Several studies have raised questions about determining the diagnosis of the narcolepsy using multiple sleep latency test (MSLT). In this study, we investigated the diagnostic change in narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) using MSLT with long-term interval.
In this retrospective study, the demographic characteristics, polysomnography (PSG), and MSLT parameters were compared at the baseline between the NT1 and NT 2 patients. Then, MSLT re-tests were conducted with a mean follow-up of 8.48 years in patients with NT 1 and 7.05 years with NT 2.
Seventy-four patients (58 with NT1 and 16 with NT2) were investigated in this study. At the baseline, demographic data showed a larger body mass index value, more sleep paralysis, and hypnogogic hallucination in NT 1 compared to NT 2. Also, at baseline MSLT, shorter mean sleep latency and higher number of sleep onset rapid eye movement periods (SOREMPs) were observed in the NT 1 than those of the NT 2. On follow-up MSLT, 6.9% (n = 4) patients with NT1 and 50% (n = 8) patients with NT2 did not satisfy the previous diagnosis. Furthermore, in all the groups who had the change in repeated-MSLT, the groups with less than 2 SOREMPs observed to be accompanied by negative MSL at follow-up.
The result of MSLT was observed not to be stable in the diagnosis of NT 2 at the study. Therefore, it is recommended to repeat MSLT at regular intervals and do a prospective multi-site survey for the accurate confirmation of a diagnosis of central hypersomnia.
Central hypersomnolence disorders are excessive daytime sleepiness in the absence of nocturnal sleep pathology or insufficient sleep [
Since measuring the concentration of hypocretin is an invasive and expensive process with a high risk of infection, the diagnosis of narcolepsy has been mainly based on MSLT [
There have not been many studies on MSLT validity in narcolepsy patients with more than 5 years of follow-up in Korean sleep centers. In this study, we intended to analyze the differences in follow up MSLT parameters of NT1 and NT2, along with their baseline clinical disparities.
We hypothesized that there will be differences in baseline and follow up MSLT between NT1 and NT2 group. Moreover, we hypothesized that the diagnostic changes and clinical course will be disparate between the two groups.
Among the patients who visited the sleep center of the St. Vincent’s Hospital, College of Medicine, Catholic University of Korea for excessive daytime sleepiness between 2001 through 2017, we retrospectively reviewed the medical records of 74 patients who underwent MSLT twice or more within the follow up period of 5 years. Narcolepsy is a rare disease, and patients get financial support with the help of the national health insurance. Re-registration is necessary every 5 years, and updated MSLT result is required each time. As baseline, all the participants were drug-naïve, and a diagnosis of narcolepsy type 1 or narcolepsy type 2 was made using the International Classification of Sleep Disorders-Second Edition [
We analyzed 74 patients who were diagnosed with either narcolepsy type 1 or narcolepsy type 2 at first with the baseline demographic data and sleep parameters of MSLT, and nocturnal polysomnography (PSG). Then, at the second visit for follow-up, the sleep parameters of MSLT were compared between the two groups.
In the first dataset, the baseline demographic data and sleep parameters of MSLT, and nocturnal PSG were compared between the NT 1 and NT 2 groups. The chi-square test was used for the categorical variable and the independent t-test was used for the continuous variable. In the second dataset, only the sleep parameters of MSLT were analyzed in the same way as above. All analyzes were judged to be significant when p < 0.05.
In the first MSLT, 58 patients were identified as NT1 and 16 as NT2, respectively.
During MSLT performed for NT1 and NT2 groups, several differences were observed in some parameters. Mean sleep latency (MSL) was 2.00 ± 1.89 and 3.11 ± 2.26 for NT1 min and NT2 groups, respectively, indicating a longer pattern in the NT2 group, which was statistically significant (p = 0.032). As for the average number of SOREMPs, 3.29 ± 1.08 for NT1 and 2.56 ± 1.15 for NT2 were observed, showing more frequent SOREMPs in NT1 group (p = 0.010).
On the other hand, rapid eye movement sleep latency and SOREMP in nocturnal PSG, were not considerably different between NT 1 and NT 2.
When MSLT was followed-up in NT 1 group and NT 2 group, the rate of NT 1 patients who showed negative results of MSLT was much lower than NT 2 patients (negative MSLT at follow-up rate of 6.9% and 50.0% in NT1 and NT2, respectively) (
In the case of the NT 1 group, when the second MSLT was conducted, 93.10% (n = 54) was maintained as NT1, 5.17% (n = 3) changed to IH, and 1.72% (n =1) diagnosed as normal (
This study is one of the longitudinal studies that analyzed the repeated MSLT results in patients with NT1 and NT 2 in the sleep center of the St. Vincent’s Hospital, College of Medicine, Catholic University of Korea. Notably, distinct differences have been demonstrated among the baseline demographic characteristics and the MSLT. Also, in the case of the repeated MSLT parameter, considerable differences were observed for the two groups.
Firstly, our results of the follow-up MSLT findings in NT 2 groups is in same line with the previous studies [
Secondly, as initially expected, the NT 1 group and NT 2 group showed some differences in the baseline characteristics. NT 1 group demonstrated a larger value of BMI than NT 2 and more sleep paralysis and hypnogogic hallucination, which was consistent with the previous studies [
Thirdly, when analyzing the data of follow-up MSLT in narcolepsy patients, we inferred that the change in SOREMP could have a greater effect on the alteration of diagnosis. In all the groups with the change of MSLT, the groups under negative SOREMPs ≥ 2 were observed to be accompanied by negative MSL at follow-up. It should be noted, however, that there is an evident limitation that the number of participants is relatively small. In addition, several studies have placed more emphasis on SOREMP on PSG as a helpful indicator of high specificity to distinguish between narcolepsy and non-narcoleptic central hypersomnia [
Recently, nocturnal PSG has been spotlighted as an alternative option for diagnosing NT1. In one study, following-up of NT 1 and NT 2 patients, respectively, NT 1 patients showed increase in N1 stage in nocturnal PSG compared to NT 2 patients [
The limitations intrinsic to this study are as follows: To begin with, our sample size was relatively small, with the sample derived from only one single sleep center, thus making it difficult to generalize the results. Besides, the follow-up MSLT was performed just twice, baseline and follow-up, and follow-up intervals were not the same among patients. Therefore, the results obtained through this research could not reflect the detailed course of parameter changes until follow-up. Moreover, because this study is designed as a cohort study, there is a high probability that patients who have been tested twice in this study had a different course of the disease from in many cases. From this fact, the selection bias could not be excluded. Besides, most of the patients undergoing repeated examinations are taking stimulants or anti-depressants because of the abnormal patterns of REM sleep (cataplexy, hallucinations, nightmares, etc.). Even though we educated patients to stop taking the drugs for more than 2 weeks for the test, it is hard for us to exclude the actual number of patients who continued the drug without reporting to the medical staff during the period. As a result, it is difficult to completely rule out of the drug effect. This study did not statistically compare the two groups of people whose diagnosis changed and those who did not. This is because the number of changes in diagnosis was too small to find a statistically significant, so it seems necessary to do it in a follow-up study. However, all NT 2 patients whose diagnosis has changed failed to meet the SOREMP as much as the diagnostic criteria, so SOREMP will need to be observed more carefully when performing MSLT in the future.
In conclusion, the MSLT measures were observed to be a good diagnostic tool for NT 1 patients, but have some limitations when diagnosing patients suffering from NT 2 because of inconsistency. Therefore, it is crucial to repeat the MSLT regularly to confirm the diagnosis in an accurate manner. Other biomarkers, if available, would be helpful for us to distinguish central hypersomnia. Concurrently, understanding the pathophysiology of type 2 narcolepsy appears to be conducive to accurate diagnosis of the patients. To end, a multi-site prospective study should be helpful to diagnose central hypersomnolence, such as objective measures of sleep history (sleep recordings and actigraphs), circadian phase assessments (dim light melatonin onset), and neuropsychological tests.
The datasets generated or analyzed in this study are available from the corresponding author through reasonable request.
Conceptualization: all authors. Data curation: Hong-Shik Chun, SungMin Kim. Formal analysis: Hong-Shik Chun, Yoo Hyun Um. Investigation: Hong-Shik Chun, Sung-Min Kim. Methadology: Seung-Chul Hong, Tae-Won Kim. Supervision: Ho-Jun Seo, Jong-Hyun Jeong. Writing—original draft: Hong-Shik Chun. Writing—review & editing: Seung-Chunl Hong, Tae-Won Kim.
Seung-Chunl Hong, a contributing editor of the
None.
Repeatability of MSLT among NT1 patients (n = 58). MSLT, multiple sleep latency test; NT1, narcolepsy type 1; IH, idiopathic hypersomnia.
Repeatability of MSLT among NT2 patients (n = 16). MSLT, multiple sleep latency test; NT2, narcolepsy type 2; IH, idiopathic hypersomnia.
Demographic, clinical, and laboratorial findings of narcolepsy patients
Type 1 narcolepsy (n = 58) | Type 2 narcolepsy (n = 16) | p value | |
---|---|---|---|
Demographic data | |||
Age at first MSLT (yr) | 36.95 ± 13.91 | 30.75 ± 15.03 | 0.060 |
Age at onset (yr) | 17.50 ± 9.20 | 20.62 ± 16.32 | 0.280 |
BMI (kg/m2) |
25.29 ± 3.62 | 23.38 ± 2.67 | 0.035 |
Sex (male) | 56.9 | 62.5 | 0.688 |
Sleep paralysis (positive) |
60.3 | 12.5 | 0.001 |
Hypnagogic hallucination (positive) |
50.0 | 12.5 | 0.009 |
Nocturnal sleep disturbance (positive) | 74.1 | 56.2 | 0.166 |
MSLT | |||
MSL (min) |
2.00 ± 1.89 | 3.11 ± 2.26 | 0.032 |
SOREMPs in MSLT |
3.29 ± 1.08 | 2.56 ± 1.15 | 0.010 |
Nocturnal PSG | |||
REML (min) | 50.36 ± 74.47 | 51.59 ± 48.79 | 0.324 |
SOREMP in PSG (positive) | 62.1 | 43.8 | 0.189 |
Values are presented as mean ± standard deviation or percent.
p < 0.05.
MSLT, multiple sleep latency test; BMI, body mass index; SOREMP, sleep onset rapid eye movement periods; REML, rapid eye movement sleep latency; MSL, mean sleep latency; PSG, polysomnography.
Results of follow-up MSLT in patients diagnosed as narcolepsy
Type 1 narcolepsy (n = 58) | Type 2 narcolepsy (n = 16) | p value | ||
---|---|---|---|---|
Duration of follow-up, mean ± SD (yr) | 8.48 ± 3.28 | 7.05 ± 3.55 | 0.118 | |
Patients with negative MSLT at follow-up (n of total population [%]) |
4 (6.9) | 8 (50.0) | < 0.001 | |
Patients not to meet with SOREMPs ≥ 2 (n of NT1 or NT2 [%]) |
4 (6.9) | 8 (50.0) | < 0.001 | |
Patients not to meet with MSL ≤ 8 minutes (n of NT1 or NT2 [%]) |
1 (1.7) | 3 (18.8) | 0.030 | |
Patients not to meet with both criteria (n of NT1 or NT2 [%]) |
1 (1.7) | 3 (18.8) | 0.030 |
p < 0.05.
MSLT, multiple sleep latency test; SD, standard deviation; SOREMP, sleep onset rapid eye movement periods; MSL, mean sleep latency; NT1, narcolepsy type 1; NT2, narcolepsy type 2.