Recent research suggests that when studying narcolepsy etiology, environmental factors may be just as important as genetics.

 If you were to pick up any one of the numerous articles published recently on narcolepsy, it would invariably start with a short paragraph that began with a description of the disorder and concluded by saying that narcolepsy is most likely caused by the combination of genetic and environmental risk factors. Despite this consensus on the importance of environmental factors in narcolepsy, there has been virtually no research in this area until recently.

Overview of Narcolepsy
In order to create a homogeneous patient population, specialists often stress the importance of cataplexy in the diagnosis of narcolepsy.1 Cataplexy is a sudden and brief loss of skeletal muscle tone with a retention of consciousness that usually occurs in response to hearing or telling a joke, laughter, or anger.2 This emphasis on cataplexy is appropriate since it is indeed the only unique symptom of narcolepsy and such methodology is crucial to research on the cause of the disorder. The drawback is many patients will present with profound idiopathic sleepiness that is not accompanied by cataplexy. Nevertheless, this article will adopt the definition of narcolepsy as the minimum combination of excessive daytime sleepiness and cataplexy.

The prevalence of narcolepsy is approximately one in 2,000, and symptoms typically appear shortly after puberty.3,4 Other core symptoms aside from sleepiness and cataplexy include intense hypnagogic hallucinations and frequent episodes of sleep paralysis. Automatic behaviors and alterations in nocturnal sleep are also commonly recognized as features of the disorder. Sleepiness is typically the most debilitating symptom, and the disorder results in severe quality of life impairments that are comparable to the impairments associated with epilepsy.5

The Genetic Side of the Equation
The prevalence of narcolepsy is approximately 30 times higher in first-degree relatives of narcolepsy patients compared to the general population.6 However, linkage studies have failed to provide evidence of Mendelian inheritance patterns in multigenerational narcoleptic families,4 and at least 80% of narcolepsy cases are actually sporadic.7

Narcolepsy also shows one of the strongest associations with a human leukocyte antigen (HLA) polymorphism of any putative autoimmune disorder; at least 85% of patients with severe cataplexy are HLA positive. Despite the fact that only recently has preliminary evidence emerged for an immune abnormality in narcolepsy,8 the HLA polymorphism is clearly important to the etiology of the disorder. The strength of the association increases with the severity of cataplexy,9 and homozygosity carries a higher risk over heterozygosity10; however, several studies have revealed that this polymorphism is neither necessary nor sufficient for narcolepsy to develop.

The discovery that narcolepsy in Doberman pinschers is caused by a recessive mutation in the gene for the hypocretin-2 (orexin-B) receptor11 clearly stands as one of the most important discoveries in sleep research since the discovery of REM sleep. Aside from leading to the discovery of the hypocretin neuropathology in post-mortem tissue from human patients,11,12 we are now aware of a new neuromodulator that is absolutely fundamental to the regulation of sleep and wakefulness; however, although a large number of human patients were screened—including several from multigenerational families—only one of these cases was caused by a hypocretin gene mutation.11 This actually fits with the observations in canine narcolepsy. Everyone thinks of the Dobermans when they think of canine narcolepsy, but in reality, sporadic cases in other breeds that are not genetically simple are much more common, just as in human narcolepsy.

The Other Side of the Equation
When defining narcolepsy as reviewed above and when considering only cases with an MSLT-supported diagnosis, 11 cases of narcolepsy in a monozygotic twin pair have been reported in the literature. Of these 11 cases, four were concordant. This would suggest that approximately 64% of the variance in whether you will develop narcolepsy is determined by environmental factors. More interestingly, in two of the four concordant twins, the difference between the ages of onset was at least 30 years.13,14 Therefore, it is likely that differential exposure to environmental risk factors controlled when symptoms began.

Consistent with this idea, 20% to 50% of patients will report that their symptoms began after a specific event. For example, in a study that examined 273 cases, 50% reported such an event and the most common events were a major change in sleeping habits (41%) and a psychological stressor (38%).15

Beware the Ides of March
The idea that birth month can serve as an environmental risk factor for neurological and psychiatric disorders is well established. For example, the month-of-birth pattern of schizophrenia patients in the northern hemisphere displays a prominent plateau of births in late winter/early spring. This effect is reversed in the southern hemisphere and cannot be explained by the presence of other confounding variables.16 Theories to explain this pattern have focused on the fact that the second trimester is a sensitive period of neurodevelopment. If an individual were born in the late winter/early spring, the second trimester would correspond to the peak of the flu season. Several studies have demonstrated that the incidence of schizophrenic births increases after an influenza epidemic.

The first study to evaluate the month-of-birth pattern in narcolepsy used 886 patients from France, the United States, and Canada.17 This research demonstrated that there is a prominent and isolated peak of narcolepsy births in March. Although the general population percentages for month of birth do not deviate greatly from the equal expected proportion of 8.3%, this study verified the statistical significance of this peak by comparing it to data from national birth registries from each country. The proportion of patients born in March was 11.9%, while the proportion of the general population born in March was 8.5%.

This finding was soon replicated using another sample of 436 narcolepsy patients from the United States.18 Similar to the previous study, this research verified the statistical significance of the March peak by comparing the obtained proportion of narcolepsy births to the expected proportion based on data from the National Center for Health Statistics. The proportion of patients born in March in this sample was 13.1% while the proportion of the general population born in March was 8.3%. The fact that the magnitude of the effect size is very similar in both studies supports the veracity of this discovery.

The same study also extended this finding by performing a separate analysis to determine whether the presence and severity of cataplexy would moderate this relationship. This is a crucial question since the strength of the association with the HLA polymorphism increases as cataplexy severity increases. A group of 94 patients without cataplexy was added to the sample, and the patients with cataplexy were separated according to severity of this symptom. Similar to the pattern observed with the HLA polymorphism, as cataplexy severity increased, the proportion of patients who were born in March increased. At the most severe ratings of cataplexy, 30% of the patients were born in March; however, in contrast to the HLA association, there was no elevation in March births for patients without cataplexy and patients with mild cataplexy.

Although future research on the pattern itself is certainly warranted (collecting data from the southern hemisphere), the most immediate question pertains to the potential causes of the March peak. In a similar vein as the theories proposed to explain the pattern in schizophrenia, the second trimester may be a sensitive period of neurodevelopment where a noxious agent could increase the liability for developing narcolepsy; however, a March birth would correspond to a second trimester that precedes the peak of flu infections near January; the second trimester would instead fall closer to September. Interestingly, this closely corresponds to the yearly peak of rhinovirus infections.

Case-Control Research
Only two case-control studies have examined the role of environmental risk factors in narcolepsy. The first was published as part of the proceedings for the 4th International Symposium on Narcolepsy held more than 10 years ago.19 This study examined the risk of life events (major psychological stressors) that occurred in the year prior to symptom onset using a structured questionnaire. The results revealed that 84% of the narcolepsy patients reported one or more life events in the year prior to cataplexy onset, compared with 36% in a matched year for the control group. The most common life events were a major change in sleeping habits (26%), a major personal injury or illness (20%), and a major change in the health of a family member (16%).

The second case-control study will be presented at this year’s Associated Professional Sleep Societies meeting in Denver.20 This study examined the cumulative risk of infectious diseases and psychological stressors throughout the life span prior to cataplexy onset. The control group was frequency matched on current age and reported events prior to the age of 20 since this is the median age of cataplexy onset. Participants were mailed a structured questionnaire (The Narcolepsy Environmental Triggers Survey) that assessed the frequency and timing of each risk factor. Unexplained fever and a major change in sleeping habits were significant risk factors; however, the most remarkable finding of this study was that stressors in general acted as a risk factor only if they occurred before puberty. In association with the month-of-birth results and the fact that narcolepsy typically appears shortly after puberty, this finding supports the idea that there may be a sensitive period where environmental risk factors trigger a process that ultimately leads to the development of narcolepsy later in life.

Conclusion
Several avenues exist for future research in this area. Most important, more case-control studies are needed. It may also be useful to explore the use of preventative strategies in recent onset cases. Case study research suggests that the removal of the environmental trigger may result in permanent remission.21 Symptoms in this case began 6 months prior to diagnosis and coincided with the initiation of an irregular sleep schedule. Normalization of the patient’s sleeping habits resulted in a remission of symptoms as assessed both clinically and polysomnographically. The patient was followed for an additional 10 years and was still in remission. Given there is usually a long delay between the onset and diagnosis of narcolepsy, research on preventative strategies would need to be preceded by programs designed to increase the awareness of narcolepsy in medical, academic, and public circles.

It is unequivocal that human narcolepsy is not a genetically simple disorder. There is a consensus that the best model for narcolepsy is one that incorporates both genetic and environmental risk factors. As such, any future research must take environmental factors into account if a complete understanding of the etiology of narcolepsy is to emerge.

Dante Picchioni, PhD, is a graduate of the doctoral program in experimental psychology at the University of Southern Mississippi, Hattiesburg. His training focused on the epidemiology and pathophysiology of narcolepsy as well as the neural control of normal sleep.

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