Introduction and clinical features

Narcolepsy is not a rare disorder, with an estimated prevalence of 1 per 2000 in white populations. However, differences in case ascertainment and the availability of sleep services have led to considerable variance in reported rates worldwide. Moreover, there is undoubtedly a spectrum of severity and many mildly affected individuals are either undiagnosed or diagnosed only after many years of symptoms. It most often starts in adolescence, with a second minor peak in early middle age. Symptoms are generally life-long, although most people with the condition develop coping strategies to minimize the impact of the syndrome.

Narcolepsy is important, not least because it is usually disabling, influencing every aspect of daily living. Many people with narcolepsy feel a sense of underachievement, partly because treatment is frequently either delayed or only partially effective. A perceived lack of medical interest in the disease, together with the adverse effects on schooling, careers, and relationships, understandably produces frustration. Secondary mood disorders are seen in many patients.

Rather than reflecting true hypersomnolence over a 24-hour period, narcolepsy is best viewed as a primary disorder of sleep–wake regulation (Fig. 24.5.3.2), with an inability to stay awake for more than a few hours as the most obvious symptom. Indeed, excessive daytime sleepiness not explained by another disorder remains an essential diagnostic criterion. Many patients describe sudden and irresistible urges to sleep, often in public or inappropriate situations, invariably worse if they are unoccupied or bored. In contrast to most other sleep disorders, short naps lasting minutes can often be restorative. A few people with the condition are relatively unaffected by excessive daytime sleepiness and other features of the syndrome predominate.

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Fig. 24.5.3.2

Comparisons of typical hypnograms over 24 h in a control person and someone with untreated narcolepsy. In the narcoleptic trace, there is severe disruption of the usual pattern with numerous daytime naps containing rapid eye movement (REM) sleep. Overnight, the usual sleep architecture is disorganized in the person with narcolepsy with several awakenings and associated movement. MT, significant movements; W, wake.

Cataplexy

Cataplexy is a curious phenomenon, highly specific to narcolepsy and present to varying degrees in two-thirds of patients. It is particularly important to identify typical cataplexy because its presence in a person with excessive daytime sleepiness is diagnostic of narcolepsy. Full-blown episodes reflect an intrusion of profound muscle paralysis that descends over a few seconds from head to the lower limbs, often causing collapse to the floor. Identifiable triggers usually have an emotional content. Laughter or other positive emotions such as a pleasant surprise are the most common precipitants, although frustration and anger can also reliably provoke episodes. In some individuals the mere thought or anticipation of an emotional event can cause collapse. Reassuringly, attacks are rare in dangerous situations and most patients report cataplexy only when relatively relaxed in familiar environments with friends. It is therefore very uncommon for doctors to witness episodes, making a reliable history crucial for confident diagnosis. Importantly, partial or focal attacks are common and can be subtle, perhaps confined to the jaw or neck. Occasionally, an inability to tell the punchline of a joke due to a stuttering dysarthria may be the only manifestation. Facial twitching or head bobbing is very common as an episode starts and can lead to diagnostic confusion. Crucially, awareness is preserved in cataplexy, although in rare instances, when attacks last more than a minute or so, dream-like intrusions and altered consciousness may intercede. Severely affected individuals may have over 20 attacks a day, often reporting that the amusement or frustration induced by the cataplectic episodes themselves can prolong the period of weakness.

It is widely thought that cataplexy occurs because REM sleep paralysis intrudes inappropriately into the wakeful state. Indeed, as in REM sleep, a person is rendered temporarily areflexic during an episode as a result of descending inhibitory neural impulses from lower brainstem centres directly on to motor neurons. Some evidence suggests that this phenomenon may occur to a minor degree during emotion in control individuals, adding credibility to the adage ‘going weak with laughter’.

Sleep paralysis and hallucinations

Sleep paralysis and hallucinations around sleep–wake transition are the other two components of the narcoleptic ‘tetrad’ first described in 1957. However, only 25% of patients have all four elements, and the presence of these other symptoms, particularly sleep paralysis, is not specific to narcolepsy. Sleep paralysis is usually frightening, primarily because of an inability to take deep breaths voluntarily. Most episodes occur at the point of waking, although people with narcolepsy may also report episodes at sleep onset. Accompanying sensations of being crushed, with or without vivid visual hallucinations, may add to the distress of the episodes. Similar to cataplexy, this phenomenon reflects the intrusion of REM sleep elements into the wakeful or drowsy state.

Hallucinations occurring at sleep onset (hypnagogic) or as the person wakes (hypnopompic) are usually visual and can be both vivid and disturbing, especially in children. They represent fragments of dream mentation intruding into the conscious state, reinforcing the notion that people with narcolepsy cannot adequately maintain a consistent and stable state of wakefulness or sleep.

When questioned, most people with narcolepsy have fragmented nocturnal sleep. Although this may be due to the intrusion of a parasomnia or obstructed breathing, both of which are more common in people with narcolepsy, the primary problem is one of sleep regulation and maintenance. The notion that people with narcolepsy have problems sleeping at night is counterintuitive to some but is an important addition to the original descriptions of the syndrome.

Other symptoms

In addition to obvious naps, most people with narcolepsy will experience numerous ‘micro-sleeps’ through the day, in which awareness during activities is compromised for a few seconds. The resulting lapses lead to automatic and inappropriate behaviours, with worrying consequences for complex and potentially dangerous tasks such as driving. Although difficult to characterize, many people with narcolepsy also report significant problems with memory and concentration as a result of their sleep–wake difficulties. Furthermore, increasing evidence suggests abnormalities of appetite, particularly at night, with cravings for sweet foods. Moderate obesity is more common in narcolepsy and may have a metabolic explanation because there is no link with excessive food intake. Indeed, some evidence suggests that overweight people with narcolepsy eat less than average.

Pathogenesis and diagnosis

Since the discovery in 1984 that Japanese people with narcolepsy were extremely likely to carry the human leucocyte antigen (HLA) haplotype DR2, an autoimmune basis for the syndrome has been thought likely. The predisposing antigen has since been established to be DQ-B1*0602, which is present in over 90% of people with narcolepsy and cataplexy and around 50% of those without cataplexy, compared with a frequency of 20% in control populations. Of interest, homozygosity for DQ-B1*0602 appears to confer an even greater risk for the syndrome. Direct evidence for autoimmunity, in the form of either serum markers or CSF abnormalities, remains elusive and narcolepsy is rarely associated with other manifestations of autoimmunity. A minority of patients studied close to disease onset appear to have increased titres of specific immunoglobulins such as antistreptolysin O, although the significance of this remains uncertain. Further possible support for an autoimmune aetiology comes from the observation in Finland and Sweden that a significant surge in childhood cases appeared to associate temporally with vaccination against pandemic H1N1 influenza. This finding has not been observed clearly in other European countries and case-control studies will be needed to clarify the potential link. However, of interest, a threefold increase in narcolepsy was reported in China in 2009 following the H1N1 pandemic in the absence of a significant vaccination programme. This may imply that any nonspecific activation of the immune system may confer an increased risk of narcolepsy, potentially in those with a predisposition for the disease.

A major breakthrough in understanding the neurobiology of narcolepsy occurred in 1999 when two groups independently demonstrated abnormalities of a recently described neuropeptide, hypocretin (also called orexin), in separate animal models. The well-established autosomal recessive Doberman model was shown to have dysfunctional hypocretin receptors, whereas a mouse hypocretin knockout model developed convincing clinical features of narcolepsy with cataplexy. Subsequently, it has been demonstrated that CSF hypocretin is virtually absent both in sporadic canine models and in people with narcolepsy and cataplexy. Indeed, a CSF hypocretin level of less than 110 pg/ml is now considered diagnostic. Postmortem evidence has confirmed that pathology in narcoleptic brains is confined specifically to hypocretin neurons, potentially supporting the theory that they are destroyed by an autoimmune process. Confusingly, however, in rare familial narcolepsy and in sporadic cases without typical cataplexy, hypocretin levels can be preserved, implying that there is more than one pathogenic mechanism for certain forms of the syndrome.

Following the unexpected involvement of the hypocretin system in human narcolepsy, it has been intensely studied in intact animals. Around 30 000 neurons containing the peptide are confined to the lateral hypothalamus but innervate all the arousal systems in the brain. Levels of hypocretin rise towards the end of the waking day, especially in the presence of peptide hunger signals or if the person is expecting food. Activity of hypocretin neurons therefore appears to stabilize a state of wakefulness when the organism needs to be alert. In narcolepsy their absence leads to inappropriate switches between sleep and wakefulness. Moreover, transitions between behavioural states may be incomplete, explaining the intrusion of REM sleep phenomena such as paralysis into wakefulness. The mechanism by which emotional stimuli (in particular) trigger cataplexy remains elusive. However, recent evidence from functional brain imaging techniques suggests that narcoleptic patients may have abnormal processing of emotional information.

If typical cataplexy is absent and CSF hypocretin levels cannot easily be measured, a positive diagnosis of narcolepsy can be made following a multiple sleep latency test. This test measures the propensity for a person to fall asleep by recording the average length of time to reach light sleep in a conducive environment over four or five nap opportunities between 9.00 am and 3.00 pm. If the mean sleep latency is less than 8 min and REM sleep is achieved within 15 min on at least two occasions, the criteria for narcolepsy are fulfilled. Reliable results depend on ensuring a reasonable night’s sleep preceding the investigation, and the test also requires a strict protocol to avoid false-negative results.

Secondary narcolepsy

Narcoleptic symptoms including cataplexy have been reported in other neurological conditions. Given the recent advances in the understanding the neurobiology of the primary syndrome, it is not surprising that pathology in the region of the hypothalamus such as tumours around the third ventricle can lead to secondary narcolepsy, presumably by depletion of hypocretin-containing neurons. However, the mechanism of severe sleepiness or sleep–wake dysregulation after head injury or as components of other conditions such as multiple sclerosis and Parkinson’s disease can be difficult to explain.

The various subtypes of narcolepsy are shown in Table 24.5.3.3.

Treatment

Advice on lifestyle helps some people with narcolepsy. Planned naps, especially after meals, may improve wakefulness. Furthermore, the avoidance of large meals rich in refined carbohydrates is reportedly beneficial to some. Most people with narcolepsy, however, benefit from medication to improve daytime wakefulness (Table 24.5.3.4), although few are normalized. Modafinil is the most widely used wake-promoting agent and has partly replaced traditional psychostimulants. Its mechanism of action remains obscure, but a direct effect on arousal centres in the hypothalamus is postulated. It has no definite positive effect on cataplexy. Side effects are rare and include headache or gastrointestinal upset. Interactions with the oral contraceptive pill and uncertainty over safety in pregnancy may limit its use in young women.

In severe sleepiness or if modafinil is unsuccessful, central stimulants with a predominantly dopaminergic action, such as dexamfetamine, are helpful, especially if used flexibly. Despite prescriber concerns, it is rare for psychological addiction to occur in narcolepsy, although tolerance may require increasing doses with time. Cardiovascular side effects such as hypertension are relatively rare but necessitate caution in older people. Given the different mechanisms of action, a combination of modafinil and a psychostimulant is appropriate. Additional use of caffeine and setting aside time for planned naps may reduce the need for medication.

About a half of people with narcolepsy also require specific treatment for cataplexy. Although the evidence base is small, most antidepressants will suppress cataplexy by increasing cerebral monoaminergic activity and inhibiting the tendency to enter REM sleep, although the side-effect profile of most antidepressant drugs, particularly the tricyclics, may limit their usefulness. A new approach for troublesome cataplexy is to use sodium oxybate, and trial evidence suggests that this drug helps daytime sleepiness as well. It is a liquid preparation taken before bed and—due to its short half-life—once during the night if the person is awake. The effects on cataplexy are striking after several weeks of therapy, with almost 90% of attacks abolished. Inadvertent daytime naps, and objective and subjective measures of daytime sleepiness also improve. The agent appears to work, in part, by inducing deep restorative sleep early in the night, such that the sleep drive is effectively dissipated by the following morning. The drug should be used with extreme caution in any patient living alone or with young children in case confusional episodes from deep sleep are provoked. However, if disturbed nocturnal sleep is a major symptom, it appears a logical treatment given that standard benzodiazepine hypnotic agents rarely induce refreshing sleep in narcolepsy.

Following the recent findings that most people with narcolepsy are deficient in the neuropeptide hypocretin, an obvious therapeutic goal will be to develop replacement therapy. There appear to be clinical effects if hypocretin levels are increased in animal models by intracerebral infusion, hence the development of an oral analogue that penetrates the blood–brain barrier is a current pharmacological goal for treatment in humans.

In line with the theory that narcolepsy may have an autoimmune basis, a number of small open trials have examined various forms of immunomodulation in treatment, especially if it is diagnosed near disease onset. However, results have generally been disappointing and it is thought placebo effects on cataplexy, for example, may have been substantial.