of population.
There are two peaks in symptoms onset – 15 years and 35 years but it can start in any age group.
Narcolepsy without cataplexy is more common but cataplexy may appear later in the course of the disease.
First degree relatives have about 1.5% chance of developing narcolepsy. There is a strong association of certain genetic markers with narcolepsy – HLA-DR2 in Japanese and HLA-DQB1*0602 in Whites and African Americans.
Cause of Narcolepsy
Narcolepsy is believed to be an autoimmune disease that destroys specific nerve cells (neurons) in the brain. These cells are situated in the area called lateral hypothalamus. Damage of this area by any other mechanism may cause similar symptoms.
Neurons in the lateral hypothalamus produce a special protein – hypocretin (orexin). Hypocretin is an essential component that triggers a chain of events that leads to REM sleep control.
Cerebrospinal fluid hypocretin level is found to be very low in the patients suffering narcolepsy with cataplexy.
Diagnosis of Narcolepsy
The diagnosis of narcolepsy is based on a typical combination of daytime sleepiness, associated cataplexy, and other symptoms described above.
Other causes of daytime sleepiness have to be ruled out if cataplexy is absent.
A brain MRI is helpful ruling out lesions in the hypothalamus.
Measurement of hypocretin level in the cerebrospinal fluid is commercially available but is rarely done. Low hypocretin level is expected only in classical narcolepsy with cataplexy. The same holds true for HLA type testing.
The most common diagnostic modalities for the evaluation of daytime sleepiness are polysomnography (sleep study) and Multiple Sleep Latency Test (MSLT).
Treatment and Prognosis of Narcolepsy
Unfortunately, this is a life-long condition and there is no known cure for narcolepsy. Once the neurons producing hypocretin are lost, there is no way to bring them back. There is only symptomatic treatment available.
Treatment of Excessive daytime sleepiness
The excessive daytime sleepiness is managed by stimulants and wake-promoting agents.
Stimulants (d-Amphetamine, Methamphetamine, Methylphenidate) have been the principal medications for daytime sleepiness for years. They are usually taken twice a day (morning and noon). The main concerns are high abuse potential (especially Methamphetamine), elevated blood pressure and contraindications in heart disorders (especially d-Amphetamine). All of them have maximum daily dose of 60 mg.
Wake-promoting agents (Modafinil and Armodafinil) are more favored for daytime sleepiness than stimulants due to minimal abuse potential and much milder influence on the heart and blood pressure. Modafinil is shorter acting and is given twice a day (morning and afternoon) with a maximum dose of 400 mg per day. Armodafinil is given either 150 mg or 250 mg once a day in the morning.
Treatment of Cataplexy
The most effective medications for cataplexy are antidepressants. Cataplexy has nothing to do with depression. Antidepressants, however, increase the levels of serotonin and epinephrine in the brain, which leads to cataplexy control.
The best medication is Venlafaxine. Older tricyclic antidepressants (Imipramine, Protriptyline, Clomipramine) are also effective but they have less favorable side effect profiles.
The antidepressant dose for cataplexy control is much lower than the one used in depression.
SSRIs (selective serotonin reuptake inhibitors) are often prescribed but they are less effective.
Treatment of Disturbed Nighttime Sleep
Any agent for disturbed nighttime sleep in narcolepsy has to be able to suppress REM sleep while promoting NREM sleep.
The best medication for narcolepsy is Gamma-Hydroxybutyrate, also known as Sodium Oxybate. This drug had a bad reputation in the past as a “date rape drug” and also for the reason of high abuse potential.
A well designed study revived interest to this medication. It was shown to be effective for both, improvement of sleep quality and cataplexy.
The best results are achieved by combination of Gamma-Hydroxybutyrate during the night and Modafinil in the morning. Gamma-Hydroxybutyrate is taken in two doses, first at bed time and the second 2 to 4 hours later in the night.
Since this substance is tightly controlled by the authorities, it is available excusively through Xyrem Success Program. Both, the doctor and the patient have to participate in the program.
The major concerns associated with this medication are withdrawal seizures, respiratory suppression, and abuse.
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