Abstract
Objective:
To retrospectively describe childhood presentations of primary hypersomnia with an emphasis on narcolepsy-cataplexy in a Chinese population.
Methods:
A total of 417 children (< 18 years old) successively presenting with complaints of hypersomnia without anatomic cause or sleep apnea risk were evaluated using the Stanford Sleep Inventory, human leukocyte antigen (HLA) DQB1*0602 typing, and MSLT recordings. CSF hypocretin-1 was measured in 47 cases to document hypocretin deficiency. A subgroup (“narcolepsy/hypocretin deficiency”) with likely hypocretin deficiency (low hypocretin-1 or HLA positive with clear-cut cataplexy) was further examined for presentations prior to, around, or after puberty.
Results:
Narcolepsy with (n = 361) or without (n = 17) cataplexy presented at an earlier age and with increased male predominance when compared to idiopathic hypersomnia (n = 39, P < 0.01). Nearly 70% of those with narcolepsy/hypocretin deficiency (n = 271) had disease onset before age 10 y, and 15% had onset before age 6, an unusually young age distribution. Onset was prior to puberty in 78% of cases. Clinical features were similar in presentations across puberty groups except for sleep paralysis, which increased in frequency with age/puberty. Mean sleep latency (MSL) decreased and the number of sleep onset REM periods (SOREMPs) increased with age/puberty, but MSLT diagnosis criteria (MSL ≤ 8 min, ≥ 2 SOREMPs) were similarly positive across groups. Familial clustering was present in only 1.7% of probands.
Conclusion:
In children presenting with a complaint of primary hypersomnia to a sleep clinic in China, 86% (361/417) meet criteria for narcolepsy with cataplexy. Puberty did not affect positivity on the MSLT as a diagnostic feature. Sleep paralysis was the only symptom that increased with increasing age. In addition, narcolepsy with cataplexy in our clinic population appeared to begin at a younger age than usually reported in other studies.
Citation:
Han F; Lin L; Li J; Aran A; Dong SX; An P; Zhao L; Li M; Li QY; Yan H; Wang JS; Gao HY; Li M; Gao ZC; Strohl KP; Mignot E. Presentations of primary hypersomnia in Chinese children. SLEEP 2011;34(5):627-632.
Keywords: Narcolepsy, childhood, hypocretin, MSLT, HLADQB1*0602
INTRODUCTION
Narcolepsy-cataplexy (NC) occurs worldwide. In China, there is a population prevalence of 0.034% in patients in South China presenting to sleep centers in Hong Kong1,2 and a prevalence of 0.014% in Korean adolescents with similar clinical and biological presentations.3–5 Studies in North America and Europe estimates are similar. As the origin and mechanisms that produce narcolepsy are not well understood, comparisons of clinical presentations in collections of several characterized patient groups can inform future studies of clinical and genetic epidemiology.
Narcolepsy-cataplexy is said to present in the second to third decade of life, with 70% to 80% of patients reporting onset between 10-20 years of age. Large sample size observations from the United States, Canada, Europe, and Japan report that half of adult patients with narcolepsy report narcolepsy onset prior to 15 years old, and only exceptionally at 5 or younger.6–9 Studies in the 1980s-1990s reported a median delay > 10 years between onset and diagnosis,10 whereas a more recent report suggests the delay can be only a few years, particularly in children.11 A focus on the pediatric population could help address issues related to puberty, genetic predisposition, and environmental triggers, and possibly shed light on factors that might delay diagnosis.
We report on findings from a pediatric cohort of patients who presented with primary hypersomnia to a sleep clinic in Beijing, China over a period of ∼10 years. All were evaluated in a standard fashion and classified as narcolepsy with or without cataplexy or idiopathic hypersomnia. Our purpose was to describe age of onset and clinical features of primary hypersomnia among a mainland Chinese cohort of children, and to compare the findings to the literature.
METHODS
Patients
Patients were children, defined as < 18 years of age, successively presenting with hypersomnia seen over a period of ∼10 years (September, 1998 to May, 2009) at People's Hospital, Beijing University, Beijing. A total of 417 children (63%) were drawn from a population of 671 adults and children with hypersomnia. The hospital has a pulmonary medicine department-based sleep center, which sees both children and adults, and receives referrals from all of mainland China. It is estimated that 70% of the diagnosed narcolepsy patients in mainland China are seen at this center at People's Hospitals.12 A prior report focused on the impact of a narcolepsy recognition strategy in a pediatric neurology clinic,13 whereas this report retrospectively describes a cohort with a broader symptom profile, evaluated using a standardized methodology. Patients gave written assent, and parents consented for inclusion into this study. All patients were clinically interviewed in the presence of the parent(s). The local institutional review board of Beijing University approved the study.
Baseline Evaluation
Age and sex were noted, body mass index (BMI) was calculated, and all 417 patients and their parent(s) completed the Stanford Sleep Inventory (SSI) from Stanford Center for Narcolepsy, translated from English to Chinese. The SSI is a validated questionnaire predictive of cataplexy; it also evaluates the presence and severity of various other narcolepsy symptoms such as sleepiness, napping, disturbed nocturnal sleep, sleep paralysis, and hypnagogic hallucinations (see http://med.stanford.edu/school/Psychiatry/narcolepsy/).8,14 Typical versus atypical cataplexy (some cataplexy symptoms, but no usual trigger such as joking, laughing or unusually long lasting events) was determined by interview. A blood sample for HLA-DQB1*0602 typing was collected. MSLT was conducted in all subjects except for 14 cases with clear-cut cataplexy. In 90 cases, the MSLT was performed after a normal night of sleep at home rather than after in-lab polysomnography (all other cases). Cerebrospinal fluid (CSF) was drawn in 47 patients to determine CSF hypocretin-1.
Inclusion Criteria
To be included in this study, and diagnosed as “primary hypersomnia,” children had to nap repeatedly or inappropriately (e.g., during a meal, in conversation, or in playtime) during the day when compared to age standards. Symptoms were severe enough to disturb functioning in family, social, and school settings, and had to be present ≥ 6 months. Patients were not classified as having primary hypersomnia if there were periods of times with hypersomnolence alternating with periods of normal behavior (i.e., recurrent hypersomnia), or if brain MRI and/or CT scanning showed evidence of brain injury or neoplasia. Parents reported adequate sleep time at night for their children, excluding insufficient sleep. If typical cataplexy was present, snoring or documented sleep apnea (AHI ≥ 1) was acceptable. In patients without cataplexy, patients were excluded if AHI was ≥ 1 or snoring was present.
Group Stratification
Children were first stratified using ICSD-2 criteria15 into narcolepsy-cataplexy (n = 361), narcolepsy without cataplexy (n = 17), or idiopathic hypersomnia (IH, n = 39). Narcolepsy without cataplexy was defined per ICSD-2 as those without typical cataplexy but with a short MSL (≤ 8 min) and multiple SOREMPs on the MSLT. Of note, the ICSD-2 definition of IH requires an abnormal MSLT (MSL < 8 min, 0 or 1 SOREMP) and/or with a prolonged nocturnal sleep time (> 10 h), The IH group thus included children with long night sleep time (> 10 h/night) and a normal MSLT, a more frequent occurrence in children who have longer nocturnal sleep. The ICSD-2 IH definition is not age appropriate, and the group thus rather represents patient with unexplained symptoms of excessive daytime sleepiness (without sleep apnea or sleep deprivation).
In addition, a subgroup of narcolepsy-cataplexy patients with probable hypocretin deficiency was created. This group of 271 patients was defined either by the presence of documented hypocretin deficiency (n = 47; CSF hypocretin-1 ≤ 110 pg/mL) or, if hypocretin deficiency was not documented through CSF studies (CSF hypocretin-1 unavailable), by the presence of clear cataplexy and HLA-DQB1*0602. Using this definition, approximately 98% of cases included are predicted to have hypocretin deficiency4 if CSF hypocretin-1 had been measured in all subjects.
Data and Statistical Analysis
Data are reported as means ± SEM or as percentage, whenever most appropriate. Statistical comparisons were conducted using ANOVA across groups, χ2 tests, or Fisher exact tests, with post hoc comparison when appropriate. Details are given where appropriate in the text or Table legend. To address maturational factors potentially related to puberty, age was available in cases as an index of pubertal timing.16 Patients were grouped as follows: prepuberty: female age < 10, male age < 11; puberty: female age between 10-13, male age between 11-14, post puberty: female age > 13, male age > 14. Differences were considered statistically significant at P values ≤ 0.05.
RESULTS
Clinical, Genetic and Biochemical Features of Children with Complaints of Primary Hypersomnia
Table 1 compares clinical and biological characteristics for those meeting ICSD-2 criteria for narcolepsy-cataplexy (NC), narcolepsy without cataplexy (NWC), and idiopathic hypersomnia (IH). The majority of children were classified as having NC (361/417, 86% of all cases, see Table 1). Both narcolepsy groups included more males (∼2/3 ratio) compared to IH cases. Patients with narcolepsy (with and without cataplexy) were also heavier than those with IH (Table 1). Besides the MSLT findings and lack of cataplexy inherent in the ICSD-2 definition, patients with IH were older, and had fewer ancillary symptoms (disturbed nocturnal sleep, sleep paralysis, hypnagogic hallucinations). HLA positivity was high in narcolepsy with (95%) and without (91%) cataplexy but not IH (28%) cases. HLA-DQB1*0602 positivity in controls was 16% to 25% in China (data not shown).
Table 1.
Clinical characteristics of each diagnostic group
| NC | NWC | IH | 3 way-P value | |
|---|---|---|---|---|
| n = 361 | N = 17 | n = 39 | ||
| Age (y) | 10.3 ± 0.18** | 10.5 ± 0.80 | 12.4 ± 0.54 | < 0.01 |
| Sex (male) | 67%** | 76%‡ | 44% | < 0.01 |
| BMI (kg/m2) | 21.6 ± 0.3 (343)** | 23.2 ± 1.30 | 19.8 ± 0.90 (38) | < 0.05 |
| % DQB1*0602 | 95%*** | 91% | 28% | < 0.001 |
| % Typical cataplexy | 100% | 0% | 0% | NA |
| % Atypical cataplexy | 0% | 38% (16)‡ | 8% (37) | < 0.001 |
| No cataplexy | 0% | 62% | 92% | < 0.001 |
| Age of disease onset* (y) | 8.4 ± 0.15 (358)* | 7.8 ± 0.75 (15)‡ | 10.1 ± 0.47 (38) | < 0.01 |
| Age of onset (sleepiness) (y) | 8.5 ± 0.15 (355)* | 7.8 ± 0.74 (15)‡ | 10.1 ± 0.47 (38) | < 0.01 |
| Age of onset (cataplexy) (y) | 8.7 ± 0.15 (336) | NA | NA | NA |
| % Hypnagogic hallucinations | 56% (327)*** | 27% (11) | 16% (31) | < 0.001 |
| Age of onset (hallucinations) (y) | 8.6 ± 0.22 (178) | 7.3 ± 1.71 (3)‡ | 12.2 ± 1.32 (5) | < 0.05 |
| % Sleep paralysis | 27% (346)** | 6% (16)† | 11% (38) | < 0.05 |
| Age of onset (sleep paralysis) (y) | 10.3 ± 0.33 (81) | 5.0 (1) | 14.0 ± 2.11 (2) | < 0.05 |
| % Disturbed nocturnal sleep | 90% (244)** | 83% (12) | 56% (25) | < 0.001 |
| % Snoring | 11% (225) | 13% (8) | 3% (30) | |
| MSLT sleep latency (min) | 3.4 ± 0.15 (332)*** | 2.7 ± 0.67‡‡ | 12.3 ± 0.45 (38) | < 0.001 |
| MSLT SOREMP numbers | 4.3 ± 0.06 (347)*** | 4.2 ± 0.27‡‡ | 1.2 ± 0.18 (38) | < 0.05 |
| %MSLT < 8 and ≥ 2 SOREMP | 93% (331)* | 100% | 0% | NA |
| AHI | 1.1 ± 0.14 (232)*** | 0.3 ± 0.95 (5)†† | 0.2 ± 0.41 (27) |
*Sleepiness or cataplexy, whichever symptom came first. NC, Narcolepsy-cataplexy; NWC, Narcolepsy without cataplexy; IH, idiopathic hypersomnia; NA, not applicable. Values in parentheses are the sample size for that variable. NC versus IH: *P < 0.05; **P < 0.01; ***P < 0.001. NC versus NWC: †P < 0.01; ††P < 0.001. NWC versus IH: ‡P < 0.05; ‡‡ P < 0.001.
Chinese Children with Narcolepsy-Cataplexy/Hypocretin Deficiency and Disease Onset
To examine a more homogeneous population, we created a subgroup of 271 patients with probable hypocretin deficiency (all but 2 without cataplexy), as defined previously (Table 2). Nearly 70% (188 of these 271) had disease onset prior to 10 years old, i.e., in the first decade of life; some 15% (41 of 271) had onset at 5 years or younger. A striking 76% percent of cases reported onset prior to puberty (206/271). Early onset was especially evident for symptoms of sleepiness, cataplexy, and hypnagogic hallucinations, rather than for sleep paralysis, which had an older onset than the other symptoms. Males (8.6 ± 0.20 y) had a slightly later age of onset than females (7.9 ± 0.31 y) (P < 0.05).
Table 2.
Age of onset of narcolepsy/hypocretin deficiency cases
| Characteristics | N | Mean ± SEM or % |
|---|---|---|
| Disease onset* age (y) | 271 | 8.3 ± 0.16 |
| Disease onset* age ≤ 9 y | 271 | 69% |
| Disease onset* age ≤ 5 y | 271 | 15% |
| Sleepiness onset age (y) | 270 | 8.4 ± 0.17 |
| Cataplexy onset age (y) | 269 | 8.7 ± 0.16 |
| hypnagogic hallucinations onset age (y) | 147 | 8.7 ± 0.19 |
| Mean sleep paralysis onset age (y) | 66 | 10.5 ± 0.38 |
| Mean delay cataplexy- sleepiness onset (y) | 268 | 0.3 ± 0.07 |
| Mean disease duration at evaluation (y) | 267 | 2.2 ± 0.16 |
Sleepiness or cataplexy, whichever symptom came first.
Clinical Presentation of Patients by Puberty Grouping
In view of the large number of cases included in this study, for puberty status, analyses were done in relation to age of onset (Table 3), or age at time of diagnosis (Table 4). In general, age had little relation to symptoms or MSLT results. The only 2 exceptions included a trend for an increasing prevalence of sleep paralysis with increasing age, and a lower mean number of SOREMPs in prepubertal children (Table 3). These differences were most likely related to age alone rather than age of onset, as similar results were observed when patients were classified by puberty status at diagnosis (Table 4). Importantly, even though the mean number of SOREMPs was lower in very young subjects with narcolepsy, overall percentage positivity for the MSLT did not differ in this study (Tables 3, 4). Only 4 of the 206 (1.9%) with prepubertal onset and one of the 60 (1.7%) with puberty onset had a family history of typical narcolepsy-cataplexy.
Table 3.
Narcolepsy with cataplexy by age at disease onset
| Prepuberty onset | Puberty onset | Post puberty onset | 3 way-P value | |
|---|---|---|---|---|
| n = 206 | n = 60 | n = 5 | ||
| Age (y) | 9.36 ± 0.21* | 13.67 ± 0.38† | 16.80 ± 1.32 | < 0.001 |
| Sex (male) | 68.45% | 63.33% | 100.00% | |
| BMI (kg/m2) | 21.16 ± 0.38 (203)* | 23.75 ± 0.71 (59) | 21.89 ± 2.44 | < 0.05 |
| Disease age of onset (y) | 7.08 ± 0.12* | 11.92 ± 0.22† | 15.20 ± 0.77 | < 0.001 |
| Age of onset (sleepiness) (y) | 7.20 ± 0.12 (205)* | 12.02 ± 0.22† | 15.20 ± 0.76 | < 0.001 |
| Age of onset (cataplexy) (y) | 7.47 ± 0.13 (202)* | 12.12 ± 0.24† | 15.40 ± 0.83 | < 0.001 |
| % Hypnagogic hallucinations | 53.96% (202) | 62.07% (58) | 60.00% | |
| Age of onset (hallucinations) (y) | 7.29 ± 0.19 (107)* | 12.47 ± 0.32 (36) | 15.00 ± 1.12 (3) | < 0.001 |
| % Sleep paralysis | 18.09% (199)* | 52.63% (57) | 60.00% | < 0.001 |
| Age of onset (sleep paralysis) (y) | 8.26 ± 0.35 (34)* | 12.62 ± 0.38 (29) | 15.00 ± 1.17 (3) | < 0.001 |
| % Disturbed nocturnal sleep | 93.42% (152) | 86.49% (37) | 100% (4) | |
| % Snoring | 10.87% (138) | 9.52% (42) | 25.00% (4) | |
| MSLT sleep latency (min) | 3.14 ± 0.16 (203) | 3.27 ± 0.30 (56) | 5.47 ± 1.01 | |
| MSLT SOREMP numbers | 2.12 ± 0.11 (201)* | 3.03 ± 0.20 (58) | 3.87 ± 0.68 | < 0.001 |
| %MSLT < 8 and ≥ 2 SOREMP | 95.55% (202) | 94.64% (56) | 80.00% |
Values in parentheses are the sample size for that variable. Pre puberty versus puberty:
P < 0.001. Puberty versus post puberty:
P < 0.001.
Table 4.
Narcolepsy with cataplexy by age at diagnosis
| Diagnosis pre-puberty | Diagnosis during puberty | Diagnosis post puberty | 3 way-P value | |
|---|---|---|---|---|
| n = 143 | n = 75 | n = 53 | ||
| Age (y) | 7.59 ± 0.12*** | 12.25 ± 0.16††† | 15.66 ± 0.19‡ | < 0.001 |
| Sex (male) | 70.35% | 63.64% | 66.04% | |
| BMI (kg/m2) | 19.70 ± 0.42 (143)*** | 22.78 ± 0.57 (75) | 25.88 ± 0.68‡ | < 0.001 |
| Disease age of onset* (y) | 6.76 ± 0.19 (142)*** | 9.43 ± 0.26†† | 10.79 ± 0.31‡ | < 0.001 |
| Age of onset (sleepiness) (y) | 6.82 ± 0.18 (141)*** | 9.57 ± 0.25†† | 11.02 ± 0.30 (52)‡ | < 0.001 |
| Age of onset (cataplexy) (y) | 6.96 ± 0.18 (142)*** | 9.83 ± 0.24 (75)††† | 11.67 ± 0.29 (51)‡ | < 0.001 |
| % Hypnagogic hallucinations | 58.70% (138)* | 42.67% (75) | 66.04% | |
| Age of onset (hallucinations) (y) | 6.94 ± 0.24 (80)*** | 9.42 ± 0.39 (31)††† | 12.20 ± 0.37 (35)‡ | < 0.001 |
| % Sleep paralysis | 15.33% (137) | 26.39% (72)†† | 54.72%‡ | < 0.001 |
| Age of onset (sleep paralysis) (y) | 7.74 ± 0.57 (19)** | 10.67 ± 0.59 (18)† | 12.17 ± 0.46 (29)‡ | < 0.001 |
| % Disturbed nocturnal sleep | 96.30% (108) | 88.89% (45) | 85.37% (41) | |
| % Snoring | 14.29% (91) | 7.69% (52) | 7.14% (42) | |
| MSLT sleep latency (min) | 3.22 ± 0.19 (141)* | 2.64 ± 0.26 (74)†† | 3.99 ± 0.31 (52) | < 0.005 |
| MSLT SOREMP numbers | 2.09 ± 0.13 (139) | 2.39 ± 0.18 (75) | 3.10 ± 0.21 | < 0.005 |
| %MSLT < 8 and ≥ 2 SOREMP | 96.43% (140) | 94.60% (74) | 92.31% (52)‡ |
* Sleepiness or cataplexy, whichever symptom came first. Values in parentheses are the sample size for that variable. Prepuberty versus puberty: *P < 0.05, **P < 0.005, *** P < 0.001. Puberty versus post puberty: †P < 0.05, ††P < 0.005, †††P < 0.001. Prepuberty versus post puberty: ‡P < 0.001.
DISCUSSION
In this retrospective study, we evaluated a large group of children in Beijing China with primary hypersomnia and found that 86% have narcolepsy-cataplexy. Chinese patients with narcolepsy (with and without cataplexy) were heavier and younger than those with idiopathic hypersomnia (independent of age and sex). Most were male (67% for NC), a result consistent with other reports in Japan (60%)7, Korea (57%)4, France (67%)9, Canada (54%)9 but not the United States (44%)8. Finally, there were few (1% to 2%) reports of familial clusters, and no difference related to age of onset for these few subjects.
Our main finding is that disease onset for narcolepsy occurred at a strikingly young age in Chinese children of both sexes (≤ 5 years of age in 15% of cases; mean age of onset 8.6 ± 0.20 years old in males, 7.8 ± 0.31 years old in females, 8.3 ± 0.16 years old overall). It is also notable that the large majority of the children identified in this study (76%) had onset prior to puberty. This profile contrasts with reports of children from the United States17,18 and Europe,19–21 where mean age of onset ranges from 9.4-10.3 years old in case series of children, and where the majority of children have onset at or following puberty and rarely prior to 5 years old.18–22 Referral bias could explain this significantly earlier onset. For example, narcolepsy could be diagnosed earlier in Chinese children for cultural reasons, e.g. the high value placed on children in China in the context of the one-child policy leading to immediate referral. Also possible would be the effect of the internet where medical information is more readily and directly available to patients, families, and extensive family networks, as the referral center can be identified in the absence of a physician referral. Finally, one could suspect that an earlier onset is reportedly associated with more severe disease, and that more severe patients are more frequently diagnosed from this large population.23 Nonetheless, we consider this explanation based on referral bias less likely considering the high proportion of children (15%) with onset prior to 6 years, an exceptional occurrence in the literature.6,7,11,17,19,20,24
Differences in age of onset could be genetic and/or environmental. The hypothesis of a genetic difference specific to the Chinese population is possible. Honda et al.7 reported earlier onset in cases with a family history, thus an as-yet unknown polymorphism could be associated with earlier onset and could be more frequent in the Chinese population, although in our cases, the large majority (98%) had no family history of typical narcolepsy-cataplexy. Environmental triggers such as winter infections could also be involved and be more frequent or recurrent in Northern China. One environmental factor we examined was recent streptococcal infection as suggested by an elevated ASO.25,26 Another population-based study also found that streptococcal infections prior to age 21 could increase risk of developing narcolepsy,27 but this finding was also correlated with lower socioeconomic status and African American ethnicity.28 Recent works also suggests that cases of narcolepsy could be precipitated by influenza or adjuvant H1N1 vaccination.29 Such immune challenges have been proposed to act as a second hit, reactivating a dormant autoreactive immune system and favoring brain pathology at the age when these infections are more frequent. Additional studies in the Chinese population may be useful to understand this interplay of genetic and environmental pathogenetic factors in narcolepsy.
In regard to other demographic and clinical characteristics, Chinese patients with narcolepsy (with and without cataplexy) were younger and leaner than children with hypersomnia, and reported disturbed less often nocturnal sleep, sleep paralysis, and hypnagogic hallucinations. These are interesting clinical findings, which could be related to the effects of hypocretin deficiency on metabolism,30–32 and the more targeted effect on sleep-wake physiology seen in narcolepsy as opposed to the heterogeneity of the syndrome called idiopathic hypersomnia.11 As for planning data collections for disease in Chinese children, one could target a cluster of symptoms and include weight and relative weight gain as indicators of risk or disease suspect status, as family history does not seem to be a strong marker for these features.
The large sample size permitted an examination of phenotypic differences according to age and age as a rough marker for puberty status. Remarkably little was found, with the exception of strong age dependence in the development of sleep paralysis across increasing age groups. A similar tendency was also found in a study in Caucasian children.18 A possible explanation may be the difficulty for younger children to verbalize this symptom; however, no difference was reported for hypnagogic hallucinations, making the possibility of a singular underreporting of sleep paralysis less likely. Instead, the development of sleep paralysis may be developmentally regulated and only partially gated by puberty. A minor difference was the observation of decreased SOREMP numbers in presumably prepubertal subjects, a difference that may explain the more frequent report of negative MSLT results in the prepubertal population.11,17 In this population, however, the percent of those with a positive MSLT (mean sleep latency ≤ 8 min, ≥ 2 SOREMPs) overall did not differ across puberty group, thus the MSLT was found to be an adequate diagnostic test in children (Tables 3 and 4). There are case reports on precocious puberty and narcolepsy-cataplexy.33 While pubertal stage could be more rigorously determined in future trials, the cost-effectiveness, as well as cultural implications, of a physical examination of a child for Tanner Stage does not appear to be high, compared to weight change or sleep symptoms, for an epidemiologic study.
In summary, 85% of Chinese children (age < 18 y) evaluated for primary hypersomnia in a referral clinic in China's capital city had narcolepsy with cataplexy, and 76% of these children developed narcolepsy prior to puberty, a younger onset than reported in other Western and Asian populations. Clinically, younger children with narcolepsy had less sleep paralysis, and less sleep onset REM periods during the MSLT. Family history were non-informative, and less remarkable that suspected from the literature. The unusually young age of onset in this population may indicate differences in environmental triggers and genetic background for narcolepsy in Northern China.
DISCLOSURE STATEMENT
This was not an industry supported study. Dr. Strohl has received research support from INSPIRE and is the scientific officer of Starr Technology LLC. Dr. Mignot owns mutual funds with Resmed and has received research support from Jazz, Actelion, and Cephalon. He is on the advisory board of Eli Lily and Actelion and has received lecture fees from Roche. The other authors have indicated no financial conflicts of interest.
ACKNOWLEDGMENTS
This work was supported by research grants from NSFC (81070069) and The Sino-German Center for Research Promotion (GZ538) to F. Han and NIH-NS23724 grant to E. Mignot, and the VA Research Service and the NIH (HL 047380) to K.P. Strohl. We thank parents and most importantly the children for their participation.
Table S1.
Narcolepsy with cataplexy by puberty status at both onset and diagnosis
| Diagnosis/Onset Prepuberty | Diagnostic-Puberty Onset-Prepuberty | Diagnosis/Onset Puberty | Diagnostic-Postpuberty Onset-Prepubery | Diagnostic-Postpuberty Onset-Puberty | Diagnosis/Onset Postpuberty | |
|---|---|---|---|---|---|---|
| n = 142 | n = 42 | n = 35 | n = 23 | n = 24 | n = 5 | |
| Age (y) | 7.56 ± 0.12† | 12.12 ± 0.22§,††† | 12.40 ± 0.24††† | 15.39 ± 0.29†† | 15.71 ± 0.29 | 16.80 ± 0.63 |
| 70.21% | 66.67% | 60.00% | 60.87% | 66.67% | 100.00% | |
| Sex | 19.61 ± 0.42 (139)† | 22.80 ± 0.77 (41)§§ | 22.75 ± 0.85 (34)§§ | 27.59 ± 1.03 | 25.22 ± 1.01 | 21.89 ± 2.21 |
| BMI (kg/m2) | 6.72 ± 0.14† | 7.76 ± 0.25* | 11.43 ± 0.28††† | 8.04 ± 0.34** | 12.58 ± 0.34†† | 15.20 ± 0.73 |
| Age of disease onset (sleepiness or cataplexy) (y) | 6.78 ± 0.13 (140)† | 8.00 ± 0.25* | 11.46 ± 0.27††† | 8.26 ± 0.33** | 12.79 ± 0.33†† | 15.20 ± 0.71 |
| Age of onset (EDS) (y) | 6.92 ± 0.14 (140)† | 8.38 ± 0.26 (40)* | 11.49 ± 0.28††† | 9.38 ± 0.36 (21)** | 13.00 ± 0.34†† | 15.40 ± 0.74 |
| Age of onset (cataplexy) (y) | 58.39% (137) | 38.10% | 48.49% (33) | 56.52% | 79.17% | 60.00% |
| % Hypnagogic hallucinations | 6.80 ± 0.18 (79)† | 7.13 ± 0.40 (15)&&&,* | 11.56 ± 0.39 (16)** | 10.46 ± 0.43 (13)** | 12.95 ± 0.36 (19)†† | 15.00 ± 0.90 (3) |
| Age of onset (hallucinations) (y) | 14.71% (136) | 15% (40) | 40.63% (32) | 43.48% | 66.67%†† | 60.00% |
| % Sleep paralysis | 7.17 ± 0.39 (18)† | 8.83 ± 0.68 (6)* | 11.58 ± 0.48 (12)&&&,** | 9.90 ± 0.52 (10)** | 13.06 ± 0.41 (16)†† | 15.00 ± 0.96 (3) |
| Age of onset (sleep paralysis) (y) | 96.26% (107) | 86.21% (29) | 93.75% (16) | 87.50% (16) | 80.00% (20) | 100% (4) |
| % Disturbed nocturnal sleep | 14.29% (91) | 7.14% (28) | 8.33% (24) | 0% (19) | 11.11% (18) | 25.00% (4) |
| MSLT sleep latency (min) | 3.24 ± 0.19 (138) | 2.67 ± 0.34 | 2.60 ± 0.39 (23) | 3.37 ± 0.47 | 4.28 ± 0.471 (23) | 5.47 ± 1.00 |
| MSLT SOREMP numbers | 4.48 ± 0.08 (137) | 4.57 ± 0.14 | 4.00 ± 0.16 (33) | 4.39 ± 0.19 | 4.25 ± 0.18 | 3.80 ± 0.40 |
| MSLT SOREMP (mean latency) | 2.09 ± 0.13 (136) | 1.98 ± 0.23 | 2.91 ± 0.26 (33) | 2.60 ± 0.32 | 3.23 ± 0.31 | 3.87 ± 0.68 |
| MSLT % < 8 and ≥ 2 SOREMP | 96.35% (137) | 95.24% | 93.75 % (32) | 91.30% | 95.65% (23) | 80.00% |
| AHI | 10.8 ± 0.18 (104) | 1.10 ± 0.32 (33)§ | 1.40 ± 0.38 (24) | 0.60 ± 0.40 (22) | 0.77 ± 0.39 (23) | 1.00 ± 0.83 |
| % AHI > 10 | 0.96% (104) | 3.03% (33) | 4.17% (24) | 0% (22) | 0% (23) | 0% |
| % Hypocretin-1 ≤ 110 | 85.71% (7) | 87.5% (8) | 100% (6) | 100% (8) | 100% (5) | 50% (2) |
| % Hypocretin-1 ≤ 200 | 100% (7) | 87.5% (8) | 100% (6) | 100% (8) | 100% (5) | 50% (2) |
| DQB1*0602 | 94.66% (131) | 96% (50) | 94.83% (58) | 100% (17) | 100% (20) | 90% (10) |
| % ASO ≥ 100 | 25.86% (58) | 8.33% (12) | 46.15% (13) | 50% (10) | 21.05% (19) | 33.33% (3) |
| % ASO ≥ 200 | 20.69% (58) | 8.33% (12) | 46.15% (13) | 20% (10) | 5.26% (19) | 33.33% (3) |
| % ADB ≥ 480 | 12.07% (58) | 0% (12) | 15.39% (13) | 20% (10) | 0% (19) | 0% (3) |
| Disease duration (blood sample-onset) (y) | 0.85 ± 0.13 (135)† | 4.39 ± 0.24 (41)***,& | 0.97 ± 0.26§§ | 7.30 ± 0.32** | 3.13 ± 0.31†† | 1.60 ± 0.69 |
Unadjusted comparisons:
P < 0.001 vs other groups.
P < 0.05 vs group 3;
P < 0.001 vs group 4, 5, 6;
P < 0.01 versus group 6;
P < 0.01 versus group 4, 5;
P < 0.05 versus group 5;
P < 0.001 versus group 1, 3, 5, 6;
P < 0.05 versus group 4;
P < 0.001 versus group 3, 4, 6;
P < 0.001 versus group 5, 6.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1.
Narcolepsy with cataplexy by puberty status at both onset and diagnosis
| Diagnosis/Onset Prepuberty | Diagnostic-Puberty Onset-Prepuberty | Diagnosis/Onset Puberty | Diagnostic-Postpuberty Onset-Prepubery | Diagnostic-Postpuberty Onset-Puberty | Diagnosis/Onset Postpuberty | |
|---|---|---|---|---|---|---|
| n = 142 | n = 42 | n = 35 | n = 23 | n = 24 | n = 5 | |
| Age (y) | 7.56 ± 0.12† | 12.12 ± 0.22§,††† | 12.40 ± 0.24††† | 15.39 ± 0.29†† | 15.71 ± 0.29 | 16.80 ± 0.63 |
| 70.21% | 66.67% | 60.00% | 60.87% | 66.67% | 100.00% | |
| Sex | 19.61 ± 0.42 (139)† | 22.80 ± 0.77 (41)§§ | 22.75 ± 0.85 (34)§§ | 27.59 ± 1.03 | 25.22 ± 1.01 | 21.89 ± 2.21 |
| BMI (kg/m2) | 6.72 ± 0.14† | 7.76 ± 0.25* | 11.43 ± 0.28††† | 8.04 ± 0.34** | 12.58 ± 0.34†† | 15.20 ± 0.73 |
| Age of disease onset (sleepiness or cataplexy) (y) | 6.78 ± 0.13 (140)† | 8.00 ± 0.25* | 11.46 ± 0.27††† | 8.26 ± 0.33** | 12.79 ± 0.33†† | 15.20 ± 0.71 |
| Age of onset (EDS) (y) | 6.92 ± 0.14 (140)† | 8.38 ± 0.26 (40)* | 11.49 ± 0.28††† | 9.38 ± 0.36 (21)** | 13.00 ± 0.34†† | 15.40 ± 0.74 |
| Age of onset (cataplexy) (y) | 58.39% (137) | 38.10% | 48.49% (33) | 56.52% | 79.17% | 60.00% |
| % Hypnagogic hallucinations | 6.80 ± 0.18 (79)† | 7.13 ± 0.40 (15)&&&,* | 11.56 ± 0.39 (16)** | 10.46 ± 0.43 (13)** | 12.95 ± 0.36 (19)†† | 15.00 ± 0.90 (3) |
| Age of onset (hallucinations) (y) | 14.71% (136) | 15% (40) | 40.63% (32) | 43.48% | 66.67%†† | 60.00% |
| % Sleep paralysis | 7.17 ± 0.39 (18)† | 8.83 ± 0.68 (6)* | 11.58 ± 0.48 (12)&&&,** | 9.90 ± 0.52 (10)** | 13.06 ± 0.41 (16)†† | 15.00 ± 0.96 (3) |
| Age of onset (sleep paralysis) (y) | 96.26% (107) | 86.21% (29) | 93.75% (16) | 87.50% (16) | 80.00% (20) | 100% (4) |
| % Disturbed nocturnal sleep | 14.29% (91) | 7.14% (28) | 8.33% (24) | 0% (19) | 11.11% (18) | 25.00% (4) |
| MSLT sleep latency (min) | 3.24 ± 0.19 (138) | 2.67 ± 0.34 | 2.60 ± 0.39 (23) | 3.37 ± 0.47 | 4.28 ± 0.471 (23) | 5.47 ± 1.00 |
| MSLT SOREMP numbers | 4.48 ± 0.08 (137) | 4.57 ± 0.14 | 4.00 ± 0.16 (33) | 4.39 ± 0.19 | 4.25 ± 0.18 | 3.80 ± 0.40 |
| MSLT SOREMP (mean latency) | 2.09 ± 0.13 (136) | 1.98 ± 0.23 | 2.91 ± 0.26 (33) | 2.60 ± 0.32 | 3.23 ± 0.31 | 3.87 ± 0.68 |
| MSLT % < 8 and ≥ 2 SOREMP | 96.35% (137) | 95.24% | 93.75 % (32) | 91.30% | 95.65% (23) | 80.00% |
| AHI | 10.8 ± 0.18 (104) | 1.10 ± 0.32 (33)§ | 1.40 ± 0.38 (24) | 0.60 ± 0.40 (22) | 0.77 ± 0.39 (23) | 1.00 ± 0.83 |
| % AHI > 10 | 0.96% (104) | 3.03% (33) | 4.17% (24) | 0% (22) | 0% (23) | 0% |
| % Hypocretin-1 ≤ 110 | 85.71% (7) | 87.5% (8) | 100% (6) | 100% (8) | 100% (5) | 50% (2) |
| % Hypocretin-1 ≤ 200 | 100% (7) | 87.5% (8) | 100% (6) | 100% (8) | 100% (5) | 50% (2) |
| DQB1*0602 | 94.66% (131) | 96% (50) | 94.83% (58) | 100% (17) | 100% (20) | 90% (10) |
| % ASO ≥ 100 | 25.86% (58) | 8.33% (12) | 46.15% (13) | 50% (10) | 21.05% (19) | 33.33% (3) |
| % ASO ≥ 200 | 20.69% (58) | 8.33% (12) | 46.15% (13) | 20% (10) | 5.26% (19) | 33.33% (3) |
| % ADB ≥ 480 | 12.07% (58) | 0% (12) | 15.39% (13) | 20% (10) | 0% (19) | 0% (3) |
| Disease duration (blood sample-onset) (y) | 0.85 ± 0.13 (135)† | 4.39 ± 0.24 (41)***,& | 0.97 ± 0.26§§ | 7.30 ± 0.32** | 3.13 ± 0.31†† | 1.60 ± 0.69 |
Unadjusted comparisons:
P < 0.001 vs other groups.
P < 0.05 vs group 3;
P < 0.001 vs group 4, 5, 6;
P < 0.01 versus group 6;
P < 0.01 versus group 4, 5;
P < 0.05 versus group 5;
P < 0.001 versus group 1, 3, 5, 6;
P < 0.05 versus group 4;
P < 0.001 versus group 3, 4, 6;
P < 0.001 versus group 5, 6.