Excessive Sleepiness and Narcolepsy: Clues from Genetics and Polysomnography

Abstract & Commentary

By Alan Z. Segal, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical Center. Dr. Segal reports no financial relationships relevant to this field of study.

Synopsis: The accurate diagnosis of narcolepsy requires detailed history as well as physiological and genetic testing.

Source: Morrison I, et. al. Diagnosing narcolepsy with cataplexy on history alone: Challenging the International Classification of Sleep Disorders (ICSD-2) criteria. European J Neurol 2010 doi:10.1111/j.1468-1331.2010.03223.x. Goel N, et. al. DQB1*0602 predicts interindividual differences in physiologic sleep, sleepiness, and fatigue. Neurology 2010;75:1509-1519.

A clinical diagnosis of narcolepsy is made based on a history of excessive daytime somnolence (EDS), sleep paralysis, and hypnagogic hallucinations. Given these features, narcolepsy then can be categorized into two groups based on the presence or absence of cataplexy. This categorization has important implications in terms of making a definitive diagnosis. If cataplexy is absent, then a sleep study—overnight polysomnogram (PSG) followed by a multiple sleep latency test (MSLT)—is required to confirm a diagnosis. In contrast, when cataplexy is present, the International Classification of Sleep Disorder (ICSD-2) allows for the diagnosis of narcolepsy without further study and states that a PSG and MSLT "should whenever possible" be performed.

There is considerable overlap between the symptoms described by narcoleptics and normal people. Sleep paralysis can be present as an isolated parasomnia and EDS can be multifactorial in nature, most prominently occurring as a result of unrecognized sleep disordered breathing. More importantly, the diagnosis of narcolepsy carries important implications in terms of treatment, most notably being long term therapy with amphetamines. These drugs carry the potential for abuse, or may be desirable as performance enhancers in otherwise normal people. There is the potential to "fake" cataplexy, with drop attacks occurring on a volitional basis.

The present study by Morrison et al., an extended case series, examined five individuals previously diagnosed with narcolepsy with cataplexy. Three cases were diagnosed by a primary care physician and two by a neurologist. None had prior sleep studies. When formally studied, no subject had an MSLT diagnostic of narcolepsy. One patient attempted to simulate rapid eye movement sleep (REM) by rolling her eyes. Three of five patients refused to accept that they were not narcoleptic. One patient did admit to "embellishing her history." As the authors note, while a constellation of spells of transient muscle weakness precipitated by emotion, EDS, vivid dreams, and hallucinations around sleep are compelling features in making a diagnosis of narcolepsy, data from PSG and MSLT can contradict the clinical picture. Furthermore, all five cases were studied genetically as well and none had the HLA DQB1*0602 allele. While this allele can be absent in 30%-50% of cases of narcolepsy without cataplexy, it should be positive in nearly 100% of patients with classic narcolepsy and cataplexy. As the authors note, measurement of CSF hypocretin levels (not done here) could provide additional diagnostic clarification.

In the second study referenced here, Goel et al examine whether DQB1*0602 status in a set of normal subjects, without a sleep disorders diagnosis, is correlated with sleep, subjective reports, and neurobehavioral measures. There were 92 DQB1*0602 negative and 37 DQB1*0602 positive subjects. Each subject was studied for two 10-hour baseline nights, followed by a Partial Sleep Deprivation (PSD) paradigm of 5 nights, with only 4 hours of total time in bed.

DQB1*0602 positive subjects were subjectively sleepier and more fatigued at baseline. On an objective test of sleepiness (the ability to resist sleep), however, DQB1*0602 positive subjects did not differ from DQB1*0602 negative subjects. The authors used spectral analysis of EEG to average delta activity across the night, defined as slow wave energy (SWE). This SWE can be understood as an overall homeostatic pressure to sleep. This SWE was lower in the positive subjects, although this was not a consistent finding in all EEG leads. SWE would be expected to decline over the course of the night, as sleep is accrued. This decline was seen in both groups, but was more prominent in positive subjects. Following PSD, both positive and negative subjects demonstrated a comparably greater sleep drive (increased SWE during the night), but positive subjects still had higher subjective reports of sleepiness and fatigue. Cognitive performance declined in both groups due to sleep deprivation and was not more severe in positive subjects.

During PSD, DQB1*0602 subjects showed a greater decrease in REM sleep latency compared to negative subjects. This tendency toward a shortened REM sleep latency, while not equivalent to the sleep onset REM seen in narcoleptics, may represent a suggestion of a shared trait between these DQB1*0602 subjects and narcoleptic patients.


Although all differences were not statistically significant, in general, the quality of sleep achieved by DQB1*0602 positive subjects overall was poorer, with difficulty staying asleep (more awakenings and wake after sleep onset) and less stage 3 sleep on PSG, during baseline and PSD. These data suggest that the DQB1*0602 positivity in normal subjects may be a marker for reduced homeostatic sleep pressure during sleep as well as associated with some features of narcolepsy, such as fragmentation of sleep architecture and a complaint of excessive daytime sleepiness. These data are suggestive that DQB1*0602 positivity may identify a subset of individuals who are not infrequently encountered in clinical practice—people who are sleepy during the day and complain of wakefulness at night.

The studies of Morrison and Goel, while very different in their subject populations and methodology, emphasize that accurate diagnosis of sleep disorders requires a combination of detailed and extensive history taking, neuro-physiological study (polysomnography), and adjunctive testing such as the use of genetic markers or possibly hormone levels.