Narcolepsy

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Definition/Description

Narcolepsy, from the Greek words "narco," meaning numbness, or stiffness, and "lepsy," meaning fit or seizure, literally translates to mean a fit of stiffness. Narcolepsy is a lifelong sleep disorder characterised by a classic tetrad of[1]:

· Excessive daytime sleepiness with irresistible sleep attacks

· Cataplexy (sudden bilateral loss of muscle tone)

· Hypnagogic hallucinations

· Sleep paralysis 

There are two main types of narcolepsy:

·     Type 1: Narcolepsy with Cataplexy

·     Type 2: Narcolepsy without Cataplexy

History

The first unequivocal case of the disease was reported by Westphal in 1877 and subsequently called narcolepsy ("seized by somnolence") by Gelineau three years later. Westphal and Gelineau described the combination of severe daytime sleepiness and attacks of muscle weakness triggered by emotions, later termed 'Cataplexy'. Gelineau proposed that narcolepsy could either be a primary disorder or be triggered by other pathologic conditions, the most common example at the time being neurosyphilis[2].

More than half a century later, Danielsin 1930, was the first to report the relationship between excessive daytime sleepiness, cataplexy, hypnagogic/hypnopompic hallucinations, and sleep paralysis in narcolepsy[2] [3].

The connection between narcolepsy and sleep onset rapid eye movement (SOREM) was demonstrated in 1960 by Vogel. The International Symposium on Narcolepsy in 1975 characterised narcolepsy by excessive sleepiness and sleep (particularly REM sleep)-wake cycle instability. The major symptoms of narcolepsy were identified as excessive sleepiness and the pathologic manifestations of REM sleep, including cataplexy, sleep paralysis, and hypnagogic hallucinations[3].

In the 1980s, researchers in narcolepsy found an association with leukocyte antigen HLA-DR2, with further studies identifying an association with HLA DQB1*0602. These leukocyte antigens are found in many non-narcoleptic individuals; however, their discovery in patients with narcolepsy suggested a possible genetic susceptibility for events such as autoimmune activation[3].

In 1998, two independent research groups discovered Hypocretin 1 and Hypocretin 2[4][5]. Researchers identified that narcolepsy could be caused by a severe and highly selective loss of Hypocretin neurons, which results in low levels of hypocretin in the brain and cerebrospinal fluid[6]. This discovery led to the recognition of two distinct types of narcolepsy: Type 1 Narcolepsy, and Type 2 Narcolepsy.

Epidemiology

The prevalence of Type 1 narcolepsy is between 25 and 100 per 100,000 people, and the incidence is estimated to be 0.74 per 100,000 person-years[7]. Although there is little epidemiological data on Type 2 narcolepsy, it is thought that people with narcolepsy without cataplexy account for 36% of all narcolepsy patients[8]. Significant sex differences are not observed; however, a slight male predominance has been reported, whilst females showed a slightly earlier manifestation of symptoms[7].

Symptoms often start in childhood, adolescence, or young adulthood (ages 7 to 25), but can occur at any time in life. Symptoms most commonly arise in the second decade; but the age at onset ranges significantly, between the first and fifth decades. The incidence of narcolepsy has a bimodal distribution, with the biggest peak at approximately age 15 and a second smaller peak in the mid30s[7].

Diagnosis is often delayed and may be influenced according to gender, with one study showing that 85% of men were likely to be diagnosed by 16 years after symptom onset, compared to 28 years in women[9]. However, with the increases in awareness and the efficiency of the diagnosis, this delay is expected to improve.

Aetiology/Causes

Primary Narcolepsy

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[10].

These factors include[10]:

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.

Secondary Narcolepsy

Rarely, narcolepsy results from traumatic injury to parts of the brain that regulate wakefulness and REM sleep or from tumours and other diseases in the same regions. Lesions of the hypothalamus and nearby structures can produce narcolepsy-like symptoms. Just as in primary narcolepsy, these entities may or may not include cataplexy as a symptom. Multiple sclerosis, tumours, and strokes have all been associated with narcolepsy as well.

Vaccine-Related Narcolepsy

An increased incidence of narcolepsy was observed in six European countries after the pandemic influenza A virus, A(H1N1) pdm09 ("swine flu"), vaccination campaign during the winter of 2009-2010. The first signal was observed in Finland and Sweden, followed by France, England, Ireland, and Norway, all countries where AS03-adjuvanted pandemic vaccine Pandemrix (GlaxoSmithKline Biologicals, Wavre, Belgium) was widely used[11].

Epidemiological data from observational studies assessing the risk of narcolepsy after H1N1 pandemic vaccines show that:

  1. The risk of narcolepsy appears to have increased in children, adolescents and to a lesser extent also in adults after vaccination with Pandemrix.
  2. The elevated risk is only associated with Pandemrix- vaccine and not any other AS03 adjuvanted or any other pandemic or seasonal vaccine.
  3. The risk is associated only with narcolepsy type 1
  4. The risk seems to remain at an increased level for two years after vaccination.
Country Pre-vaccine Incidence Post-vaccine Incidence Fold Increase Reference
Sweden 0.2/100,000 6.6/100,000 25 Fold [12]
Finland 0.31/100,000 5.31/100,000 17 Fold [13][14]
Norway 0.5-1.0/100,000 10/100,000 10-20 Fold [15]
United Kingdom 0.42/100,000 6.05/100,000 14.4 Fold [16]
Ireland 0.41/100,000 5.7/100,000 13.9 Fold [17]

Characteristics/Clinical Presentation

Narcolepsy consists of excessive daytime sleepiness combined with the intrusion of REM sleep-associated phenomena (hypnagogic hallucinations, sleep paralysis, and possibly cataplexy) into wakefulness[18].

Excessive Daytime Sleepiness

Excessive daytime sleepiness (EDS) of narcolepsy presents as an increased propensity to fall asleep, nodding or easily dozing in relaxed or sedentary situations, or a need to exert extra effort to avoid sleeping in these situations[19]. EDS is characterised by persistent sleepiness, regardless of how much sleep an individual gets at night[10].   

Additionally, people with narcolepsy can experience "sleep attacks" which manifest as an irresistible or overwhelming urges to sleep. They commonly occur from time to time during wakeful periods in untreated narcolepsy patients[18]. Sleep attacks are not instantaneous lapses into sleep, as is often thought by the general public, but represent the episodes of profound sleepiness experienced by those with marked sleep deprivation or other severe sleep disorders[18].

In addition to frank sleepiness, EDS can cause related symptoms, including poor memory, reduced concentration or attention, and irritability. Although people with narcolepsy feel refreshed following a short nap, this does not last long, and they become sleepy again within a few hours[10].

Cataplexy

https://www.nejm.org/doi/full/10.1056/NEJMra1500587

Cataplexy is transient muscle weakness triggered by emotion and is a specific feature of narcolepsy type 1. Cataplexy is thought to represent intrusion of REM sleep and its associated muscle atonia during wakefulness. It often begins in the facial muscles and can manifest with slackening of the jaw or brief dropping of the head. However, episodes can be more dramatic and, if the trunk and limb muscles are affected, can result in collapsing to the ground[7].

Episodes can last from a few seconds to 2 minutes, and patients are usually alert and oriented during the event despite their inability to respond.  While scary, the episodes are not dangerous as long as the individual finds a safe place in which to collapse[18]. Positive emotions such as laughter more commonly trigger cataplexy than negative emotions; however, any strong emotion is a potential trigger. Startling stimuli, stress, physical fatigue, or sleepiness may also be important triggers that exacerbate cataplexy.

Deep tendon reflexes disappear in cataplexy, so checking reflexes during a witnessed episode can be clinically valuable[20].

Cataplexy usually has its onset at about the same time as the sleepiness associated with narcolepsy, but it can arise even years later[21]. The symptoms of cataplexy may appear weeks or even years after the onset of EDS. In about 10 percent of cases of narcolepsy, cataplexy is the first symptom to appear and can be misdiagnosed as a seizure disorder[18].  

Hypnagogic/Hypnopompic Hallucinations

Hallucinations are very vivid and sometimes frightening images that can accompany sleep paralysis and usually occur when people are falling asleep (hypnagogic) or waking up (hypnopompic)[10]. Hallucinations may be visual, tactile, auditory, or multisensory events, and are usually brief but occasionally persist for a few minutes[18].

These hallucinations may contain combined elements of dream sleep and consciousness and are often bizarre or disturbing to patients. The hallucinations are often vivid and usually visual, although other types of hallucinations are possible[7]. Unlike those that occur in psychotic disorders, the hallucinations experienced by people with narcolepsy tend to be associated with preserved insight that they are not real[22].

Sleep Paralysis

Sleep paralysis is a potentially terrifying experience, that is similar to REM-induced inhibitions of voluntary muscle activity[10]. It occurs around the edges of sleep when people are falling asleep or awakening. Patients find themselves temporarily unable to move limbs, speak, or breathe deeply whilst remaining fully aware of their condition and able to recall it later[18]. Sleep paralysis may be anxiety-provoking at first; but with time, most patients learn that the episodes are benign, rarely last more than a few minutes and end spontaneously.

Sleep paralysis can be associated with a sensation of fear or suffocation, especially when initially experienced. Although accessory respiratory muscles may not be active during these episodes, diaphragmatic activity continues, and air exchange remains adequate[18]. Sleep paralysis may occur as an independent and isolated phenomenon in up to 3% to 5% of the normal population, but occurs in approximately 50% to 60% of narcoleptics[23]. 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[10].

Fragmented sleep and insomnia

Although they are very sleepy, people with narcolepsy generally cannot stay asleep for very long. Their sleep tends to be extremely fragmented, and they often wake up several times a night[7]. Sleep may be disrupted by insomnia, vivid dreaming, sleep apnoea, acting out while dreaming, and periodic leg movements. Other commonly reported symptoms to include automatic behaviour (“absent-minded” behaviour or speech that is often nonsensical which the patient does not remember) and fragmented nocturnal sleep (frequent awakenings during the night)[18].

Automatic behaviours

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[10].

Associated Co-morbidities

Narcolepsy can be associated with a wide range of medical and psychiatric comorbidities. Symptom overlap with these comorbid medical and psychiatric conditions can result in misdiagnosis[24]

Some comorbidities, such as the increased rates of sleep apnoea and obesity, have been well established in the literature. Other associations, such as between narcolepsy and schizophrenia or between narcolepsy and migraine headaches, have been inconsistent and have occasionally demonstrated contradictory findings[18].

It is important to consider the significant and unrecognised relationship between narcolepsy and psychiatric disorders. Narcolepsy is frequently misdiagnosed initially as a psychiatric condition, which contributes to the protracted time to accurate diagnosis and treatment. Narcolepsy is a disabling neurodegenerative condition that carries a high risk for the development of social and occupational dysfunction[25].

Deterioration in function may lead to the secondary development of psychiatric symptoms. Inversely, the development of psychiatric symptoms can lead to deterioration in function and quality of life. Comprehensive care for patients with narcolepsy should include surveillance for psychiatric illness and appropriate treatment when necessary[25].

Clinician vigilance in screening for these conditions can prevent delays in diagnosis and treatment of many comorbid medical illnesses[18].

Classification

The current diagnostic criteria for narcolepsy are outlined in the third edition of the International Classification of Sleep Disorders (ICSD-3), which were published by the American Academy of Sleep Medicine in 2014[26]. The diagnostic criteria for both types of narcolepsy are outlined in the table below.

Type 1 Narcolepsy
Both criteria A and B must be met:
A The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months.
B The presence of one (or both) of the following:
Cataplexy and a mean sleep latency of 8 minutes and two or more SOREMPs on an MSLT performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal PSG may replace one of the SOREMPs on the MSLT.
CSF hypocretin-1 concentration, measured by immunoreactivity, is either 110 pg/mL or < 1/3 of mean values obtained in normal subjects with the same standardised assays.
Type 2 Narcolepsy
Criteria A-E must be met:
A The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months.
B A mean sleep latency of 8 minutes and two or more SOREMPs are found on an MSLT performed according to standard techniques.
C Cataplexy is absent
D Either CSF hypocretin-1 concentration has not been measured or CSF hypocretin-1 concentration measured by immunoreactivity is either >110 pg/mL or > 1/3 of mean values obtained in normal subjects with the same standardised assay.
E The hypersomnolence and/or MSLT findings are not better explained by other causes such as insufficient sleep, obstructive sleep apnoea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal.

Diagnostic Tests

Clinical Examination

A clinical examination and detailed medical history are essential for diagnosis and treatment of narcolepsy. This examination can rule out or identify other neurological conditions that may be causing the symptoms. Individuals may be asked by their doctor to keep a sleep journal noting the times of sleep and symptoms over a 1-2 week period. Although none of the major symptoms are exclusive to narcolepsy, cataplexy is the most specific symptom and occurs in almost no other diseases [10]. The history should include specific questions about the hallmark features of narcolepsy, including cataplexy, sleep paralysis, and sleep-related hallucinations[7]. It is imperative to rule out insufficient sleep and other sleep disorders as a cause of daytime sleepiness. This can be done with a careful clinical history, actigraphy with sleep logs, and polysomnography[7].

Actigraphy

In the 2-4 weeks before actigraphy and subsequent testing, all medications with alerting or sedating properties (including antidepressants) should be tapered off to prevent influence on the results of the study[7]. Testing should start with a 1- to a 2-week monitoring period. The patient wears a bracelet that measures sleep-wake patterns and objectively quantifies sleep duration, bedtimes, and wake-up times. While undergoing this test, the patient should also keep a sleep log, noting perceived sleep quantity and schedule over the time period. This confirms whether sleep quantity is sufficient and helps rule out circadian rhythm disorders such as delayed sleep-phase disorder and insufficient sleep syndrome[7]. If actigraphy data suggest a circadian rhythm disorder or insufficient sleep that could explain the symptoms of sleepiness, then further testing should be halted, and these specific issues should be addressed. If actigraphy demonstrates the patient is maintaining a regular sleep schedule and allowing adequate time for nightly sleep, the next step is polysomnography[7].

Polysomnography

Polysomnography.jpg

Polysomnography (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[10]. The overnight PSG may show a sleep onset REM period (SOREMP) within the first 15 minutes of sleep onset, increased stage N1 sleep, and increased periodic limb movements[18]. A shortened REM latency may also be seen. In addition, polysomnography can assure that adequate sleep was obtained before the next step in testing[7].

Multiple sleep latency tests (MSLT)

If sufficient sleep is obtained on polysomnography (at least 6 hours for an adult) and no other sleep disorder is identified, a multiple sleep latency test is performed. The MSLT assesses daytime sleepiness by measuring how quickly a person falls asleep and whether they enter REM sleep.  On the day after the PSG, an individual is asked to take five short naps separated by two hours over the course of a day.  If an individual falls asleep in less than 8 minutes on average over the five naps, this indicates excessive daytime sleepiness.  However, individuals with narcolepsy also have REM sleep start abnormally quickly.  If REM sleep happens within 15 minutes at least two times out of the five naps and the sleep study the night before, this is likely an abnormality caused by narcolepsy[10].

A urine toxicology screen is typically performed on the day of the test to ensure that drugs are not affecting the results. Given the propensity for REM sleep in narcolepsy, another essential feature for diagnosis is the sleep-onset REM period (SOREMP). A SOREMP is defined as a REM latency of fewer than 15 minutes. A diagnosis of narcolepsy requires a SOREMP in at least 2 of the naps in a multiple sleep latency test (or one nap if the shortened REM latency is seen during polysomnography)[7].

Lumbar Puncture

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 and measure the level of hypocretin-1. In the absence of other serious medical conditions, low hypocretin-1 levels almost certainly indicate type 1 narcolepsy[10].

Differential Diagnosis

Narcolepsy is associated with a diagnostic delay of 8 to 15 years, and this delay may be more prolonged in females with narcolepsy[27].

This diagnostic delay may be attributable to several factors such as the mildness or gradual onset of initial symptoms, the lack of recognition of the condition by the patient or clinician, and mistaken diagnosis with other sleep disorders such as sleep deprivation or obstructive sleep apnea[28].

Furthermore, there is a high comorbidity burden in patients with narcolepsy, and the overlap of symptoms present in some disorders may also contribute to the lack of recognition of narcolepsy. It is important that clinicians have an awareness of narcolepsy, as delayed diagnosis results in delayed treatment, which increases the burden of the disease with detrimental effects on health care resource use, employment, and quality of life[28].

The table below contains a number of conditions that share similar symptoms to that of narcolepsy.

Classification Condition

Similarities

References
Sleep-related breathing Disorders Obstructive Sleep Apnoea Syndrome Excessive daytime sleepiness [18]
Central Sleep Apnoea Syndrome Excessive daytime sleepiness [18]
Frequent nocturnal awakenings  
Central Disorders of Hypersomnolence Idiopathic Hypersomnia Excessive daytime sleepiness [7]
Kleine-Levine Syndrome Excessive daytime sleepiness [29]
Neurological Disorders  Brain Tumours Excessive daytime sleepiness may occur in any intracranial hypertension syndrome or from tumours of the diencephalon or peduncular region, with no associated intracranial hypertension. [18]
Stroke Excessive daytime sleepiness is often a transient state between confusion, agitation, or even coma marking the initial period of the stroke.  [30]
Parkinson's Disease Excessive daytime sleepiness present in 16–50 % of people with Parkinson’s. [31]
Sudden irresistible sleep episodes facilitated by the intake of dopaminergic agonists.
Epilepsy Excessive daytime sleepiness in 17–28 % of patients with epilepsy [32][33]
Frontal lobe epilepsy causes increased sleep fragmentation and excessive daytime sleepiness.
Many antiepileptic drugs are known to induce excessive daytime sleepiness.
Hypersomnia Due to Medication/Substance Alcohol Intoxication Causes sedation for 3–4 hours and then insomnia  [18]
Stimulants, e.g. Cocaine/Caffeine Consumption can cause insomnia, and their withdrawal can cause sedation. 
Opioids Sedation which may eventually result in excessive daytime sleepiness. 
Amphetamine Excessive daytime sleepiness peaks during the first week of withdrawal and can persist for up to several weeks. 
Pscychiatric Conditions  Depression Fatigue/lack of energy [18][25]
Sleep initiation/maintenance difficulties
Reduced cognition
Poor school performance
Social withdrawal
Appetite changes (weight gain/loss) 
Anxiety Disorders Panic attacks and social phobias have been reported in as many as 53% of patients with narcolepsy.   [34]
Eating Disorders People with narcolepsy are frequently overweight 

Report irresistible and persistent craving for foods  

[25]
Binge eating with lack of control/restrictive actions to correct binging   [35]
Schizophrenia Excessive Daytime Sleepiness/Mania  [25][36]
Sleep initiation or maintenance difficulties
Hallucinations (auditory)
Catatonia
Reduced REM latency/increased REM density 
Social Isolation
Memory loss, slowness inactivity, mental confusion
Lifestyle Factors  Insufficient Sleep Syndrome Abnormal sleepy with daily periods of irrepressible need to sleep or daytime lapses into sleep [18][37]
Neurobehavioral deficits: including lapses of attention, slowed working memory, reduced cognitive function, depressed mood, and fatigue. 

Outcome Measures

Outcome Measure Description Reference
Epworth Sleepiness

Scale

The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire with eight questions that assess 'daytime sleepiness'. Using a 4-point scale (0-3), respondents are asked to rate their usual chances of dozing off or falling asleep while engaged in eight different activities. Most people engage in those activities at least occasionally, although not necessarily every day. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that person’s average sleep propensity in daily life (ASP), or their ‘daytime sleepiness’.  [38]
Functional Outcome of

Sleep Questionnaire 

This is the first self-report measure designed to assess the impact of disorders of excessive sleepiness (DOES) on multiple activities of everyday living. It assesses five factors: activity level, vigilance, intimacy and sexual relationships, general productivity, and social outcome. Thus, the FOSQ can be used to determine how disorders of excessive sleepiness affect patients' abilities to conduct normal activities and the extent to which these abilities are improved by effective treatment of DOES.  [39]
Narcolepsy Severity Scale The NSS is a 15-item scale that was developed to assess the frequency and severity of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted nighttime sleep.  [40]
Actigraphy Actigraphy utilises a portable device (actigraph) that records movement over extended periods of time. Actigraphy is based on the principle that there is reduced movement during sleep and increased movement during waking hours. Sleep-wake patterns are analysed from periods of activity and inactivity based on this principle.  [41]

Medical Management/Medications

Medications to Treat Excessive Daytime Sleepiness in Narcolepsy
Compound Doses Side effects/notes
Sympathomimetic stimulants:
D-amphetamine Sulfate 5–60 mg Irritability, mood changes, headaches, palpitations, tremors, excessive sweating, insomnia, anxiety, nausea, anorexia, tremor, psychosis, cardiovascular effects like hypertension and arrhythmias, abuse (rare)
Methylphenidate HCl 10–60 mg Same as amphetamines, less reduction of appetite or increase in blood pressure.
Pemoline 20–115 mg Less sympathomimetic effect, milder stimulant slower onset of action, occasionally produces liver toxicity
Non-amphetamine wake-promoting compounds:
Modafinil 100–400 mg No peripheral sympathomimetic action, headaches, nausea, anxiety, dry mouth, anorexia, diarrhoea, reduction of efficacy of oral contraceptives, Stevens-Johnson syndrome (rare)
Armodafinil 100–300 mg Similar to those of modafinil
Compounds improving disturbed night-time sleep and EDS
GHB

Sodium oxybate

20–40 mg/kg/night Overdoses (a single dose of 60–100 mg/ kg) induces dizziness, nausea, vomiting, confusion, agitation, epileptic seizures, and hallucinations and coma with bradycardia and respiratory depression evidence of withdrawal syndrome
Table adapted from: [18]
Medications to Treat Cataplexy in Narcolepsy
Medication Dose Side effects
Sodium oxybate 3g/night in divided doses titrated up to 4.5–9 g (once before bedtime and then 2.5–4 hours later) Nausea, mood swings, enuresis, headache, weight loss, sedation, sleepwalking, worsening of obstructive sleep apnoea; High salt content can worsen pre-existing hypertension, heart failure, and renal impairment.
Venlafaxine Short-acting: 37.5–75 mg twice daily; may transition to long-acting formulation once on a stable dose Nausea, dizziness, dry mouth, headache, insomnia, sexual dysfunction
Fluoxetine 20–60 mg once daily Nausea, headache, dry mouth, diarrhoea, sexual dysfunction
Sertraline 50–150 mg once daily Nausea, headache, dry mouth, diarrhoea, sexual dysfunction
Protriptyline 5–10 mg twice daily Dry mouth, constipation, light-headedness, urinary retention
Table adapted from: [18]

Non-Pharmacological Management

Management Strategies Target References
Structured

Nocturnal

Sleep

Avoid deprivations and shifts in sleep schedule Reduction of daytime sleepiness attacks [42]
Reduction of daytime sleepiness attacks 
Regular timing of nocturnal sleep (e.g., 10:30 p.m. to 7 a.m.)
Relaxation techniques before nocturnal sleep [131]
Avoidance of intense stimulation before nocturnal sleep
Daytime

Sleep

Schedules

Strategically timed naps 15-min naps at 12:30 and 5:00 p.m are significant on MWT [132]. Reduction of daytime sleepiness attacks [43][44][45]
Reduction of daytime sleepiness attacks 
Single long naps are better than multiple short naps, which in turn are better than not napping at all.
Planning napping strategies before using medications.
Dietary

Practice

Taking non-prescription stimulants(tea, coffee, etc.) at scheduled times. The caffeine content of six cups of strong coffee has about the same stimulant effect as 5 mg of dexamphetamine [113] Ensuring good sleep

hygiene and reduction of daytime sleepiness attacks

[46]
Abstinence or minimal use of alcohol.
Counselling

or Other Assistance

Counselling for reorganisation of lifestyle Improving

Quality of Life    

[46]
Counselling for reconsideration of the type of work
Individual or group psychotherapies [138]
Assist scheduling of alertness-requiring activities
Advocacy by a professional against employers
Table adapted from: [18]

Cognitive Behavioural Therapy

Cognitive behavioural therapy (CBT) is also used in the management of narcolepsy. It is proposed that CBT for narcolepsy should have three components[47]:

  • The cognitive component is aimed at modifying beliefs, motivations, and emotions that might play an important role in maintaining narcolepsy and emphasising the psychosocial effect of the disorder.
  • The behavioural component begins with specific techniques aimed at changing sleep-disordered behaviours or sleep-related disorder variables that are not compatible (e.g., sleep satiation and nap training).
  • The educational component seeks to instruct the patient regarding the nature of the disease, the mechanism of drug action, and precautions regarding the use of medication to achieve an overall understanding of the problem.

Cognitive Behavioural Therapy

Management Strategy  Target References
Systematic Desensitisation Reduction of cataplexy attacks [47]
Stimulus control Reduction of cataplexy attacks
Imagery rehearsal therapy Reduction of hypnagogic hallucinations and the ability to cope with them
Muscle relaxation Reduction of anxious situations that can assist in maintaining symptoms or impair patient quality of life
Lucid dreams Reduction of hypnagogic hallucinations and the ability to cope with them

Role of Physiotherapy

The relationship between sleep and physical activity in people with narcolepsy is not fully known and is likely complex.

People with narcolepsy are less physically active than people without this condition. People with narcolepsy exhibit more barriers to physical activity than controls, and generally have fewer opportunities to participate in activities due to time constraints associated with sleeping and social isolation. A vicious cycle can then be set up with inactivity promoting worse sleepiness[7], and then the symptoms of the disease reducing habitual physical activity (Matoulek et al., 2017). Less spontaneous activity has also been noted in narcolepsy patients[48]. Similarly, fewer steps are also taken by narcolepsy patients, with 35% fewer steps per day shown compared to healthy non-sedentary adults[49].

There are many comorbidities associated with narcolepsy, with data from a Danish National Patient Registry shows that patients with narcolepsy have a higher prevalence of diabetes, obesity, chronic obstructive lung disease, low back pain and arthritis and exhibit a trend towards higher mortality compared to controls. Furthermore, disease onset is frequently accompanied by a rapid weight gain, resulting in overweight or obesity[50]. Exercise could play a vital role in the management of these conditions and improve the quality of life in people with narcolepsy.

Lastly, evidence from a cross-sectional study showed that cardiopulmonary fitness was inversely related to the degree of sleepiness and the number of cataplexy attacks per month. Results from this study also showed that patients with narcolepsy have lower cardiopulmonary fitness compared to the general population[49]. Exercise could potentially be used as a non-pharmacological method to manage narcolepsy-related symptoms.

Resources

https://www.wakeupnarcolepsy.org/

American Sleep Association (ASA)

Talk About Sleep

National Sleep Foundation

References

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