Narcolepsy is a chronic neurological condition producing disruption to the normal sleep pattern. This produces excessive sleepiness. Narcolepsy may occur with or without cataplexy. Cataplexy is a sudden loss of muscle tone and power in response to strong emotion¹ - it always and only occurs as part of narcolepsy.

The term "narcolepsy" was first used by Gelineau in 1880 to describe a pathological state of daytime sleepiness and is a term derived from the Greek "seized by somnolence".²

Epidemiology²

• Prevalence is estimated as 25 per 100,000 in Caucasian populations.³
• Age of onset is typically around adolescence. A smaller number of cases presents at around 35 years.
• There is a male predominance.
• First-degree relatives are at increased risk of narcolepsy compared with the general population.

Aetiology^1,2

The precise cause is unknown; both environmental and genetic factors may play a part:

• The peptide hypocretin (orexin) may be involved. This is derived from the hypothalamus and is thought to be involved in sleep/wake cycles, food intake and pleasure-seeking behaviour. Narcolepsy may be caused by the loss of a relatively few neurons that are responsible for producing the neuropeptide hypocretin in the CNS. Possibly, immunological mechanisms may lead to loss of hypocretin.
• Narcolepsy is associated with a specific HLA allele, DQB1*0602.
• Most cases are sporadic, but a familial form occurs in a small proportion of narcolepsy patients.
• Possible triggers include head trauma, infection and change in sleep habits.
• Studies from Sweden and Finland have suggested a possible association with the influenza vaccine H1N1 ('swine flu' vaccine). Research on this topic is ongoing.^4,5

Physiology¹

• Patients with narcolepsy usually have a total sleep time similar to that of non-narcoleptic patients, but their sleep is fragmented, with loss of night-time sleep and daytime naps.
• Dysregulation of rapid eye movement (REM) sleep may be part of the mechanism; people with narcolepsy may enter REM sleep more quickly than those without narcolepsy. Cataplexy, sleep paralysis and hypnagogic hallucinations may be due to REM sleep intruding into wakefulness.⁶

Presentation^1,2

There is a tetrad of classic symptoms: excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations and sleep paralysis. However, many patients do not have all these features. EDS and cataplexy are the key diagnostic symptoms.

EDS

• Patients have persistent sleepiness, which may be irresistible.
• They may nap during normal activities such as eating and talking.
• Automatism occurs in many narcolepsy patients - when affected by severe sleepiness, they may have episodes in which they appear to be awake, but lack full awareness, and may behave inappropriately at such times.
• EDS symptoms can severely disrupt daily life.

Cataplexy^7,8

Cataplexy is defined as a sudden loss of voluntary muscle tone, with preserved consciousness, triggered by emotion.³ The emotional stimulus may be, for example, laughter, pleasure, anger or excitement. The attacks can last just a few seconds or many minutes. Cataplexy is pathognomonic for narcolepsy, and is present in 50-90% of narcolepsy patients.

Features of a cataplexy attack:

• Severity can vary, e.g. from a barely susceptible slackening of the facial muscles, dropping of the jaw or the entire head, to weakness at the knees or collapse on to the floor. In severe attacks, all voluntary muscles except the diaphragm may be affected.
• May have slurred speech and visual symptoms such as blurred vision or diplopia.
• Hearing, awareness and consciousness are intact.
• Frequency varies, from several attacks per day to less than one per year.³
• The weakness is usually bilateral, but one case report describes unilateral attacks.⁹

Sleep paralysis:

• May occur as the patient is falling asleep or awakening.
• Patients are aware, but are, briefly, unable to move or open their eyes.
• Affects approximately a third of narcolepsy patients.
• May be alarming, and associated with a sensation of inability to breathe (although diaphragmatic breathing usually continues through the episodes).

Hypnagogic hallucinations

• These occur at the onset of sleep (hypnagogic) or on awakening (hypnopompic).
• Often visual, but may be auditory, tactile or multisensory.

Assessment

History

A thorough history is important with particular reference to:

• Normal sleep pattern.
• Sleepiness in unusual situations, e.g. using Epworth Sleepiness Scale.¹⁰
• Other medical conditions, employment, alcohol or drugs, medication and family history.
• A careful description of symptoms/attacks (if considering cataplexy, sleep paralysis or hallucinations).
• Specifically ask patients about partial weakness, e.g mild facial or jaw weakness, which they may not report.

Investigations^2,3

• The Epworth Sleepiness Scale is helpful for quantifying daytime sleepiness.¹⁰
• Sleep studies - overnight polysomnogram followed by multiple sleep latency test (MSLT). The MSLT is an objective test of sleepiness.
• EEG.
• Brain MRI to exclude other causes, e.g. space-occupying lesions.
• CSF hypocretin levels - low CSF hypocretin is thought to be a sensitive test in cataplexy patients; its usefulness for narcolepsy without cataplexy is uncertain.

Diagnosis

Diagnosis is clinical, based on a thorough history, analysis of sleep patterns and (if necessary) exclusion of other causes.²

Diagnostic criteria³

For narcolepsy with cataplexy:

1. Excessive daytime sleepiness, almost daily for ≥ 3months.
2. Cataplexy, defined as sudden, transient episodes of loss of muscle tone, triggered by emotions.
3. If possible, confirm the diagnosis by nocturnal polysomnography followed by a multiple sleep latency test (MSLT) - see 'Investigations', above. Alternatively, confirm by CSF hypocretin-1 levels ≤110 pg/ml, or one third of mean control values.
4. The hypersomnia is not better explained by another condition (sleep disorder, medical or neurological condition, mental disorder, substance misuse or medication).

For narcolepsy without cataplexy:

1. Excessive daytime sleepiness, almost daily for ≥3 months.
2. The diagnosis must be confirmed by nocturnal polysomnography followed by an MSLT - see 'Investigations', above.
3. The hypersomnia is not better explained by another condition (sleep disorder, medical or neurological condition, mental disorder, substance misuse or medication).
4. Typical cataplexy not present, though atypical or uncertain episodes may be reported.

Differential diagnosis²

There is a wide differential diagnosis:

• Excessive daytime sleepiness - alternative causes are sleep deprivation, obstructive sleep apnoea, drugs/toxins, and various other causes of hypersomnia.
• Automatism - may mimic partial complex seizures.
• Cataplexy - may mimic drop attacks, syncope, seizures/epilepsy, transient ischaemic attack, periodic paralysis (channelopathies), psychiatric disorder, or cataplectic-like episodes (the latter can occur in healthy people).
• Sleep paralysis - can be an isolated, physiological occurence; other causes are periodic paralysis, familial sleep paralysis or upper brain stroke.
• Hypnagogic hallucinations - may mimic psychosis, sleep onset rumination, or temporo-occipital brain lesions.

Management^2,3

Referral¹⁰

Patients with suspected cataplexy/narcolepsy should be referred to a sleep disorder service. Once diagnosed, management should be under a clinician with experience of narcolepsy management.

Nondrug treatment

For excessive daytime sleepiness (EDS)

• Good sleep hygiene - a strict sleep schedule providing 7-8 hours' night-time sleep.
• Strategic daytime naps - scheduled naps can reduce EDS.
• Regular exercise may improve energy and sleep patterns.
• Education of family, friends and colleagues, who need to understand that the urge to sleep can be irresistible.

For cataplexy

• Support and information for the patient and their family, as full-blown cataplectic attacks can be frightening.
• Family members can learn to recognise the onset of attacks, to help prevent falls and injuries.
• There is no known cure - treatment aims to control symptoms. Therefore, drug treatment should be avoided if cataplexy is not causing a significant problem for the patient.

Drug treatment

Drug treatment of EDS and other sleep symptoms

• Stimulants (amfetamines and methylphenidate) have been used for decades, but with significant side-effects.
• Modafinil:
  • Its sole indication (currently) is for narcolepsy, to treat EDS. It may also help cataplexy symptoms.
  • Caution is advised in a recent Medicines and Healthcare products Regulatory Agency (MHRA) notice (see box).
• Antidepressants (tricyclic or selective serotonin reuptake inhibitors (SSRIs)) may improve symptoms of sleep paralysis or hypnagogic hallucinations.
• Benzodiazepines (short-acting) are sometimes used to consolidate night-time sleep, in refractory cases.

European guidelines of 2006 suggest the following strategy for drug treatment of EDS:³
First-line is modafinil (but note subsequent new MHRA warnings, below); second-line is methylphenidate; third-line (in severe cases) is modafinil combined with sodium oxybate.

Drug treatment of cataplexy³

Note: if anticataplectic drugs are stopped abruptly, rebound cataplexy can occur - including, rarely, status cataplecticus (see 'Complications', below). Drug treatment options are:

• Sodium oxybate (previously known as gamma-hydroxybutyrate (GHB)):
  • European guidelines suggest this as first-line treatment.
  • Most patients improve within a few days of starting the drug, but the full response response may take three months.
• Antidepressants:
  • Tricyclic antidepressants, particularly clomipramine. Low doses (e.g. 10-20 mg daily of clomipramine) can be very effective, so start at low dose.³
  • SSRIs - probably less active against cataplexy, but they have fewer adverse effects.
  • Newer antidepressants such as venlafaxine and reboxetine have been used, although there are fewer clinical data regarding their effectiveness with cataplexy.¹³ One report suggests that there is a difference in effectiveness between the different formulations of venlafaxine, with the extended-release formulation being less effective for cataplexy.⁷
  • Although clinical consensus is that antidepressants can be helpful for cataplexy, the evidence base is lacking.¹⁴
• Selegiline is another possible treatment for both EDS and cataplexy, but its use is limited by potential drug and diet interactions, and there is little clinical experience with its use in this scenario.¹³

Complications^1,2

• Problems related to tiredness, e.g. poor concentration and memory.
• Interference with life and work - daytime sleepiness and cataplexy attacks may affect employment, driving, social/personal relationships and general wellbeing.
• Falls or injuries during cataplexy attacks.
• Status cataplecticus - can occur if anticataplectic medication is stopped abruptly. Patients may have frequent or prolonged cataplexy attacks, which can be frightening.

Prognosis^3,8

• Symptoms are usually lifelong, but may be improved with treatment or after retirement.
• Cataplexy may sometimes disappear over time, either spontaneously or with treatment. Again, it may improve after retirement.

Research¹

Possible future treatments might involve:

• Immunological therapies, e.g. intravenous immunoglobulin, immunosuppression.
• Histamine H3 receptor agonists.
• Hypocretin replacement (difficult, as does not cross the blood brain barrier).

Document references

1. Peacock J, Benca RM; Narcolepsy: clinical features, co-morbidities & treatment. Indian J Med Res. 2010 Feb;131:338-49. [abstract]
2. Khan F, Hazin R, Iqbal M; Narcolepsy: clinical decision making for the primary care physician. South Med J. 2009 Dec;102(12):1246-52. [abstract]
3. EFNS guidelines on management of narcolepsy, European Federation of Neurological Societies (2006)
4. Watts G; New findings on H1N1 vaccine prompt revised prescribing advice. BMJ. 2011 Apr 18;342:d2524. doi: 10.1136/bmj.d2524.
5. Caplan AL; Duty to warn?-the ethics of disclosing information about possible risks Sleep. 2010 Nov;33(11):1426-7.
6. Nishino S, Okuro M, Kotorii N, et al; Hypocretin/orexin and narcolepsy: new basic and clinical insights. Acta Physiol (Oxf). 2010 Mar;198(3):209-22. Epub 2009 Jun 25. [abstract]
7. Plazzi G, Montagna P, Provini F, et al; Treatment of narcolepsy with cataplexy. Lancet. 2007 Mar 31;369(9567):1081.
8. Dauvilliers Y, Arnulf I, Mignot E; Narcolepsy with cataplexy. Lancet. 2007 Feb 10;369(9560):499-511. [abstract]
9. McCarty DE; A case of narcolepsy with strictly unilateral cataplexy. J Clin Sleep Med. 2010 Feb 15;6(1):75-6. [abstract]
10. Zeman A, Britton T, Douglas N, et al; Narcolepsy and excessive daytime sleepiness. BMJ. 2004 Sep 25;329(7468):724-8.
11. At a Glance Guide to the Current Medical Standards of Fitness to Drive, Driver and Vehicle Licensing Agency, Swansea
12. Drug Safety Update - Modafinil; Medicines and Healthcare products Regulatory Agency (MHRA), March 2011
13. Morgenthaler TI, Kapur VK, Brown T, et al; Practice parameters for the treatment of narcolepsy and other hypersomnias of Sleep. 2007 Dec 1;30(12):1705-11. [abstract]
14. Vignatelli L, D'Alessandro R, Candelise L; Antidepressant drugs for narcolepsy. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003724. [abstract]

Internet and further reading

• Peterson PC, Husain AM; Pediatric narcolepsy. Brain Dev. 2008 Nov;30(10):609-23. Epub 2008 Mar 28. [abstract]
• Dauvilliers Y, Arnulf I, Mignot E; Narcolepsy with cataplexy. Lancet. 2007 Feb 10;369(9560):499-511. [abstract]
• Horsley W; Sodium oxybate in the management of narcolepsy with cataplexy, North East Treatment Advisory Group, December 2009
• Bozorg AM et al; Narcolepsy, Medscape, Feb 2010
• Zaharna M, Dimitriu A, Guilleminault C; Expert opinion on pharmacotherapy of narcolepsy. Expert Opin Pharmacother. 2010 Jul;11(10):1633-45. [abstract]

Acknowledgements