"Why am I sleepy?"
Sorting the Somnolent

NEIL J. DOUGLAS

The University of Edinburgh, Respiratory & Sleep Medicine Unit, Department of Medicine, Royal Infirmary, Edinburgh, Scotland

	INTRODUCTION

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All respiratory physicians should know the causes of sleepiness, and many interested in obstructive sleep apnea/hypopnea syndrome (OSAHS) will manage patients with other causes of sleepiness, so they must keep abreast of developments in these areas. In this article, I will review the differential diagnosis of sleepiness, update the nonrespiratory causes of sleepiness, and describe how I manage sleepy patients who do not have OSAHS.

Sleepiness must first be differentiated from muscle fatigue, and this may be difficult. Detailed questioning on falling asleep or feeling sleepy is required, and in this the Epworth Sleepiness Scale (1) may be useful. Sleepy patients must first be asked whether they are getting 7 to 8 h sleep at night as sleepiness is often caused by sleep deprivation because of social or work reasons, and then psychologic factors or OSAHS must be considered (Table 1). A minority of cases of sleepiness have other medical causes that are the main topic of this article.

	UPDATE ON NONRESPIRATORY CAUSES OF SLEEPINESS

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Narcolepsy

Of the classic tetrad of narcolepsysleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysiscataplexy is the most specific. Sleep paralysis and hypnagogic hallucinations occur in several sleep disorders (2), and sleep paralysis occurs in normal subjects, particularly in young adults with irregular sleep times. The clinical features of narcolepsy usually begin in the teens or twenties, although they may start as early as 2 yr of age (3). However, delay in obtaining a diagnosis means that the diagnosis of narcolepsy is often made a decade or more after symptoms start. Onset after 50 yr of age is unusual.

Narcolepsy is about one hundredth as common as OSAHS, occurring in 2 to 5 per 100,000 white individuals (4). The prevalence is similar in American blacks.

Sleepiness. The sleepiness is most marked in the usual soporific situations, but many narcoleptics get irresistible sleep attacks in bizarre situations such as walking or standing.

Cataplexy. This is the sudden decrease or loss of voluntary muscle tone after emotion, usually laughter, sometimes anger or surprise. Typically, the jaw drops, the head nods, the arms drop to the side and the knees sag, but partial attacks are common. In some patients, attacks may be limited to head nodding. The presence of facial twitching during attacks is a useful pointer (5). Cataplectic episodes usually last only a few seconds but can last as long as 10 min. Usually, awareness continues throughout the attacks. Cataplectic attacks may be misdiagnosed as epilepsy (6).

HLA type. More than 85% of white and Japanese narcoleptics are HLA DR2 DQw1 positive (7). However, in Afro-Americans DR2 occurs in only 75%, whereas the association with DQw1 is as strong as in white individuals (8). Genomic mapping of the HLA DQw1 region shows that the DQB1*0602 allele is closely linked with narcolepsy across ethnic groups and is positive in 84 to 95% of narcoleptics with clear cataplexy (7, 9). However, it is present in around 22% of the normal white population and 40% of the normal black population (9), and so is of little diagnostic specificity. Interestingly, DQB1*0602 may be associated with short sleep latency in normal persons (10). There is some evidence that the best association with narcolepsy across ethnic groups is with DQB1*0602 and DQA1*0102 (11).

Gene defects. Doberman Pinscher dogs can have familial narcolepsy with sleepiness and cataplexy. This is transmitted as an autosomal recessive, and the gene point mutation causes a deletion in the transcript of the hypocretin type 2 receptor (Hcrtr2) (12). Hcrt gene knockout mice exhibit episodes of behavioral arrest that probably represent cataplexy (13). Hypocretins (also called orexins) are expressed by neurons in the lateral hypothalamus, which project into the brainstem and forebrain. The lateral hypothalamic region in which the Hcrt neurons are found includes the "appetite control center." Hcrt-producing cells express leptin receptor immunoreactivity, and genetically obese mice have down-regulated Hcrt gene expression. Microinjection of Hcrt induces feeding and increases basal metabolic rate (14).

However, human narcolepsy is rarely familial, twin studies have shown discordance (15), and narcoleptics do not appear to have defects in their hypocretin receptor genes. Thus, the relevance of these canine gene abnormalities to human narcolepsy is unclear, and environmental factors may be important. The association of narcolepsy with HLA types has led to the suggestion that it is an autoimmune disease, which results in destruction of hypocretin-producing cells, analogous to insulin-dependent diabetes, but this is unproven (16). Hypocretin levels were undetectable in seven of nine patients with narcolepsy, suggesting impaired hypocretin production (17) in many but, perhaps, not all narcoleptics. There is also recent evidence of decreased numbers of hypocretin-producing neurons in narcoleptics (18).

Investigation of Narcolepsy

When narcolepsy is suspected, a Multiple Sleep Latency Tests is the most useful diagnostic test; mean sleep latency is usually < 8 min, compared with > 10 min in normal persons. Sleep onset REM (SOREM), defined as REM sleep within 15 min of sleep onset, is common in narcolepsy. A less than 8-min mean sleep latency with 2 SOREM periods is clinically helpful when present but may occur in OSAHS, Periodic Limb Movement Disorder, circadian rhythm disturbances, and REM sleep deprivation (19). Conversely, only 71% of narcoleptics with cataplexy have a mean sleep latency of < 8 min and two or more SOREMs on initial MSLT, and even after repeated MSLTs this will not rise above 80% (19). Thus, not all narcoleptics show the classic changes.

However, I find the MSLT diagnostically helpful. I believe every effort should be made to confirm the diagnosis before embarking on potentially lifelong therapy with drugs that may be addictive. Another reason for doing MSLTs routinely is that the increasing publicity for narcolepsy has resulted in cases of Munchausen's syndrome presenting with classic features of narcolepsy but with normal MSLTs. In our experience, these patients may not sleep at all during MSLTs.

Treatment of Narcolepsy

Optimizing nocturnal sleep duration and planned daytime naps remain the cornerstones of therapy. Almost all patients will require medication for their sleepiness and/or their REM sleep intrusion phenomenon.

Sleepiness. The chose of stimulant to use in any particular patient is a balance between benefits and side effects, and trial and error is usually required. Unfortunately, most patients cannot achieve full alertness because of side effects. I start with milder drugs with fewer side effects and work down this list until the side effect/benefit ratio is optimized. The order I use is (and daily dose) Modafinil (200 to 800 mg), Mazindol (2 to 8 mg), Methylphenidate (10 to 100 mg), Selegiline (2.5 to 10 mg), and finally Dexamphetamine (5 to 60 mg), Modafinil is the agent with the greatest "evidence-based medicine" backing therapeutic efficacy (20, 21) However, there have been no head-to-head trials with other agents.

REM intrusive phenomena. Cataplexy, sleep paralysis, and hypnagogic hallucinations can be treated with REM-suppressing antidepressants. Fluoxetine 20 to 40 mg daily is probably the current treatment of choice, although protriptyline 5 to 30 mg daily, clomipramine 20 to 200 mg daily, or imipramine 50 to 250 mg daily may also be effective. Several different drugs may need to be tried before optimal control is achieved.

	PERIODIC LIMB MOVEMENT DISORDER

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This ill-defined condition is an association between recurrent limb movements every 20 to 40 s during non-REM sleep and daytime sleepiness, frequent nocturnal awakenings, or difficulty initiating sleep. Most people with periodic limb movements during sleep (PLMS) are asymptomatic and PLMS are extremely common, occurring in 30% of those 50 to 65 yr of age and nearly 50% of those older than 65 yr of age (22). Although PLMS are associated with evidence of arousalalbeit sometimes not detectable on the EEG (23)there is no correlation between PLMs and sleepiness (23). The situation is further confused as some patients may previously have been mislabeled as having "PLMD", when they actually had OSAHS (24) with their limb movements occurring in association with hypopnea-induced arousals. However, their hypopneas may have been missed because inadequate (thermal) sensors (25) were used. PLMD is associated with the Restless Leg Syndrome (RLS), which is characterized by an intense urge to move the legs and motor restlessness, which are worse in the evening or night (26). There has been considerable interest in the finding that patients with RLS have low iron levels (27). This consistent finding is of considerable pathophysiologic interest, but its clinical significance is unclear, and placebo-controlled trials of iron therapy for 12 wk have shown no clinical benefit (28). There are placebo-controlled studies showing benefit in patients with RLS from L-dopa (29, 30) or pergolide (31) in terms of reducing PLMS and improving subjective sleep quality. However, there are no adequately powered randomized controlled trials investigating the benefits of any therapy in PMLD without restless legs (32). It is thus questionable whether it is necessary to investigate sleepy patients for PLMD, unless they have symptoms of RLS, or whether PLMD even exists as a distinct clinical syndrome causing sleepiness (33).

	IDIOPATHIC HYPERSOMNOLENCE

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Idiopathic hypersomnolence was named before OSAHS was identified. As idiopathic hypersomnolence is a diagnosis of exclusion, the condition has gradually become less common and is now believed to affect around 4 per 100,000, a prevalence one-tenth that of narcolepsy and one-thousandth that of OSAHS (34, 35).

Nocturnal sleep is often prolonged; in the morning, wakening is difficult and slow and sleep drunkenness may occur. Naps tend to be prolonged and are usually unrefreshing. The combination of the unrefreshing naps and the potential for abnormal behavior thereafter makes some patients struggle to stay awake as long as possible. In some, idiopathic hypersomnolence is self-limiting, resolving after several years; in others, it persists.

Diagnosis

As idiopathic hypersomnolence is a diagnosis of exclusion, a "firm" diagnosis requires a typical history, including nocturnal sleep durations of > 7 h and a regular sleep-wake cycle plus normal overnight polysomnography, including the absence of recurrent arousals from sleep. OSAHS and the so-called upper airway resistance syndrome must be excluded (36). A Multiple Sleep Latency Test should also be performed both to confirm the presence of objective daytime sleepiness and to exclude the presence of SOREMs. The greatest diagnostic difficulty is often with narcolepsy without cataplexy.

Treatment

This is symptomatic only. Alcohol, sleep deprivation, and shift work should be avoided. Planned daytime naps are generally unhelpful and may result in confusional episodes. Sleepiness is treated using the same drugs as for narcolepsy.

	NEUROLOGIC LESIONS

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Tumors and infarcts in the brain can both cause marked sleepiness. This is particularly common in tumors of the posterolateral hypothalamus, pineal or upper brainstem, and infarcts affecting the paramedian thalamopeduncular area (37). Head injuries can be followed by sustained sleepiness, usually starting within 1 yr of the injury. Multiple sclerosis and encephalopathy may also be complicated by sleepiness.

	PSYCHOLOGIC/PSYCHIATRIC

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Depression is often associated with daytime sleepiness (38). Some patients react to stress by increased sleepiness with or without insomnia. This is usually temporary, but occasionally the symptoms may last months or years. Usually, there is no objective sleepiness on the MSLT.

	DELAYED SLEEP PHASE SYNDROME

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This condition is most common in adolescents and young adults and is characterized by a late sleep onset time in association with a late awakening time. Indeed, although wakening during the week is often achieved by parents, if parents are left to sleep themselves, such as at weekends, they will often sleep into the afternoon. These patients complain of difficulty awakening in the morning and marked morning sleepiness. Many cases may be associated with depression (39), but it is not clear whether this is cause or effect. Diagnosis is from history, confirmed if necessary by a sleep log and actigraphy. Treatment is by gradual phase advance (by 15 to 30 min every night) combined with bright light exposure on wakening (40).

	SHIFT WORK

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Sleep disturbance caused by shift work is a major cause of sleepiness. Problems are most common in those on night or on rotating shifts that require varying sleep times. Many workers on permanent night shift revert to nocturnal sleep patterns on weekends. This difficulty is greater in older subjects (41). Many will admit to falling asleep recurrently at work, which may have contributed to several notable accidents. Night-shift workers report falling asleep at the wheel significantly more often than do those working by day (42) and many of them, as much as 95% in one series (43), report road accidents or near accidents when driving to and from work. All sleepy patients should be carefully questioned about shift patterns and sleep times. Treatment with bright lights has been tried in some shift workers with success in terms of obtaining a more rapid phase shift, better subjective sleep, and improved mood (44, 45).

	CAUSES OF INTERMITTENT SLEEPINESS

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Kleine-Levin Syndrome

This rare syndrome is characterized by recurrent attacks of daytime sleepiness associated with bizarre eating and sometimes with hypersexuality. The onset is usually in adolescence, and the association of disturbance of sleep and sometimes temperature rhythms has led to the unsubstantiated suggestion of a hypothalamic or circadian disorder (46).

The most marked features are attacks of prolonged sleep and alterations of appetite. During episodes, patients may sleep for more than 20 h a day. Attacks last up to several weeks, with an average of 5 to 7 d, with 1 to 12 mo between attacks. There may be changes in awareness, mood, and cognitive and sexual function immediately before and during attacks. Hypersexuality occurs in 25% of cases, and is totally out of keeping with the patients' normal behavior. Overeating before and during attacks can be extreme, with weight gains of as much as 25 pounds during an attack. Episodes are often followed by depression and disgust at the overeating, but sometimes by euphoria and sleeplessness. Cases occur without coexisting eating or mental disturbance, and indeed this may be more common than the classic form. Although the Kleine-Levin Syndrome was originally reported to be self-limiting, only 20% of 96 subjects followed for a mean of 6 yr had stopped having attacks.

Diagnosis is helped if the patient is seen during a prolonged sleep attack that can be confirmed by EEG recording. Stimulants may reduce the severity of sleep attacks in some patients. Lithium or carbamazepine may reduce the frequency of subsequent episodes (47, 48).

Menstrually related. Rarely, severe sleepiness may recur at the start of the menstrual cycle (49). This usually commences in adolescence. Oral contraceptives may be effective.

	HOW I INVESTIGATE SLEEPY PATIENTS: A PERSONAL VIEW

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I believe that everyone with sleepiness causing recurrent problems with driving or work impairment or an Epworth Sleepiness Score of 12 or more (5), despite having > 7 h to sleep in bed each night, should be investigated, unless they have varying sleep times caused by shift working. How I investigate them will depend on history.

1. Sleepy snorers have a home-based limited sleep study without electroneurologic recording (50). Those with > 30 apneas + hypopneas/h in bed will proceed directly to a CPAP trial; a lower frequency will be followed by polysomnography in the sleep center to ensure adequate sleep quality and identify other possible causes of sleepiness (50, 51).

2. Patients with a history suggesting narcolepsy (possible cataplexy or frequent sleep paralysis or hypnagogic hallucinations, and onset before middle age) or idiopathic hypersomnolence will have an MSLT (52). To save overnight laboratory use and costs, we do this after a normal night's sleep at home, which does not significantly alter the MSLT result compared with spending the previous night having an in-lab polysomnography (53). To ensure an adequate sleep duration was obtain at home, that night is actigraphically monitored. Overnight investigation is not performed, unless the story suggests OSAHS. An MSLT of less than 8 min with any SOREMs and a history of cataplexy will result in treatment for narcolepsy. In those without a clear history of cataplexy, an MSLT of less than 10 min without two SOREMs results in overnight polysomnography principally aimed at occult SAHSfollowed by a repeat MSLT. Consistent objective sleepiness will result in the appropriate diagnostic label and therapy aimed at promoting wakefulness.

3. Patients with history of restless leg syndrome plus sleepiness will have overnight polysomnography to confirm the diagnosis of PLMD before treatment is commenced.

4. Any patient suspected of psychologic or psychiatric illness will be referred for an appropriate opinion either before or after initial investigation depending on likelihood.

5. Patients having MSLTs or reporting persisting sleepiness despite normal PSG will have unannounced urine drug screens to detect undeclared sedative or stimulant use.

6. If drug screen is negative and reported sleepiness severe, I perform 2 wk of home actigraphy to document sleep durations followed by an MSLT. If nocturnal sleep duration > 6.5 h, a daytime sleep latency of < 8 min will result in a trial of therapy, if sleep latency > 10 min psychologic/psychiatric assessment will be discussed.

7. Episodic sleepiness: when possible, I perform an MSLT during a sleepy episode to document objective sleepiness.

	Footnotes

Correspondence and requests for reprints should be addressed to Correspondence and requests for reprints should be addressed to Neil J. Douglas, M.D., FRCPE, Professor of Respiratory & Sleep Medicine, The University of Edinburgh, Respiratory Medicine Unit, Department of Medicine, Royal Infirmary, Edinburgh EH3 9YW, Scotland, UK. Email: n.j.douglas{at}ed.ac.uk

(Received in original form July 7, 2000 and in revised form September 6, 2000).

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TOP INTRODUCTION UPDATE ON NONRESPIRATORY CAUSES... PERIODIC LIMB MOVEMENT DISORDER IDIOPATHIC HYPERSOMNOLENCE NEUROLOGIC LESIONS PSYCHOLOGIC/PSYCHIATRIC DELAYED SLEEP PHASE SYNDROME SHIFT WORK CAUSES OF INTERMITTENT... HOW I INVESTIGATE SLEEPY... REFERENCES

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