Section 1: Epidemiology and aetiology
The term narcolepsy meaning 'to be seized by somnolence' was first coined in 1880 by Gelineau, a Parisian neuropsychiatrist. Now, it is generally considered as a rare and esoteric disorder even though it probably affects at least one in 3,000 in caucasian populations.1
Its relatively low profile may partly reflect the patchy exposure to sleep medicine most doctors receive during training. However, over the past two decades, it has become increasingly clear that narcolepsy is more than a syndrome causing excessive somnolence. Rather, it is a potentially disabling primary sleep disorder with several elements that affect patients over a 24-hour period. Moreover, it is a fascinating condition that can be rewarding to both diagnose and treat.
There is a clear peak of incidence around early adolescence although it may take many years for symptoms to be correctly diagnosed as narcolepsy.2
Cases starting in early childhood or even middle age are rarer but increasingly recognised. There are usually no defined triggers or precipitants, although individual patients may sometimes report a viral illness or minor head injury that seemed to precede their sleep-related symptoms.
In most, the onset is insidious but some develop severe somnolence and other symptoms of narcolepsy subacutely, over a matter of days or weeks. In a few patients, particularly females around puberty, there may be associated weight gain and appetite dysregulation.
Arachnoid cyst of the third ventricle causing secondary narcolepsy
From studying the genetic profile of canine narcolepsy, a landmark study in 1999 identified mutations in the receptors of a newly discovered hypothalamic neuropeptide called hypocretin (also known as orexin).3
Remarkably, it has emerged that human narcolepsy, certainly in its most severe form, is due to specific loss of these hypocretin-containing neurons, numbering around 30,000 in the lateral hypothalamus.4
Given the tight association of classical narcolepsy with a particular human leukocyte antigen phenotype (DQB1 *0602), it was immediately assumed that these neurons were specifically destroyed by a monophasic autoimmune process to cause the syndrome.
Clear evidence to support this theory remains scanty although a number of candidate potential pathogenic autoantibodies have been identified in patients with narcolepsy.5
The neurobiology of the hypocretin system is under intensive scrutiny and has provided valuable clues into how the brain regulates sleep and wake across the 24-hour cycle.
It appears to stabilise the state of wakefulness, preventing sudden 'switches' to sleep.
Almost certainly, however, its role is not confined to sleep regulation.
The fact that narcolepsy is explained by a precise and discrete neurochemical deficiency was a major breakthrough and emphasises the life-long nature of a primary sleep disorder that often starts at a young age.
Specific treatments to restore the deficiency remain a realistic if distant goal. The notion of secondary narcolepsy is also evolving given that rare cases are seen where there is clear structural or inflammatory pathology in the region of the hypothalamus (see image above).
Section 2: Making the diagnosis
Patients with narcolepsy have significant excessive daytime sleepiness (EDS) rather than simple fatigue, usually with irresistible naps in monotonous situations. Some will also experience 'sleep attacks' in which the prior desire to sleep is not recalled. Even short naps, however, may be restoring.
It is common to experience automatic behaviours in narcolepsy in which patients perform inappropriate behaviours while seemingly 'switched off', for example, placing unusual objects in the fridge or simply losing items around the house.
The most specific symptom of narcolepsy is cataplexy, which is diagnostic for the condition and therefore important to recognise accurately. It affects around 65 per cent of patients and has a wide range of severity, occasionally reflecting the most disabling aspect of the syndrome.
In cataplexy, episodes of muscle paralysis typically occur for a few seconds. Virtually all voluntary muscles may be involved in severe episodes lasting up to a few minutes. Crucially, awareness is maintained during episodes. Minor episodes may be common and go unrecognised, merely limited to head bobbing, facial jerking or slurred speech.
There are usually clear triggering emotional factors to cataplectic episodes, particularly laughter in the relaxed company of friends or family.
However, surprise, frustration, anger or even eating may precipitate events.
Poor overnight sleep is very common in narcolepsy. Parasomnias (undesirable and involuntary motor behaviours) may occur in any sleep stage and sleep maintenance is usually poor. Sleep paralysis and disturbing hallucinations in any modality may contribute. Many report vivid nocturnal dreams that may be confused with reality. It is also common for subjects to vocalise or even lash out during apparent 'dream sleep'.
A patient should fall asleep within eight minutes, at least, on a standardised multiple sleep latency test (MSLT) and rapid eye movement (REM) sleep should be attained on at least two out of four nap opportunities during the morning and early afternoon.6
The MSLT is sensitive to deviations from a strict protocol and also dependent on both sleep quantity and quality the previous night, making interpretation hard. The effects of drugs or their sudden discontinuation can also skew results. Narcolepsy in the UK may be under-diagnosed based on suboptimal data from MSLTs.
If full polysomnography is available, it may show a short latency to REM sleep and frequent non-specific arousals through the night with dysregulation of the normal cycles of non-REM/REM sleep.
The neuropeptide hypocretin can be measured in lumbar cerebrospinal fluid and levels are virtually undetectable in classical cases of narcolepsy with cataplexy. Unfortunately, it is a very specialised test and is rarely helpful in cases of clinical diagnostic doubt.
|KEY POINTS FOR DIAGNOSIS|
Section 3: Managing the condition
Even with treatment and lifestyle adjustments, it is rare for severely affected individuals to be completely normalised with respect to their sleep-wake cycles.
Excessive daytime sleepiness
EDS is usually the most disabling aspect of narcolepsy and may lead to considerable under-achievement at school and work, especially if a timely diagnosis has not been made.
Wake-promoting medication is usually appropriate. For more than 10 years, modafinil has been the first-line drug for EDS in narcolepsy. Its precise mechanism of action remains obscure although it may have a direct action on the wake-promoting systems within the hypothalamus.
A starting dose of 100mg early morning and lunchtime is typical. This may be doubled after a few weeks. Some prefer to take the drug as a single dose. Common side-effects include transitory headache and mild GI upset.
There may be mild cardiovascular consequences although the effects on BP are usually minor and serious side-effects appear rare. Severe rashes resembling Stevens-Johnson syndrome have been reported in children.
A significant proportion of patients benefit from additional treatment with more traditional and non-specific psychostimulant drugs, such as dexamfetamine or methylphenidate, although the latter is unlicensed for this use.
Low doses of both drugs (less than 30mg daily) as a supplement to modafinil are typical.
A flexible treatment regime is usually advocated.
Micrograph of brain tissue showing hypocretin (red), the neuropeptide that regulates wakefulness (Photograph: SPL)
In approximately 40 per cent of patients symptoms of cataplexy are frequent or severe enough to warrant specific therapy. By their ability to suppress REM sleep, most antidepressants will improve cataplexy which reflects REM sleep paralysis intruding into the wakeful state.
Evidence to guide choice of drug is lacking but the most widely used agent is long-acting venlafaxine (75-225mg daily). Tricyclics, such as clomipramine (10-50mg daily), may also be effective but tend to produce more side-effects.
The controversial drug sodium oxybate appears to be very effective for cataplexy. The drug is a liquid taken before bed and again in the early hours, around 2am, if the subject is spontaneously awake.
It has a short half-life and reliably enhances deep non-REM sleep and may help to restore normal nocturnal sleep. Overnight sleep continuity is improved and data suggest that daytime somnolence also responds to the drug.
Side-effects are rare and usually relate to nocturnal phenomena, such as bed-wetting or confusional arousals. Care should therefore be taken if a patient sleeps alone.
Unfortunately, although it was given a UK license for narcolepsy with cataplexy more than four years ago, it is rarely prescribed, largely due to expense. There are also potential fears of misuse, given that it is the sodium salt of gamma-hydroxybutyrate, notoriously used for 'date-rape'.
Sleep maintenance insomnia
In a significant proportion of patients it is appropriate and useful to recommend long-term hypnotic therapy, usually in the form of clonazepam (0.5-1mg), zopiclone (7.5-15mg) or long-acting melatonin (2mg). Although these drugs may improve sleep continuity, the positive effects on abnormal dreams and sleep quality are unpredictable.
If a case of narcolepsy is diagnosed within a few months of symptom onset, many specialists would recommend immunosuppressant therapy, usually IV immunoglobulin, on the theoretical grounds that there is autoimmune destruction of hypocretin-containing neurons.
The evidence for this approach is mixed. Future directions will focus on delivering hypocretin analogues to the brain, an approach which has produced promising results in animal models.
Section 4: Prognosis
Due to the nature of the condition, spontaneous improvement is not seen. Many patients feel obliged to adapt their lifestyles and avoid potentially embarrassing situations or social interactions that might trigger cataplexy.
As a result, many risk becoming reclusive. Taking higher education or holding down employment, especially in a sedentary occupation, usually presents problems unless a flexible approach is adopted, for example, if brief naps throughout the day are allowed.
Patients frequently report frustration or even secondary mood disorders, often fuelled by lack of understanding about the potentially debilitating effects of the condition. Worsening sleepiness in narcolepsy after years of stability should raise the possibility of a comorbid sleep disorder, such as obstructive sleep apnoea or restless legs syndrome.
The driving regulations regarding narcolepsy are difficult to interpret but patients need to notify the DVLA of their diagnosis. If specialist opinion deems they are satisfactorily controlled with regards to excessive somnolence and cataplexy, a normal driving licence is usually granted. Reassuringly, in practice, it appears rare for people with narcolepsy to be involved in sleep-related road accidents.
Section 5: Case study
With no prior history of sleep disorder, Mr G first developed EDS in his second year at university. His peer group found it amusing that he would fall asleep in nightclubs and that he would write nonsense prose down the page during lectures, in a state of apparent 'half sleep'. His symptoms were attributed to a hectic lifestyle but interfered greatly with his studies.
In his final year, he started to experience unusual dreams during both overnight sleep and brief daytime naps. These were vivid and occasionally disturbing with a hallucinatory component. A psychiatric concluded he had mild depression.
Around this time his sleep became fragmented and he started to sleep walk. These episodes included frequent 'sleep eating' in which he would gorge on food, gaining 20kg in weight over several months.
With hindsight, he reported subtle episodes of cataplexy over a number of years. An inability to articulate the punch line of jokes or the need to sit down if he met a friend unexpectedly were typical examples.
Despite seeing a number of specialists, including neurologists, he was not diagnosed with narcolepsy until four years after symptom onset. During this time he had been unable to work and was significantly disabled by his sleepiness and inability to engage with normal activities. He had moved back to live with his parents and had become reclusive, rarely leaving the house to socialise.
Once diagnosed, he made an initial, albeit partial, response to venlafaxine and modafinil with occasional dexamfetamine tablets (5mg) during the day. After a year of canvassing his local PCT to sanction a trial of sodium oxybate, this drug was eventually started with an immediate positive effect.
After six months of 6g taken through the night, all of his narcoleptic symptoms were markedly improved, as was his mood. Dexamfetamine and venlafaxine were discontinued and he is currently applying for work.
Section 6: Evidence base
Disappointingly, there is little controlled evidence to guide treatment choices and protocols in narcolepsy.
Several randomised trials have assessed sodium oxybate, which is the newest, most effective and, unfortunately, most expensive drug for narcolepsy. Good results for efficacy are seen in all domains.7
Sodium oxybate is considered an orphan drug and has not been assessed by NICE.
The Scottish Medicines Consortium examined the drug in 2006 for the specific treatment of cataplexy and concluded the case had not been made for cost effectiveness.8
However, the drug's license has since been expanded to include the other core symptoms of narcolepsy, which will presumably have an influence on any further economic considerations.
The most recent comprehensive guidelines were produced by the European Federation of Neurological Sciences in 2006.9
There have been no significant developments in treatment strategies since then.
Textbooks on sleep medicine tend to be unwieldy and geared more to an American readership.
A recent text more suited to a European approach covers all the sleep disorders from a neurological perspective, including narcolepsy with discussion of recent developments in its treatment and neurobiology.10
Many patients benefit from interacting with other patients, usually through the internet via patient support groups and forums.
Narcolepsy UK (www.narcolepsy.org.uk) is an increasingly influential resource and lobbying body which organises national meetings and has a website with useful information for both patients and doctors.
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1. Longstreth WT Jr, Koepsell TD, Ton TG, et al. The epidemiology of narcolepsy. Sleep 2007; 30: 13-26.
2. Morrish E, King MA, Smith IE et al. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med 2004; 5: 37-41.
3. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor gene. Cell 1999; 98: 365-76.
4. Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355: 39-40.
5. Overeem S, Black JL III, Lammers GJ. Narcolepsy: immunological aspects. Sleep Med Rev 2008; 12: 95-107.
6. International Classification of Sleep Disorders, Diagnostic and Coding Manual. 2nd Edition. Westchester, IL: American Academy of Sleep Medicine 2005.
7. Xyrem International Study Group. Further evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double-blind, placebo-controlled study in 228 patients. Sleep Med 2005; 6: 415-21.
8. The Scottish Medicines Consortium www.scottishmedicines.org.uk/SMC_Advice/Advice/sodium_oxybate__Xyrem_/so dium_oxybate__Xyrem_
9. Billiard M, Bassetti C, Dauvilliers Y et al. EFNS guidelines on management of narcolepsy. Eur J Neurol 2006; 13: 1035-48.
10.Overeem S, Reading PJ, eds. Sleep disorders in neurology: A practical approach. Wiley-Blackwell, Oxford 2010.
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