Sleep Medicine xxx (2014) xxx–xxx
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Original Article
Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China Huijuan Wu a,b, Jianhua Zhuang a,1, William S. Stone c, Lin Zhang a, Zhengqing Zhao a, Zongwen Wang a, Yang Yang a, Xiang Li a, Xiangxiang Zhao a,b, Zhongxin Zhao a,b,⇑ a
Department of Neurology, Changzheng Hospital, Second Military Medical University, Shanghai, China Institute of Neuroscience and MOE Key Laboratory of Molecular Neurobiology, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai, China c Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA b
a r t i c l e
i n f o
Article history: Received 25 October 2013 Received in revised form 12 December 2013 Accepted 19 December 2013 Available online xxxx Keywords: Narcolepsy Cataplexy Childhood Excessive weight gain Precipitating factors H1N1 pandemic Han Chinese
a b s t r a c t Objective: Our study was designed to assess symptomatology and occurrences of narcolepsy in Eastern China between 2003 and 2012. Herein we report the substantial changes in the occurrence and clinical features of narcolepsy over the last decade in China. Methods: We performed a retrospective analysis of 162 Han Chinese patients with narcolepsy at Changzheng Hospital, Shanghai, China. Clinical histories and precipitating factors were recorded, in addition to narcolepsy and H1N1 winter flu pandemic (pH1N1) occurrences at Changzheng Hospital. The occurrences also were compared between the Changzheng Hospital and the People’s Hospital, Beijing, China. Results: In our sample, narcolepsy occurred 1.73 times more frequently in men than in women. Most of the participants were children, which peaked to 91% in 2010. Excessive daytime sleepiness (EDS), disrupted nocturnal sleep, cataplexy, and weight gain were the four major symptoms. We found that 40% of patients had identifiable precipitating factors. The occurrence of narcolepsy in 2010 showed an approximate three-fold difference from the baseline levels at the Changzheng Hospital, which showed positive relationships with occurrences of pH1N1 in Shanghai and the occurrence of narcolepsy at the People’s Hospital. Conclusions: Our findings show the interactive effects of geography and H1N1 disease in relation to narcolepsy in Han Chinese populations, and strengthen the theoretic hypothesis that immune and mental factors facilitate the onset of narcolepsy. Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction In 1880 narcolepsy was first reported as an independent syndrome by Gélineau, a French physician [1]. Narcolepsy was known as ‘‘an excessive daytime sleepiness (EDS), accompanied typically by cataplexy attacks, and the symptoms associated with rapid eye movement sleep, such as sleep hallucinations and sleep paralysis’’ [2,3]. However, narcolepsy is now understood to affect multiple functions in addition to sleep. It has been estimated that the core pathologic mechanism of narcolepsy is the loss of large quantities of hypocretin (orexin) neurons in the hypothalamus [4–7].
⇑ Corresponding author at: Department of Neurology, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. Tel./fax: +86 21 81885451. E-mail address: [email protected] (Z. Zhao). 1 Equal contribution.
Narcolepsy not only destroys orexin system, but also considerably affects endocrine, metabolism, and mood regulation systems [8– 11]. Narcolepsy is not a common disease, and the prevalence of narcolepsy with cataplexy varies from 0.002% to 0.167% worldwide [12,13]. The prevalence of narcolepsy in Hong Kong, a Southern Chinese city, is approximately 0.033% [14]. It is suspected that racial difference and latitude/climate factors may contribute to these variances [15]. However, in 2010 many studies from Northern Europe reported a worldwide increased occurrence of narcolepsy following the H1N1 winter flu pandemic (pH1N1) of 2009 [16–20]. Groups in Finland and Sweden reported that children vaccinated with adjuvanted AS03 flu vaccine, a combination of squalene and a-tocopherol, had a six- to nine-fold increased risk for narcolepsy [17–19]. No association was seen between influenza A (H1N1) vaccinations and narcolepsy in Asia [20,21]. A large retrospective study in the north of China [20] revealed that pH1N1 virus
http://dx.doi.org/10.1016/j.sleep.2013.12.012 1389-9457/Ó 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: Wu H et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China. Sleep Med (2014), http://dx.doi.org/10.1016/j.sleep.2013.12.012
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H. Wu et al. / Sleep Medicine xxx (2014) xxx–xxx
infections or winter infections might increase susceptibility to narcolepsy in children, but there was no significant correlation between the increased incidence of narcolepsy and pH1N1 vaccinations in China. These studies strengthen the hypothesis that narcolepsy is associated with immunologic mechanisms [15–22]. During the review of the clinical data in our study, we found significant fluctuations in narcolepsy rates of occurrence at the Changzheng Hospital, Shanghai in Eastern China during the last 10 years. Our study was reported 3 years after the 2009 H1N1 winter flu pandemic, which was long enough to review its effects and begin to consider its relationships with other conditions. The purposes of our study were as follows. First, we examined symptoms and rates of narcolepsy based on the accumulated cases of narcolepsy at the Changzheng Hospital. Second, we examined several precipitating factors for onset of narcolepsy including the pH1N1 and other infections, in addition to emotional stimulation. Finally, we compared the trend of narcolepsy occurrence at the Changzheng Hospital with the occurrences of pH1N1 in the Shanghai area, as well as with the occurrence at the People’s Hospital, Beijing, China, to represent hospitals in Eastern and Northern China, respectively.
history of sleepiness, history of fever, respiratory infections and infections of the digestive system within 6 months prior to disease onset, history of influenza vaccination, and precocious puberty. Major clinical manifestations included EDS, attacks of cataplexy, nocturnal sleep disturbances, hypnogogic hallucinations, sleep paralysis, considerable weight gain, mood disturbances, or irritability. Because one of the symptoms of narcolepsy is nocturnal sleep disturbance, we used the criterion for nocturnal sleep disturbance as defined for insomnia [2]. Nocturnal sleep disturbance was defined as fragmented sleep during the night, night sleep awakening 2 times or more for durations longer than 30 min, or sleep efficiency less than 90% [2]. Weight gain was defined as considerable weight gain after narcolepsy onset, weight increase of more than 5% per month, or weight gain of more than 30% a year, with an increased body mass index. The clinical manifestations of precocious puberty included premature breast and pubic or axillary hair development before the age of 8 years in girls [23] and 9 years in boys [24]. Some of the younger participants also were examined for serum gonadotropic hormone stimulation curves and X-rays of the wrist to determine bone age and chronologic age ratios.
2. Material and methods
2.4. Control data
2.1. Patients
The control data for our study involved the occurrences of narcolepsy from 2003 to 2012 at the Sleep Center of People’s Hospital [25], Beijing University (permitted by F. Han), and the occurrences of pandemic H1N1 infection between 2009 and 2012 from the Shanghai municipal center for disease control and prevention (provided by H.L. Su).
Patients diagnosed with narcolepsy at the Changzheng Hospital, Second Military University, Shanghai, China were included in our study from March 2003 to December 2013. Standard nocturnal polysomnography (nPSG) and multiple sleep latency tests (MSLT) were used to diagnose narcolepsy. Diagnosis of narcolepsy was based on the International Classification of Sleep Disorders: Diagnostic and Coding Manual, second edition, criteria [2]. Due to a lack of cerebrospinal fluid of orexin detections, we used the same criteria to diagnose narcolepsy with or without cataplexy. Besides the defined history of EDS or cataplexy, the diagnosis of narcolepsy with and without cataplexy was confirmed by nPSG (NIHON KOHDEN Inc, Polysmith 3.0 sleep analysis system) followed by an MSLT. The mean sleep latency on MSLT was less than or equal to 8 min, and two or more sleep onset rapid eye movement periods were observed following sufficient nocturnal sleep (minimum of 6 h) during the night before the test. Hypersomnia was diagnosed if the symptoms could not be better explained by alternative sleep disorders, medical or neurologic disorders, mental disorders, medication use, or substance use disorders. For those patients who had clinical symptoms less than 3 months and suspected narcolepsy, we retested with nPSG and MSLT to confirm the final diagnosis.
2.5. Statistical analysis Means ± standard error of the means were presented to show yearly rates of occurrence. Inductive analysis was processed by statistical description using SPSS 18.0 statistical software. Pearson product moment correlation analysis was used to analyze relationships between the occurrence of narcolepsy at the Changzheng hospital and People’s Hospital from 2003 to 2012 and the relationships between the occurrences of narcolepsy of Changzheng hospital from 2009 to 2012, as well the cases of pH1N1 infection in the Shanghai municipal center for disease control and prevention from 2009 to 2012.
3. Results
2.2. Study design
3.1. Data of narcoleptic participants
The study was a retrospective analysis of participants with narcolepsy. Participants’ history was reported by either the patients or their parents and was recorded by two doctors, Drs. Wu and Wang, to ensure consistent historical content. For inconsistent or incomplete histories, outpatient interviews or telephone interviews were performed to confirm historical details. Participants were not included when histories were unavailable. All participants or their parents provided written informed consent before participation and the research was approved by the ethics committee of the Changzheng hospital.
A total of 162 participants met the diagnostic criteria of narcolepsy and were included in this study. Among them, 12 participants had clinical symptoms and met the criteria on nPSG and MSLT but could not be diagnosed as having first-time narcolepsy as the symptoms had not persisted for 3 months. However, all 12 of these participants were finally diagnosed as narcolepsy after 3 months. All the participants were Han Chinese and 141 participants (87.04%) were from the Eastern China area. Narcolepsy occurred 1.73 times more frequently in men (63.36%) than in women (36.64%). Among them, 75% were children. In our study, the gaps between the emergence of initial symptoms and the diagnosis varied from 2 weeks to 12 years, with an average of 2.75 ± 3.63 years. There were 135 participants diagnosed with narcolepsy with cataplexy (83.3%), and 27 participants were diagnosed with narcolepsy without cataplexy (16.7%) (Table 1).
2.3. Clinical data All narcoleptic participants had complete clinical data, including clinical manifestations, disease onset time, onset age, family
Please cite this article in press as: Wu H et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China. Sleep Med (2014), http://dx.doi.org/10.1016/j.sleep.2013.12.012
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H. Wu et al. / Sleep Medicine xxx (2014) xxx–xxx Table 1 Occurrences of narcolepsy in Changzheng H. and People’s H. 2003–2012, pH1N1 occurrences in Shanghai 2009–2012. Year
Occurrences of narcolepsy reviewed by C.Z.H.
Occurrences of narcolepsy onset diagnosed by C.Z.H.
Occurrences of narcolepsy onset diagnosed by P.H.
pH1N1 occurrences in S.H.
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Total Pearson r Sig. (2-side)
4 7 9 10 9 5 12 31 45 30 162
5 3 3 13 6 11 15 47 18 9 130
14 4 11 35 13 33 51 201 49 31* 442 0.990a P < 0.001
3195 896 254 107 4452 1.0b P = 0.012
Occurrences of narcolepsy onset diagnosed by P.H. (permitted by F. Han). C.Z.H. Changzheng Hospital; P.H. People’s Hospital; S.H. Shanghai; a Narcolepsy occurrences in C.Z.H. vs. in P.H. (2003–2012). b Narcolepsy occurrences in C.Z.H. (2010–2012) vs. pH1N1 occurrences in S.H. (2009–2011). * Data curtailed after September 1, 2012 in People’s Hospital.
3.2. Characteristics of disease onset age Among the 162 participants, 130 (80.25%) were diagnosed with narcolepsy onset between 2003 and 2012, while 32 participants (19.75%) showed disease onset before 2003. The mean age of narcolepsy onset was 10.30 ± 5.21 years, with a median age of 8.42 years. Most of the participants were children less than the age of 12 years (75.38%). The age of disease onset considerably decreased during 2009, 2010, and 2011. The average age of the participants in 2009 was 9.50 ± 3.66 years, with 80.00% being children. The lowest average age in 2010 was 8.62 ± 3.80 years (median, 7.83 years), with 91.49% being children. There was a slight increase of average age to 8.73 ± 2.69 years old in 2011, 88.89% being children; and the age increased to an average age of 11.07 ± 4.53 years in 2012, with 77.78% being children. Thus, children less than the age of 12 years were the mostly likely individuals to develop narcolepsy in the Chinese Han population in Eastern China, especially in 2010 (Table 2; Figs. 1 and 2). 3.3. Aspects of narcolepsy symptoms Analysis of the symptoms of the 162 participants revealed that EDS was the most prominent symptom of narcolepsy in 160 participants (98.78%), while only two participants(1.22%) showed cataplexy attacks as the most prominent. The incidence of major clinical symptoms ranged from high to low as follows: 162 participants (100%) showed EDS, 140 participants (87.7%) showed sleep disturbances during the night, 135 participants (83.3%) showed cataplexy, 126 participants (77.8%) showed weight gain, 112 participants (88.9%) showed cataplexy, 119 participants (73.5%) showed affective disorders, 67 participants (41.4%) showed hypnagogic hallucinations, and 52 participants (32.1%) showed sleep paralysis. Limited data from 2008 to 2012 showed that seven participants (7.4%; n = 94) revealed obvious signs of precocious puberty (Fig. 3). 3.4. Precipitating factors To minimize memory errors, we only analyzed the precipitating factors in participants with disease onset within 1 year of their first interview. There were 102 participants who met these criteria, and they were asked about their infection history, vaccination history, family history, and important life events within 6 months before disease onset. A total of 41 participants (40.2%) were reported to
have identified potential precipitating factors within 6 months before clinical symptoms onset, in which only five participants (4.90%) had a history of influenza vaccination. Three participants (2.94%) reported their parents or other relations having histories of EDS. Of 41 participants with precipitating factors, 26 (63.41%) had clear histories of fever, upper respiratory tract or other pulmonary infections, or digestive system infections. Some participants had recurring infections. Twenty one participants (51.22%) experienced strong emotional stimulations within 1 month before the onset of symptoms of narcolepsy. A review of 21 participants with strong emotional stimulants, possibly from a wide range of experiences, showed that seven of the participants (17.07%) were reprimanded by their parents or teachers, five participants (12.20%) witnessed a traffic accident or other disturbing scenes, three participants (7.32%) fought with another person without significant injuries, three participants (7.32%) were frightened by a burglary, two participants (4.88%) played adventure games in the playground, and one participant (2.44%) was frightened and chased by a dog but was not injured (Fig. 4).
3.5. Stability of narcolepsy occurrence during the 10-year period The fluctuations of narcolepsy occurrence during the10-year period (2003–2012) showed a considerable peak in 2010, with 47 newly diagnosed patients at the Changzheng Hospital. The occurrence in 2010 was 3.13 times greater than those in 2009 (15 participants), 2.61 times greater than those in 2011 (18 participants), and 5.22 times greater than those in 2012 (nine participants). (Table 1; Fig. 5). We compared the tendency of narcolepsy occurrence at the Changzheng Hospital from 2009 to 2012 with the occurrences of pH1N1 within the same time period as in the Shanghai, China area. A close positive relationship was detected with Pearson product moment correlation coefficients (r = 1.00; P = .012; Table 1; Fig. 1). We also compared the occurrence of narcolepsy within the Changzheng Hospital and the People’s Hospital during the same decade, and we found significant positive relationships between the two hospitals (r = 0.990; P < .001; Table 1; Fig. 1). The occurrence of narcolepsy at the People’s Hospital was approximately three-fold higher than those at the Changzheng Hospital during the past decade, with a small increase in 2010 (four-fold). (Table 1; Fig. 5).
Please cite this article in press as: Wu H et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China. Sleep Med (2014), http://dx.doi.org/10.1016/j.sleep.2013.12.012
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H. Wu et al. / Sleep Medicine xxx (2014) xxx–xxx
Numbers
4. Discussion In our retrospective study, we evaluated a large group of Han Chinese narcoleptic patients in Eastern China over the course of a decade and found that 75.4% of participants were children (612 years), and far fewer were adults. The average ages of onset were 10.30 ± 5.21 years, with a median age of 8.42 years, and interquartile range: 6.8–14.9 years. Narcolepsy occurs 1.73 times more commonly in males (63.36%) than in females. EDS was the first symptom of disease onset in 98.8% of the participants, while cataplexy was the first symptom in 1.2% of participants. The average gap between the emergence of initial symptoms and diagnosis was 2.75 ± 3.63 years. It was reported that the mean age at onset was 23.4 years in Montpellier and 24.4 in Montreal in 2001 [26]. Okun [27] reported that the mean age of onset for sleepiness was 19.20 years, despite different ethnic groups in the United States in 2002; in contrast, a median age of onset of 14 (interquartile range, 10–18) was reported in King County, Washington in 2009 [28]. The average ages of onset in our study (10.30 ± 5.21 years) was notably different from these prior studies, but the ages were only slightly different from a report from Northern China [29]. These authors reported a disease onset age of 8.75 ± 2.88 years in 2011. Besides ethnic, country or region, and latitude or climate differences, it seems that the age of onset is becoming younger. Interestingly, the age of onset in 2010 was younger (8.62 ± 3.80 years) than the other years [29], and 91.3% of participants were children in our study. In addition, the average age of onset increased in 2011 and 2012. This pattern may reflect the influence of the pH1N1 infection in the 2010 data and underscore the role of environmental triggering factors in the age of onset of narcolepsy.
25 20 15 10 5 0
1
4
7
10 13 16 19 22 25 28 31 34 37 Age
Numbers
2 per. Mov. Avg. (Numbers)
Fig. 1. The age distribution of narcolepsy onset at the Changzheng Hospital (n = 130, from 2003 to 2012).
often is affected. Poli et al. [9] reported higher occurrences of precocious puberty (17%) in narcoleptic patients. In our study, we only detected seven children (7.4%) with precocious puberty. Possible reasons for this finding may be the long interval between the onset and the interview, which made us miss the observation period. Ethnic differences between studies should also be considered.
4.1. Narcolepsy is more than just a sleep disorder
4.2. Infection and strong emotional stimulation may be precipitating factors of narcolepsy
In addition to the presence of typical symptoms of narcolepsy (i.e., EDS, cataplexy, hypnogogic hallucinations, sleep paralysis), our study showed that the rates of the major symptoms ranged from high to low: EDS, disrupted nocturnal sleep, cataplexy, excessive weight gain, mood disorder, and precocious puberty. Similarly the occurrence of excessive weight gain (77.8%) and mood disorder (73.5%) in our participants was much higher than that of hypnogogic hallucinations (41.4%) and sleep paralysis (32.1%). We tend to treat hypnogogic hallucinations and sleep paralysis as two symptoms that belong to disrupted nocturnal sleep. The results consist of many reports linking childhood narcolepsy with cataplexy to obesity or weight gain [30–33]; however, we focused on dramatic weight gain after the onset of narcolepsy. We found that the weight of narcoleptic children significantly increased within 1 year after the disease onset. Obesity accompanies narcolepsy with cataplexy but seldom narcolepsy without cataplexy. Besides this metabolic problem, the endocrine system also
We found that 40.20% of participants had possible precipitating factors within the previous 6 months before the onset of narcolepsy. Of the participants with precipitating factors, 63.41% had histories of infection and 51.22% experienced strong emotional stimulation; only 5% of these participants reported a history of vaccination. All of the emotional stimulants were within 1 month preceding the onset of their condition, and some of the stimulants occurred just one week before the initiation of the study. These emotional stimulants included serious reprimand by parents and teachers, the sight of traffic accidents or other terrible scenes, fights with other individuals without serious injuries, fright caused by a burglary, adventure game playing, among others. These data provide evidence that strong mental stimulation may be a triggering factor in the onset of narcolepsy. Although much attention has been paid to emotional disorders accompanying narcolepsy, the mechanisms by which mental stimulation may induce narcolepsy are not yet sufficiently understood.
Table 2 Age distribution of onset of narcolepsy patients in C.Z.H. (2003–2012) (n = 130). Year
Number of patients
Disease onset age
612 years no. (%)
12–18 years no. (%)
>18 years no. (%)
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Total
5 3 3 13 6 11 15 47 18 9 130
14.40 ± 5.13 10.17 ± 3.75 15.83 ± 7.94 11.68 ± 4.83 13.95 ± 11.15 13.53 ± 8.97 9.50 ± 3.66 8.62 ± 3.80 8.73 ± 2.69 11.07 ± 4.53 10.30 ± 5.21
2 (40.00) 2 (66.67) 1 (33.33) 6 (46.15) 3 (50.00) 6 (55.54) 12 (80.00) 43 (91.49) 16 (88.89) 7 (77.78) 98 (75.38)
2 (40.00) 1 (33.33) 1 (33.33) 5 (38.46) 2 (33.33) 3 (27.27) 2 (13.33) 3 (6.38) 2 (11.11) 1 (11.11) 22 (16.92)
1 (20.00) 0 (0.00) 1 (33.33) 2 (15.38) 1 (16.67) 2 (18.18) 1 (6.67) 1 (2.12) 0 (0.00) 1 (11.11) 10 (7.69)
Please cite this article in press as: Wu H et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China. Sleep Med (2014), http://dx.doi.org/10.1016/j.sleep.2013.12.012
H. Wu et al. / Sleep Medicine xxx (2014) xxx–xxx
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Fig. 2. The mean age of narcolepsy onset was 10.30 ± 5.21 (2003–2012). The average age was 9.50 ± 3.66 years in 2009; the lowest average age was 8.62 ± 3.80 years in 2010. There was a slight increase of average age to 8.73 ± 2.69 years n 2011, increasing to 11.07 ± 4.53 years in 2012.
Fig. 3. The incidence of major clinical symptoms are shown from high to low in turn as following: 162 cases (100%) had excessive daytime sleepiness; 140 cases (87.7%) showed sleep disturbing during the night; 135 cases (83.3%) showed cataplexy; 126 cases (77.8%) showed excessive weight gain; 119 cases (73.5%) showed affective disorders; 67 cases (41.4%) showed hypnagogic hallucination; and 52 cases (32.1%) showed sleep paralysis; ⁄Limited data from 2008–2012 showed 7 cases (7.4%, n = 94) having obvious precocious puberty.
Orellana et al. [34] reported in 1994 that the presence of life events in the year preceding the onset of narcolepsy was significantly greater than in control participants. In their paper, life events included major changes in mental stress, sleep schedule changes, head injuries, and pregnancy. It is known that mental stimulation can induce a variety of sleep problems and mental disorders [35,36], but the relationship between mental stimulation and impaired brain function is not totally clear. Nevertheless, our data show clear evidence that emotional stimulation is an important mental factor in the clinical onset of narcolepsy.
4.3. The fluctuation of narcolepsy occurrence during the 10-year period The fluctuation of narcolepsy occurrence at the Changzheng Hospital showed a significant peak during 2010, before returning to baseline levels in 2011 and 2012. Our study strengthens the evidence of a close relationship between narcolepsy and pH1N1.
The report from Han et al. [20] first demonstrated a relationship between narcolepsy and pH1N1 in China. Our study strengthened and extended this relationship in two ways. First, statistical analyses showed a positive correlation between occurrences of narcolepsy at the Changzheng Hospital and the occurrence of pH1N1 in Shanghai, China. Second, the fluctuation of the occurrence of narcolepsy at the Changzheng Hospital during the last decade was important and adds to the common occurrence in the China Han population. The occurrence of narcolepsy at the People’s Hospital was approximately three-fold higher than those at the Changzheng Hospital during the last decade, with a small increase in 2010 (four-fold). Winter infection and climate differences could possibly have affected this variance, and pH1N1 contributed more to the changes in 2010 [20]. There are several notable limitations in our study. First, although the narcoleptic patients diagnosed at the Changzheng Hospital were mainly from Eastern China, the occurrences of narcolepsy at the Changzheng Hospital did not represent the incidence of narcolepsy in Eastern China. However, our data are a good
Please cite this article in press as: Wu H et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China. Sleep Med (2014), http://dx.doi.org/10.1016/j.sleep.2013.12.012
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H. Wu et al. / Sleep Medicine xxx (2014) xxx–xxx
Without Precipitat ing factors (59.8%)
With Precipitat ing factors (40.2%)
influenza vaccination:: 5 cases (4.9%)
infection: 26 cases (25.5%)
strong emotional stimulants: 21 cases (20.6%)
Fig. 4. Precipitating factors. A total of 41 patients (40.2%) were reported to have potential precipitating factors within half a year prior to the Narcolepsy onset. 5 cases (4.9%) had history of influenza vaccination; 26 cases (25.5%) had clear histories of infection; 21 cases (20.6%) experienced strong emotional stimulation within a month prior to the occurrence of symptoms of narcolepsy. Some patients have overlapped precipitating factors.
narcolepsy, and strengthen the theoretic hypothesis that immune and mental factors facilitate the onset of narcolepsy. Our study also shows the utility of assessing interactive effects of geography and H1N1 disease in Han Chinese populations. Our results should facilitate additional studies to improve assessment and ultimately to improve clinical interventions in these and other regions and populations. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.12.012.
Acknowledgments This work was supported by research grants from NSFC (81100990, 81171252); The Ministry of Science and Technology Plan Fund Major Projects (2011ZXJ09202-015); Shanghai Science and Technology Fund Projects (11411950203). We thank Prof. Fang Han for consultant, Dr. Hualin Su for providing the data of pH1N1, and parents and most importantly the children for their participation. References
Fig. 5. Fluctuation of narcolepsy occurrences in C.Z.H and in P.H. in a decade. Positive relationship (Pearson r = 1.00, P = 0.012) was detected between the fluctuation of narcolepsy occurrences in C.Z.H. (2010–2012) ( ) and occurrences of pH1N1 in the S.H. (2009–2011) ( ). Positive relationship (Pearson r = 0.990, P < 0.001) was also found between the occurrences of C.Z.H. and that of P.H. ( ) during a decade. The occurrences of narcolepsy in P.H. were about a three-fold increase over that of the C.Z.H. during the past decade, and about a four-fold increase in 2010.
sampling from several big hospitals in Eastern China, which allow us to clearly understand the fluctuation of narcolepsy incidence during the indicated decade. Second, we did not measure pH1N1 DNA in narcoleptic patients and in the general population to show if there was a direct cause and effect relationship, therefore limiting the ability to establish a strong relationship between narcolepsy and pH1N1. Third, we did not test hypocretin (orexin) levels in cerebrospinal fluids, and we lacked genomics analyses. Fourth, our data showed that emotional stimulation was the precipitating factor of narcolepsy. However, due to the retrospective nature of our study, the possibility of recall bias may be notable. For this reason, our findings should be interpreted with caution. It will be important for future investigation to revisit this issue using prospective designs to assess the nature, magnitude, and significance of emotional stimulation on narcolepsy closer to the times they actually occur. We hope for a more comprehensive study including hypocretin and genomics data that could be performed in our future studies. In addition, well-designed clinical research for detecting the pH1N1 antibody in narcolepsy patients and in the general population would provide a beneficial method to clarify the positive relationship between narcolepsy and pH1N1. As noted in the introduction, our report is now 3 years after the 2009 H1N1 winter flu pandemic. Fortunately, we have found that the effects of pH1N1 were transient, at least with respect to narcolepsy. These findings add to and extend a relatively small literature documenting narcolepsy in different regions of China by showing that particular infections and a range of emotional stimuli trigger
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Original Article
Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China Huijuan Wu a,b, Jianhua Zhuang a,1, William S. Stone c, Lin Zhang a, Zhengqing Zhao a, Zongwen Wang a, Yang Yang a, Xiang Li a, Xiangxiang Zhao a,b, Zhongxin Zhao a,b,⇑ a
Department of Neurology, Changzheng Hospital, Second Military Medical University, Shanghai, China Institute of Neuroscience and MOE Key Laboratory of Molecular Neurobiology, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai, China c Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA b
a r t i c l e
i n f o
Article history: Received 25 October 2013 Received in revised form 12 December 2013 Accepted 19 December 2013 Available online xxxx Keywords: Narcolepsy Cataplexy Childhood Excessive weight gain Precipitating factors H1N1 pandemic Han Chinese
a b s t r a c t Objective: Our study was designed to assess symptomatology and occurrences of narcolepsy in Eastern China between 2003 and 2012. Herein we report the substantial changes in the occurrence and clinical features of narcolepsy over the last decade in China. Methods: We performed a retrospective analysis of 162 Han Chinese patients with narcolepsy at Changzheng Hospital, Shanghai, China. Clinical histories and precipitating factors were recorded, in addition to narcolepsy and H1N1 winter flu pandemic (pH1N1) occurrences at Changzheng Hospital. The occurrences also were compared between the Changzheng Hospital and the People’s Hospital, Beijing, China. Results: In our sample, narcolepsy occurred 1.73 times more frequently in men than in women. Most of the participants were children, which peaked to 91% in 2010. Excessive daytime sleepiness (EDS), disrupted nocturnal sleep, cataplexy, and weight gain were the four major symptoms. We found that 40% of patients had identifiable precipitating factors. The occurrence of narcolepsy in 2010 showed an approximate three-fold difference from the baseline levels at the Changzheng Hospital, which showed positive relationships with occurrences of pH1N1 in Shanghai and the occurrence of narcolepsy at the People’s Hospital. Conclusions: Our findings show the interactive effects of geography and H1N1 disease in relation to narcolepsy in Han Chinese populations, and strengthen the theoretic hypothesis that immune and mental factors facilitate the onset of narcolepsy. Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction In 1880 narcolepsy was first reported as an independent syndrome by Gélineau, a French physician [1]. Narcolepsy was known as ‘‘an excessive daytime sleepiness (EDS), accompanied typically by cataplexy attacks, and the symptoms associated with rapid eye movement sleep, such as sleep hallucinations and sleep paralysis’’ [2,3]. However, narcolepsy is now understood to affect multiple functions in addition to sleep. It has been estimated that the core pathologic mechanism of narcolepsy is the loss of large quantities of hypocretin (orexin) neurons in the hypothalamus [4–7].
⇑ Corresponding author at: Department of Neurology, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. Tel./fax: +86 21 81885451. E-mail address: [email protected] (Z. Zhao). 1 Equal contribution.
Narcolepsy not only destroys orexin system, but also considerably affects endocrine, metabolism, and mood regulation systems [8– 11]. Narcolepsy is not a common disease, and the prevalence of narcolepsy with cataplexy varies from 0.002% to 0.167% worldwide [12,13]. The prevalence of narcolepsy in Hong Kong, a Southern Chinese city, is approximately 0.033% [14]. It is suspected that racial difference and latitude/climate factors may contribute to these variances [15]. However, in 2010 many studies from Northern Europe reported a worldwide increased occurrence of narcolepsy following the H1N1 winter flu pandemic (pH1N1) of 2009 [16–20]. Groups in Finland and Sweden reported that children vaccinated with adjuvanted AS03 flu vaccine, a combination of squalene and a-tocopherol, had a six- to nine-fold increased risk for narcolepsy [17–19]. No association was seen between influenza A (H1N1) vaccinations and narcolepsy in Asia [20,21]. A large retrospective study in the north of China [20] revealed that pH1N1 virus
http://dx.doi.org/10.1016/j.sleep.2013.12.012 1389-9457/Ó 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: Wu H et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China. Sleep Med (2014), http://dx.doi.org/10.1016/j.sleep.2013.12.012
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infections or winter infections might increase susceptibility to narcolepsy in children, but there was no significant correlation between the increased incidence of narcolepsy and pH1N1 vaccinations in China. These studies strengthen the hypothesis that narcolepsy is associated with immunologic mechanisms [15–22]. During the review of the clinical data in our study, we found significant fluctuations in narcolepsy rates of occurrence at the Changzheng Hospital, Shanghai in Eastern China during the last 10 years. Our study was reported 3 years after the 2009 H1N1 winter flu pandemic, which was long enough to review its effects and begin to consider its relationships with other conditions. The purposes of our study were as follows. First, we examined symptoms and rates of narcolepsy based on the accumulated cases of narcolepsy at the Changzheng Hospital. Second, we examined several precipitating factors for onset of narcolepsy including the pH1N1 and other infections, in addition to emotional stimulation. Finally, we compared the trend of narcolepsy occurrence at the Changzheng Hospital with the occurrences of pH1N1 in the Shanghai area, as well as with the occurrence at the People’s Hospital, Beijing, China, to represent hospitals in Eastern and Northern China, respectively.
history of sleepiness, history of fever, respiratory infections and infections of the digestive system within 6 months prior to disease onset, history of influenza vaccination, and precocious puberty. Major clinical manifestations included EDS, attacks of cataplexy, nocturnal sleep disturbances, hypnogogic hallucinations, sleep paralysis, considerable weight gain, mood disturbances, or irritability. Because one of the symptoms of narcolepsy is nocturnal sleep disturbance, we used the criterion for nocturnal sleep disturbance as defined for insomnia [2]. Nocturnal sleep disturbance was defined as fragmented sleep during the night, night sleep awakening 2 times or more for durations longer than 30 min, or sleep efficiency less than 90% [2]. Weight gain was defined as considerable weight gain after narcolepsy onset, weight increase of more than 5% per month, or weight gain of more than 30% a year, with an increased body mass index. The clinical manifestations of precocious puberty included premature breast and pubic or axillary hair development before the age of 8 years in girls [23] and 9 years in boys [24]. Some of the younger participants also were examined for serum gonadotropic hormone stimulation curves and X-rays of the wrist to determine bone age and chronologic age ratios.
2. Material and methods
2.4. Control data
2.1. Patients
The control data for our study involved the occurrences of narcolepsy from 2003 to 2012 at the Sleep Center of People’s Hospital [25], Beijing University (permitted by F. Han), and the occurrences of pandemic H1N1 infection between 2009 and 2012 from the Shanghai municipal center for disease control and prevention (provided by H.L. Su).
Patients diagnosed with narcolepsy at the Changzheng Hospital, Second Military University, Shanghai, China were included in our study from March 2003 to December 2013. Standard nocturnal polysomnography (nPSG) and multiple sleep latency tests (MSLT) were used to diagnose narcolepsy. Diagnosis of narcolepsy was based on the International Classification of Sleep Disorders: Diagnostic and Coding Manual, second edition, criteria [2]. Due to a lack of cerebrospinal fluid of orexin detections, we used the same criteria to diagnose narcolepsy with or without cataplexy. Besides the defined history of EDS or cataplexy, the diagnosis of narcolepsy with and without cataplexy was confirmed by nPSG (NIHON KOHDEN Inc, Polysmith 3.0 sleep analysis system) followed by an MSLT. The mean sleep latency on MSLT was less than or equal to 8 min, and two or more sleep onset rapid eye movement periods were observed following sufficient nocturnal sleep (minimum of 6 h) during the night before the test. Hypersomnia was diagnosed if the symptoms could not be better explained by alternative sleep disorders, medical or neurologic disorders, mental disorders, medication use, or substance use disorders. For those patients who had clinical symptoms less than 3 months and suspected narcolepsy, we retested with nPSG and MSLT to confirm the final diagnosis.
2.5. Statistical analysis Means ± standard error of the means were presented to show yearly rates of occurrence. Inductive analysis was processed by statistical description using SPSS 18.0 statistical software. Pearson product moment correlation analysis was used to analyze relationships between the occurrence of narcolepsy at the Changzheng hospital and People’s Hospital from 2003 to 2012 and the relationships between the occurrences of narcolepsy of Changzheng hospital from 2009 to 2012, as well the cases of pH1N1 infection in the Shanghai municipal center for disease control and prevention from 2009 to 2012.
3. Results
2.2. Study design
3.1. Data of narcoleptic participants
The study was a retrospective analysis of participants with narcolepsy. Participants’ history was reported by either the patients or their parents and was recorded by two doctors, Drs. Wu and Wang, to ensure consistent historical content. For inconsistent or incomplete histories, outpatient interviews or telephone interviews were performed to confirm historical details. Participants were not included when histories were unavailable. All participants or their parents provided written informed consent before participation and the research was approved by the ethics committee of the Changzheng hospital.
A total of 162 participants met the diagnostic criteria of narcolepsy and were included in this study. Among them, 12 participants had clinical symptoms and met the criteria on nPSG and MSLT but could not be diagnosed as having first-time narcolepsy as the symptoms had not persisted for 3 months. However, all 12 of these participants were finally diagnosed as narcolepsy after 3 months. All the participants were Han Chinese and 141 participants (87.04%) were from the Eastern China area. Narcolepsy occurred 1.73 times more frequently in men (63.36%) than in women (36.64%). Among them, 75% were children. In our study, the gaps between the emergence of initial symptoms and the diagnosis varied from 2 weeks to 12 years, with an average of 2.75 ± 3.63 years. There were 135 participants diagnosed with narcolepsy with cataplexy (83.3%), and 27 participants were diagnosed with narcolepsy without cataplexy (16.7%) (Table 1).
2.3. Clinical data All narcoleptic participants had complete clinical data, including clinical manifestations, disease onset time, onset age, family
Please cite this article in press as: Wu H et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China. Sleep Med (2014), http://dx.doi.org/10.1016/j.sleep.2013.12.012
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H. Wu et al. / Sleep Medicine xxx (2014) xxx–xxx Table 1 Occurrences of narcolepsy in Changzheng H. and People’s H. 2003–2012, pH1N1 occurrences in Shanghai 2009–2012. Year
Occurrences of narcolepsy reviewed by C.Z.H.
Occurrences of narcolepsy onset diagnosed by C.Z.H.
Occurrences of narcolepsy onset diagnosed by P.H.
pH1N1 occurrences in S.H.
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Total Pearson r Sig. (2-side)
4 7 9 10 9 5 12 31 45 30 162
5 3 3 13 6 11 15 47 18 9 130
14 4 11 35 13 33 51 201 49 31* 442 0.990a P < 0.001
3195 896 254 107 4452 1.0b P = 0.012
Occurrences of narcolepsy onset diagnosed by P.H. (permitted by F. Han). C.Z.H. Changzheng Hospital; P.H. People’s Hospital; S.H. Shanghai; a Narcolepsy occurrences in C.Z.H. vs. in P.H. (2003–2012). b Narcolepsy occurrences in C.Z.H. (2010–2012) vs. pH1N1 occurrences in S.H. (2009–2011). * Data curtailed after September 1, 2012 in People’s Hospital.
3.2. Characteristics of disease onset age Among the 162 participants, 130 (80.25%) were diagnosed with narcolepsy onset between 2003 and 2012, while 32 participants (19.75%) showed disease onset before 2003. The mean age of narcolepsy onset was 10.30 ± 5.21 years, with a median age of 8.42 years. Most of the participants were children less than the age of 12 years (75.38%). The age of disease onset considerably decreased during 2009, 2010, and 2011. The average age of the participants in 2009 was 9.50 ± 3.66 years, with 80.00% being children. The lowest average age in 2010 was 8.62 ± 3.80 years (median, 7.83 years), with 91.49% being children. There was a slight increase of average age to 8.73 ± 2.69 years old in 2011, 88.89% being children; and the age increased to an average age of 11.07 ± 4.53 years in 2012, with 77.78% being children. Thus, children less than the age of 12 years were the mostly likely individuals to develop narcolepsy in the Chinese Han population in Eastern China, especially in 2010 (Table 2; Figs. 1 and 2). 3.3. Aspects of narcolepsy symptoms Analysis of the symptoms of the 162 participants revealed that EDS was the most prominent symptom of narcolepsy in 160 participants (98.78%), while only two participants(1.22%) showed cataplexy attacks as the most prominent. The incidence of major clinical symptoms ranged from high to low as follows: 162 participants (100%) showed EDS, 140 participants (87.7%) showed sleep disturbances during the night, 135 participants (83.3%) showed cataplexy, 126 participants (77.8%) showed weight gain, 112 participants (88.9%) showed cataplexy, 119 participants (73.5%) showed affective disorders, 67 participants (41.4%) showed hypnagogic hallucinations, and 52 participants (32.1%) showed sleep paralysis. Limited data from 2008 to 2012 showed that seven participants (7.4%; n = 94) revealed obvious signs of precocious puberty (Fig. 3). 3.4. Precipitating factors To minimize memory errors, we only analyzed the precipitating factors in participants with disease onset within 1 year of their first interview. There were 102 participants who met these criteria, and they were asked about their infection history, vaccination history, family history, and important life events within 6 months before disease onset. A total of 41 participants (40.2%) were reported to
have identified potential precipitating factors within 6 months before clinical symptoms onset, in which only five participants (4.90%) had a history of influenza vaccination. Three participants (2.94%) reported their parents or other relations having histories of EDS. Of 41 participants with precipitating factors, 26 (63.41%) had clear histories of fever, upper respiratory tract or other pulmonary infections, or digestive system infections. Some participants had recurring infections. Twenty one participants (51.22%) experienced strong emotional stimulations within 1 month before the onset of symptoms of narcolepsy. A review of 21 participants with strong emotional stimulants, possibly from a wide range of experiences, showed that seven of the participants (17.07%) were reprimanded by their parents or teachers, five participants (12.20%) witnessed a traffic accident or other disturbing scenes, three participants (7.32%) fought with another person without significant injuries, three participants (7.32%) were frightened by a burglary, two participants (4.88%) played adventure games in the playground, and one participant (2.44%) was frightened and chased by a dog but was not injured (Fig. 4).
3.5. Stability of narcolepsy occurrence during the 10-year period The fluctuations of narcolepsy occurrence during the10-year period (2003–2012) showed a considerable peak in 2010, with 47 newly diagnosed patients at the Changzheng Hospital. The occurrence in 2010 was 3.13 times greater than those in 2009 (15 participants), 2.61 times greater than those in 2011 (18 participants), and 5.22 times greater than those in 2012 (nine participants). (Table 1; Fig. 5). We compared the tendency of narcolepsy occurrence at the Changzheng Hospital from 2009 to 2012 with the occurrences of pH1N1 within the same time period as in the Shanghai, China area. A close positive relationship was detected with Pearson product moment correlation coefficients (r = 1.00; P = .012; Table 1; Fig. 1). We also compared the occurrence of narcolepsy within the Changzheng Hospital and the People’s Hospital during the same decade, and we found significant positive relationships between the two hospitals (r = 0.990; P < .001; Table 1; Fig. 1). The occurrence of narcolepsy at the People’s Hospital was approximately three-fold higher than those at the Changzheng Hospital during the past decade, with a small increase in 2010 (four-fold). (Table 1; Fig. 5).
Please cite this article in press as: Wu H et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China. Sleep Med (2014), http://dx.doi.org/10.1016/j.sleep.2013.12.012
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H. Wu et al. / Sleep Medicine xxx (2014) xxx–xxx
Numbers
4. Discussion In our retrospective study, we evaluated a large group of Han Chinese narcoleptic patients in Eastern China over the course of a decade and found that 75.4% of participants were children (612 years), and far fewer were adults. The average ages of onset were 10.30 ± 5.21 years, with a median age of 8.42 years, and interquartile range: 6.8–14.9 years. Narcolepsy occurs 1.73 times more commonly in males (63.36%) than in females. EDS was the first symptom of disease onset in 98.8% of the participants, while cataplexy was the first symptom in 1.2% of participants. The average gap between the emergence of initial symptoms and diagnosis was 2.75 ± 3.63 years. It was reported that the mean age at onset was 23.4 years in Montpellier and 24.4 in Montreal in 2001 [26]. Okun [27] reported that the mean age of onset for sleepiness was 19.20 years, despite different ethnic groups in the United States in 2002; in contrast, a median age of onset of 14 (interquartile range, 10–18) was reported in King County, Washington in 2009 [28]. The average ages of onset in our study (10.30 ± 5.21 years) was notably different from these prior studies, but the ages were only slightly different from a report from Northern China [29]. These authors reported a disease onset age of 8.75 ± 2.88 years in 2011. Besides ethnic, country or region, and latitude or climate differences, it seems that the age of onset is becoming younger. Interestingly, the age of onset in 2010 was younger (8.62 ± 3.80 years) than the other years [29], and 91.3% of participants were children in our study. In addition, the average age of onset increased in 2011 and 2012. This pattern may reflect the influence of the pH1N1 infection in the 2010 data and underscore the role of environmental triggering factors in the age of onset of narcolepsy.
25 20 15 10 5 0
1
4
7
10 13 16 19 22 25 28 31 34 37 Age
Numbers
2 per. Mov. Avg. (Numbers)
Fig. 1. The age distribution of narcolepsy onset at the Changzheng Hospital (n = 130, from 2003 to 2012).
often is affected. Poli et al. [9] reported higher occurrences of precocious puberty (17%) in narcoleptic patients. In our study, we only detected seven children (7.4%) with precocious puberty. Possible reasons for this finding may be the long interval between the onset and the interview, which made us miss the observation period. Ethnic differences between studies should also be considered.
4.1. Narcolepsy is more than just a sleep disorder
4.2. Infection and strong emotional stimulation may be precipitating factors of narcolepsy
In addition to the presence of typical symptoms of narcolepsy (i.e., EDS, cataplexy, hypnogogic hallucinations, sleep paralysis), our study showed that the rates of the major symptoms ranged from high to low: EDS, disrupted nocturnal sleep, cataplexy, excessive weight gain, mood disorder, and precocious puberty. Similarly the occurrence of excessive weight gain (77.8%) and mood disorder (73.5%) in our participants was much higher than that of hypnogogic hallucinations (41.4%) and sleep paralysis (32.1%). We tend to treat hypnogogic hallucinations and sleep paralysis as two symptoms that belong to disrupted nocturnal sleep. The results consist of many reports linking childhood narcolepsy with cataplexy to obesity or weight gain [30–33]; however, we focused on dramatic weight gain after the onset of narcolepsy. We found that the weight of narcoleptic children significantly increased within 1 year after the disease onset. Obesity accompanies narcolepsy with cataplexy but seldom narcolepsy without cataplexy. Besides this metabolic problem, the endocrine system also
We found that 40.20% of participants had possible precipitating factors within the previous 6 months before the onset of narcolepsy. Of the participants with precipitating factors, 63.41% had histories of infection and 51.22% experienced strong emotional stimulation; only 5% of these participants reported a history of vaccination. All of the emotional stimulants were within 1 month preceding the onset of their condition, and some of the stimulants occurred just one week before the initiation of the study. These emotional stimulants included serious reprimand by parents and teachers, the sight of traffic accidents or other terrible scenes, fights with other individuals without serious injuries, fright caused by a burglary, adventure game playing, among others. These data provide evidence that strong mental stimulation may be a triggering factor in the onset of narcolepsy. Although much attention has been paid to emotional disorders accompanying narcolepsy, the mechanisms by which mental stimulation may induce narcolepsy are not yet sufficiently understood.
Table 2 Age distribution of onset of narcolepsy patients in C.Z.H. (2003–2012) (n = 130). Year
Number of patients
Disease onset age
612 years no. (%)
12–18 years no. (%)
>18 years no. (%)
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Total
5 3 3 13 6 11 15 47 18 9 130
14.40 ± 5.13 10.17 ± 3.75 15.83 ± 7.94 11.68 ± 4.83 13.95 ± 11.15 13.53 ± 8.97 9.50 ± 3.66 8.62 ± 3.80 8.73 ± 2.69 11.07 ± 4.53 10.30 ± 5.21
2 (40.00) 2 (66.67) 1 (33.33) 6 (46.15) 3 (50.00) 6 (55.54) 12 (80.00) 43 (91.49) 16 (88.89) 7 (77.78) 98 (75.38)
2 (40.00) 1 (33.33) 1 (33.33) 5 (38.46) 2 (33.33) 3 (27.27) 2 (13.33) 3 (6.38) 2 (11.11) 1 (11.11) 22 (16.92)
1 (20.00) 0 (0.00) 1 (33.33) 2 (15.38) 1 (16.67) 2 (18.18) 1 (6.67) 1 (2.12) 0 (0.00) 1 (11.11) 10 (7.69)
Please cite this article in press as: Wu H et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China. Sleep Med (2014), http://dx.doi.org/10.1016/j.sleep.2013.12.012
H. Wu et al. / Sleep Medicine xxx (2014) xxx–xxx
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Fig. 2. The mean age of narcolepsy onset was 10.30 ± 5.21 (2003–2012). The average age was 9.50 ± 3.66 years in 2009; the lowest average age was 8.62 ± 3.80 years in 2010. There was a slight increase of average age to 8.73 ± 2.69 years n 2011, increasing to 11.07 ± 4.53 years in 2012.
Fig. 3. The incidence of major clinical symptoms are shown from high to low in turn as following: 162 cases (100%) had excessive daytime sleepiness; 140 cases (87.7%) showed sleep disturbing during the night; 135 cases (83.3%) showed cataplexy; 126 cases (77.8%) showed excessive weight gain; 119 cases (73.5%) showed affective disorders; 67 cases (41.4%) showed hypnagogic hallucination; and 52 cases (32.1%) showed sleep paralysis; ⁄Limited data from 2008–2012 showed 7 cases (7.4%, n = 94) having obvious precocious puberty.
Orellana et al. [34] reported in 1994 that the presence of life events in the year preceding the onset of narcolepsy was significantly greater than in control participants. In their paper, life events included major changes in mental stress, sleep schedule changes, head injuries, and pregnancy. It is known that mental stimulation can induce a variety of sleep problems and mental disorders [35,36], but the relationship between mental stimulation and impaired brain function is not totally clear. Nevertheless, our data show clear evidence that emotional stimulation is an important mental factor in the clinical onset of narcolepsy.
4.3. The fluctuation of narcolepsy occurrence during the 10-year period The fluctuation of narcolepsy occurrence at the Changzheng Hospital showed a significant peak during 2010, before returning to baseline levels in 2011 and 2012. Our study strengthens the evidence of a close relationship between narcolepsy and pH1N1.
The report from Han et al. [20] first demonstrated a relationship between narcolepsy and pH1N1 in China. Our study strengthened and extended this relationship in two ways. First, statistical analyses showed a positive correlation between occurrences of narcolepsy at the Changzheng Hospital and the occurrence of pH1N1 in Shanghai, China. Second, the fluctuation of the occurrence of narcolepsy at the Changzheng Hospital during the last decade was important and adds to the common occurrence in the China Han population. The occurrence of narcolepsy at the People’s Hospital was approximately three-fold higher than those at the Changzheng Hospital during the last decade, with a small increase in 2010 (four-fold). Winter infection and climate differences could possibly have affected this variance, and pH1N1 contributed more to the changes in 2010 [20]. There are several notable limitations in our study. First, although the narcoleptic patients diagnosed at the Changzheng Hospital were mainly from Eastern China, the occurrences of narcolepsy at the Changzheng Hospital did not represent the incidence of narcolepsy in Eastern China. However, our data are a good
Please cite this article in press as: Wu H et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in Eastern China. Sleep Med (2014), http://dx.doi.org/10.1016/j.sleep.2013.12.012
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H. Wu et al. / Sleep Medicine xxx (2014) xxx–xxx
Without Precipitat ing factors (59.8%)
With Precipitat ing factors (40.2%)
influenza vaccination:: 5 cases (4.9%)
infection: 26 cases (25.5%)
strong emotional stimulants: 21 cases (20.6%)
Fig. 4. Precipitating factors. A total of 41 patients (40.2%) were reported to have potential precipitating factors within half a year prior to the Narcolepsy onset. 5 cases (4.9%) had history of influenza vaccination; 26 cases (25.5%) had clear histories of infection; 21 cases (20.6%) experienced strong emotional stimulation within a month prior to the occurrence of symptoms of narcolepsy. Some patients have overlapped precipitating factors.
narcolepsy, and strengthen the theoretic hypothesis that immune and mental factors facilitate the onset of narcolepsy. Our study also shows the utility of assessing interactive effects of geography and H1N1 disease in Han Chinese populations. Our results should facilitate additional studies to improve assessment and ultimately to improve clinical interventions in these and other regions and populations. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.12.012.
Acknowledgments This work was supported by research grants from NSFC (81100990, 81171252); The Ministry of Science and Technology Plan Fund Major Projects (2011ZXJ09202-015); Shanghai Science and Technology Fund Projects (11411950203). We thank Prof. Fang Han for consultant, Dr. Hualin Su for providing the data of pH1N1, and parents and most importantly the children for their participation. References
Fig. 5. Fluctuation of narcolepsy occurrences in C.Z.H and in P.H. in a decade. Positive relationship (Pearson r = 1.00, P = 0.012) was detected between the fluctuation of narcolepsy occurrences in C.Z.H. (2010–2012) ( ) and occurrences of pH1N1 in the S.H. (2009–2011) ( ). Positive relationship (Pearson r = 0.990, P < 0.001) was also found between the occurrences of C.Z.H. and that of P.H. ( ) during a decade. The occurrences of narcolepsy in P.H. were about a three-fold increase over that of the C.Z.H. during the past decade, and about a four-fold increase in 2010.
sampling from several big hospitals in Eastern China, which allow us to clearly understand the fluctuation of narcolepsy incidence during the indicated decade. Second, we did not measure pH1N1 DNA in narcoleptic patients and in the general population to show if there was a direct cause and effect relationship, therefore limiting the ability to establish a strong relationship between narcolepsy and pH1N1. Third, we did not test hypocretin (orexin) levels in cerebrospinal fluids, and we lacked genomics analyses. Fourth, our data showed that emotional stimulation was the precipitating factor of narcolepsy. However, due to the retrospective nature of our study, the possibility of recall bias may be notable. For this reason, our findings should be interpreted with caution. It will be important for future investigation to revisit this issue using prospective designs to assess the nature, magnitude, and significance of emotional stimulation on narcolepsy closer to the times they actually occur. We hope for a more comprehensive study including hypocretin and genomics data that could be performed in our future studies. In addition, well-designed clinical research for detecting the pH1N1 antibody in narcolepsy patients and in the general population would provide a beneficial method to clarify the positive relationship between narcolepsy and pH1N1. As noted in the introduction, our report is now 3 years after the 2009 H1N1 winter flu pandemic. Fortunately, we have found that the effects of pH1N1 were transient, at least with respect to narcolepsy. These findings add to and extend a relatively small literature documenting narcolepsy in different regions of China by showing that particular infections and a range of emotional stimuli trigger
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