Narcolepsy

Etiology

Narcolepsy type 1 occurs when nearly all of the neurons that contain orexin (also called hypocretin) are lost. [1] The reason for this is not fully understood, but it is thought to be an autoimmune process possibly triggered by an infection. HLA haplotype DQB1*0602 is present in 95% of narcolepsy type 1 patients, but this is also present in about 20% of the general population without narcolepsy[2]. The cause of narcolepsy type 2 is not entirely clear. Current hypotheses include less destruction of orexin cells, impaired orexin receptor signaling, or an unknown mechanism. Some patients initially diagnosed with narcolepsy type 2 will develop cataplexy, indicating disease progression. Less commonly, trauma and tumors may result in narcolepsy.

In 2009 there was an increase in the number of cases of narcolepsy type 1 reported in Europe after receiving the European AS03-adjuvanted A(H1N1) pandemic influenza vaccine (Pandemrix) and it was initially thought that the immune response to the adjuvant might have been the cause of the disease. The same adjuvant was, however, also used in Canada but the corresponding increase in reported cases did not occur there. Additionally, there was an increase in the number of reported cases of narcolepsy in non-vaccinated patients after wild A(H1N1) pandemic influenza infection. [3] [4] Antibodies against streptococcal infections have also been associated with the onset of narcolepsy type 1. [5] Although a specific autoantibody that correlates with disease mechanism in narcolepsy has not yet been identified, this does strongly suggest that narcolepsy type 1 may be an autoimmune disease.

The mechanism of narcolepsy type 2 is less clear, but it is thought that it may be due to a similar but less severe loss of orexin neurons. [6]

Narcolepsy is classified as follows based on clinical features:

• Narcolepsy with hypocretin deficiency but no cataplexy
• Narcolepsy without hypocretin deficiency but with cataplexy
• Autosomal dominant cerebellar ataxia, narcolepsy, and deafness
• Autosomal dominant narcolepsy, type 2 diabetes, and obesity
• Narcolepsy caused by another medical disorder

Epidemiology

Prevalence is 14 per 100,000 people for narcolepsy type 1 and 65.4 per 100,000 people for narcolepsy type 2. Incidence is highest in the late teens to early twenties with a 50% greater female predominance in the U. S. according to data 2008-2010 [7]

Pathophysiology

During normal wakefulness, orexin-containing neurons in the lateral hypothalamus increase the activity of the nuclei of the Reticular Activating System (RAS), which increases wake-promoting neurotransmitters in the cortex; dopamine, norepinephrine, serotonin, and histamine inhibit REM and acetylcholine is increased in both wakefulness and REM. The RAS also inhibits the sleep-promoting ventrolateral preoptic area (VLPO), suppressing GABA, which in turn increases the activity of motor neurons and muscle tone. Heightened emotions increase activity in the amygdala and subsequently the orexin-containing neurons, which suppresses REM. The wake-promoting and the sleep-promoting systems are usually mutually inhibitory to ensure complete transitions. [1]

During normal REM sleep, orexin decreases, which decreases RAS activity and promotes atonia. In narcolepsy type 1, the mechanism that separates wake from sleep becomes unstable without sufficient levels of orexin. The RAS no longer consistently causes the release of wake-promoting neurotransmitters to the cortex and inconsistently inhibits the VLPO. This results in rapid transitions between sleep and wake and allows the intrusion of REM-related phenomena into wakefulness. [8][1] The pathophysiology of narcolepsy type 2 is not well understood.

The cataplexy seems to have its origin in the pons and the mesocorticolimbic dopaminergic system.

Hypocretin

The hypocretin system now appears to play a vital role in narcolepsy. Many patients with narcolepsy have no or little hypocretin in the CSF. The deficiency in hypocretin is believed to produce intermittent wake and sleep states. Unfortunately, many other neurotransmitters play a role in the sleep-wake cycle, and making a correlation with any one of them is difficult.

History and Physical

Patients present with moderate to severe daytime sleepiness. The typical patient with narcolepsy will begin experiencing symptoms in either their mid-teens or mid-thirties with a progressive increase of symptoms. The average time from onset of symptoms to diagnosis is about 15 years.[9], [10] The only required symptom for the diagnosis of narcolepsy is daily, irrepressible, rapid lapses into REM sleep known as “sleep attacks” that are present for at least three months. [11]

Cataplexy is a sudden, often bilateral muscle weakness lasting a few seconds to a couple of minutes in response to increased emotion (typically laughter) during which patients remain conscious. Cataplexy can also be brought on by excitement, anger, grief, or any intense emotion. It is pathognomonic for the disorder if it is present but is not required for the diagnosis of narcolepsy type 2. Sleep paralysis occurs when waking from sleep when patients can hear what is happening around them but are unable to open their eyes or move. They often describe a sensation of suffocating due to the paralysis of the intercostal muscles despite the diaphragm continuing to function normally. It can be associated with narcolepsy but also occurs at least once in up to 50% of the normal population.

Hypnagogic hallucinations are visual, auditory, or tactile dream-like experiences that occur as patients are falling asleep or just waking up. They can typically see human faces or experience a feeling like someone else is in the room. Additionally, these patients have significantly fragmented nighttime sleep. Unlike some other disorders with excessive daytime sleepiness, patients with narcolepsy typically find naps to be refreshing. It is also essential to do a complete physical exam to rule out other possible causes of hypersomnia.

A common feature of narcolepsy is obesity, which also increases the risk of sleep apnea.

In children, the clinical features of narcolepsy may also include motor overactivity and restlessness. Inattentiveness is often a major complaint by the parent/teacher. Others may present with drop attacks, aggression, irritability, and falls. These children are often falsely labeled as having seizures.

DSM V criteria

In order to make a diagnosis of narcolepsy, the individual must have symptoms occurring at least three times a week over the past 3 months. In addition, one of the following must be present:

1. Hypocretin deficiency
2. Episodes of cataplexy occurring at least several times a month
3. REM sleep latency of fewer than 15 minutes or two or more sleep-onset REM periods (SOREMPs) and a mean sleep latency of fewer than 8 minutes. 

Evaluation

The first step is ensuring that the patient is regularly getting at least 6 hours of sleep per night for at least two weeks. Although this can be done with a patient-reported sleep log alone and still be considered valid for additional testing, patients often overestimate their total sleep time. Two weeks of actigraphy with a sleep log is recommended before further testing. If the patient is getting less than 6 hours of sleep per night averaged over two weeks, they cannot be diagnosed with narcolepsy. [12]

If the patient is getting a minimum of 6 hours of sleep per night, then a reasonable next step is a polysomnogram (PSG) to rule out other possible sleep disorders such as sleep apnea. Following the PSG, a Multiple Sleep Latency Test (MSLT) is conducted the next day as long as there were at least 6 hours of sleep during the PSG, and no other sleep disorders are found. The patient is given four to five 20-minute nap opportunities at 2-hour intervals. A positive test will show a rapid onset of REM sleep (less than 15 minutes) at least twice during the test, and a shortened mean sleep latency averaged across all trials (less than 8 minutes). One of the sleep-onset REM periods (SOREMPs) can occur during the PSG with only one during the MSLT and still meet diagnostic criteria. If the MSLT is negative, but there is strong clinical suspicion for narcolepsy, the test should be repeated.

When conducting the MSLT, the patient must be allowed to sleep until they wake up on their own from the PSG the night before the test to prevent a possible false positive. If the patient doesn’t get enough sleep the night before the test or it is started too early in the morning, SOREMPs may be present for the first couple of naps even in a patient without narcolepsy. Those with chronic insufficient sleep can also have SOREMPs on MSLT if they are not screened appropriately with actigraphy and sleep logs before testing. This can also occur with shift workers who are tested during their usual sleep period.

Narcolepsy type 1 can also be diagnosed if hypocretin-1 is low in the cerebrospinal fluid (<110 pg/mL or <1/3 the mean normal value for a given assay). This testing could be helpful to confirm or exclude the diagnosis. Although HLA DQB1*0602 is present in most narcolepsy type 1 patients, there is no common diagnostic utility in testing for it.

Treatment / Management

Behavior modification can be effective with 15 to 20 minute long naps strategically scheduled throughout the day and maintaining an adequate nighttime sleep schedule. First-line pharmacologic treatment for excessive daytime sleepiness is modafinil (twice-daily dosing) or armodafinil (once-daily dosing). Second-line treatment would be amphetamines. First-line treatment for cataplexy is sodium oxybate, a form of gamma-hydroxybutyrate, or GHB. The medication is taken while in bed due to the short onset of sleepiness, usually 5 to 15 minutes. A second dose is given 2.5 to 4 hours later. Xyrem is a restricted medication distributed from a central pharmacy. While there are concerns about abuse, dependence, and illegal use of sodium oxybate, post-market research has not proven these concerns to be valid. Tricyclic antidepressants (protriptyline, clomipramine) and SNRI/SSRIs (venlafaxine, fluoxetine) have also been used with some success in treating cataplexy. [13][14](A1)

Nonpharmacological treatments

Besides encouraging good sleep hygiene, the following measures are important:

• Provide emotional support
• Provide mental health counseling
• Assist with disability forms and obtaining medications
• Educate about the harms of alcohol and illicit drug use

Drug therapy

While several CNS stimulants are used to treat narcolepsy, none is 100% effective in all patients. Methylphenidate does improve sleep but it also has undesirable side effects like anxiety, headache, and irritability. Modafinil does induce wakefulness but its safety in children has not yet been established. Armodafinil is also effective for narcolepsy and has the same side effect profile as methylphenidate. Sodium oxybate is the only FDA-approved treatment for cataplexy but it should not be combined with other CNS depressants or alcohol. Just recently, the FDA approved pitolisant (a histamine H3 receptor antagonist) for narcolepsy. Early studies indicate that it can improve sleep.

Currently, there is no medication that has been approved by the FDA for use in children.

Differential Diagnosis

Cataplexy

• Seizures (especially atonic seizures)
• Periodic paralysis
• Syncope
• Cardiogenic
• Orthostatic
• Neurogenic
• Psychogenic

Excessive daytime sleepiness

• Insufficient sleep syndrome/poor sleep hygiene
• Idiopathic hypersomnia
• Sleep apnea syndromes
• Chronic fatigue syndrome
• Sleep-related movement disorders (periodic limb movement disorder, restless leg syndrome, etc.)
• Circadian rhythm disorders (jet lag, shift work, delayed/advanced sleep phase disorder, non-24)
• Long sleepers (normal variant in which patient require longer sleep than average to feel well-rested with otherwise normal testing)
• Psychiatric (depression, malingering, conversion disorder, factitious disorder, etc.)
• Substance-induced sleep disorder (narcotics, benzodiazepines, antihistamines, beta-blockers, antidepressants, antipsychotics, anticonvulsants, antiretroviral, etc.)
• Kleine-Levin syndrome (recurrent hypersomnia that lasts days to weeks and recurs months later)
• Menstrual associated hypersomnia
• Hypersomnia due to a medical condition (Parkinson's disease, Multiple Sclerosis, etc.)

Idiopathic hypersomnia patients have excessive daytime sleepiness and have a decreased mean sleep latency on MSLT, but these patients do not go into REM pathologically quickly. Unlike patients with narcolepsy, they also generally fall asleep quickly and stay asleep throughout the night, find naps to be unrefreshing, and typically have significant sleep inertia upon waking in the morning.

Sleep apnea can occur with narcolepsy in up to 33% of patients, but narcolepsy can only be diagnosed after the patient has been adequately treated with CPAP for a sufficient period of time. [15]

Prognosis

Some patients diagnosed with narcolepsy type 2 will eventually present with cataplexy and have the diagnosis changed to narcolepsy type 1. Many patients have symptoms that do worsen over time. Although it is unlikely that symptoms will improve on their own over time, they are generally well managed with a combination of behavioral interventions and medications. Additionally, there are new treatments currently being investigated that may allow for immunomodulation or administration of orexin agonists small enough to cross the blood-brain barrier.[1]

Children often suffer from poor school performance and social interactions. Job impairment is common and most patients are not able to be gainfully employed.

Complications

Mood disorders such as depression and anxiety are common in patients with narcolepsy, but it is unclear if this is due to the pathophysiology of the disease or the impact it has on quality of life.