| Home | E-Submission | Sitemap | Contact us |  
top_img
Sleep Med Res > Volume 14(1); 2023 > Article
Hong, Song, Kim, and Kim: Challenges in Diagnosing Narcolepsy and Idiopathic Hypersomnia

Abstract

Narcolepsy and idiopathic hypersomnia are central disorders of hypersomnolence accompanied by excessive daytime sleepiness, which are not caused by nocturnal sleep disturbance, sleep deficiency, or circadian rhythm sleep disorders. Several studies have questioned the repeatability of the Multiple Sleep Latency Test (MSLT) in type 2 narcolepsy (NT2) patients. After two or more repeated MSLTs, the diagnosis of type 1 narcolepsy (NT1) is maintained in more than 90% of cases, while only half of the NT2 patients retain their original diagnosis. The diagnosis of NT2 may shift to idiopathic hypersomnia based on the MSLT results, making the differential diagnosis of NT2 and idiopathic hypersomnia particularly challenging. Therefore, this study suggests the need for new tests in addition to the MSLT for diagnostic consistency in NT2 and idiopathic hypersomnia.

INTRODUCTION

Narcolepsy and idiopathic hypersomnia are central disorders of hypersomnolence, characterized by excessive daytime sleepiness (EDS) in the absence of nocturnal sleep disturbance and sleep deficiency [1-4]. However, some narcolepsy cases are distinguished from idiopathic hypersomnia by the presence of cataplexy [5-12].
Cataplexy is associated with the pathophysiology of narcolepsy [1,6]. Narcolepsy occurs owing to the HLA-DQB1*0602 gene, which activates the immune system under certain environmental factors, such as infections, and destroys hypocretin-producing cells in the lateral ventricle of the brain [1,13-22]. Concordantly, the 3rd edition of the International Classification of Sleep Disorders includes hypocretin levels lower than 110 pg/mL and the presence of cataplexy in the diagnostic criteria for type 1 narcolepsy (NT1), whereas type 2 narcolepsy (NT2) can be diagnosed without cataplexy or low hypocretin levels [4].
Because measuring hypocretin levels is too invasive and of limited use, diagnosing narcolepsy mainly relies on the Multiple Sleep Latency Test (MSLT) [23-26]. The diagnostic criteria for NT1 and NT2 are the same for the MSLT, with a mean sleep latency of ≤ 8 minutes and ≥ 2 sleep-onset rapid eye movement (SOREM) episodes, while that of idiopathic hypersomnia varies by a sleep latency of ≤ 8 minutes but with ≤ 1 SOREM episodes [4,19,24,25,27-32].
Nevertheless, the validity of the MSLT has been questioned for NT2 and idiopathic hypersomnia [26,33-39]. This article reviews studies in which the diagnosis of NT2 and idiopathic hypersomnia has been changed by repeated MSLTs and discusses the potential causes and countermeasures for these diagnostic shifts.

REPEATABILITY OF MSLT IN NARCOLEPSY AND IDIOPATHIC HYPERSOMNIA PATIENTS

When the MSLT was retested in NT1 patients at intervals of 2.7–8.5 years, 73.9%–93.1% of the diagnoses were concordant with the original diagnosis, although in case of NT2 patients, only 30%–50% of the diagnosis remained consistent (Table 1) [34,37,38,40]. In the follow-up MSLT of NT2 and idiopathic hypersomnia, a considerable number of NT2 cases were converted to idiopathic hypersomnia (3/15 in Trotti’s study [37], 9/31 in Seong’s study [38], and 5/16 in Chun’s study [40]), while others were converted from idiopathic hypersomnia to NT2 (1/14 in Trotti’s study [37]). In 2013, Trotti et al. [37] showed that only 5/15 NT2 patients and 8/14 idiopathic hypersomnia patients maintained their diagnosis when the MSLT was repeated with an interval of 4.2 years.
This corroborates that the diagnostic value of MSLT in NT1 is reliable over time, whereas it is unreliable in NT2 [33-38,41]. This disparate repeatability of the MSLT results may be owing to the different progression patterns of NT1 and NT2 [37,38,40]. Specifically, symptoms or scorings may shift in NT2 and idiopathic hypersomnia patients, as their propensity for EDS and SOREM varies throughout the years, whereas NT1 remains consistent with hypocretin deficiency and cataplexy [36-38].

POSSIBLE EXPLANATIONS FOR THE POOR REPEATABILITY

There are a few possible reasons for these diagnostic shifts. MSLT results may have been influenced by undisclosed sleep problems. Sleep deprivation, obstructive sleep apnea, circadian rhythm disorder, or shift work can result in two or more SOREM episodes [36,37,39,42]. For the accuracy of the results and to rule out other sleep disorders, the patients were asked to complete a sleep log for 2 weeks, undergo actigraphy, and list their medications ahead of the MSLT.
Patients with previously diagnosed EDS, who subsequently showed improvement in their symptoms and tested normal on MSLT, may have been misdiagnosed with NT2 during their initial MSLT [34,37,38]. The presence of other aforementioned sleep disorders may have confounded the initial diagnosis.
Another reason would be that MSLT was performed incorrectly because of poor testing conditions or continuation of stimulant drugs. The amount and quality of sleep during the night before the MSLT, as well as the ability to stay awake between tests, need to be strictly controlled [34,37,40]. Thus, stimulant medication may delay sleep latency. The MSLT results were only accurate if the medication was discontinued for 2 weeks before the test. However, the patients may have continued to take the medication despite these instructions, as staying awake without medication may have been difficult during the day.
Finally, the MSLT results could have been misinterpreted. For example, in some cases, rapid eye movement is seen in only one 30 second-epoch and could have been missed while scoring [42].

CONSEQUENCE OF THE DIAGNOSTIC SHIFT

Diagnostic shifts caused by poor repeatability of MSLT could negatively impact patients’ understanding of their symptoms and curtail their ability to cope with their chronic disease by losing trust in healthcare providers.
Moreover, under current guidelines, if patients who were formerly diagnosed with and treated for NT2 show ≤ 1 SOREM at retest, they can no longer be diagnosed with narcolepsy. This causes diagnostic confusion but also a major difference in a patient’s therapeutic options. Unlike narcolepsy, the insurance company of the South Korean government does not cover the medical expenses for treating idiopathic hypersomnia. The patient would still need narcolepsy medications, including Provigil, Nuvigil, and Wakix, as they would continue to experience the same EDS symptoms.

STRATEGIES FOR MINIMIZING THE RISK OF MISDIAGNOSIS IN TYPE 2 NARCOLEPSY PATIENTS

To overcome the limitations of the current diagnostic standards and methods, we suggest: 1) repeating MSLT at intervals of ≥ 3 months, 2) meticulously ruling out other sleep disorders with EDS from narcolepsy at the first visit, and 3) identify the pathophysiology of NT2 and idiopathic hypersomnia [34,37,38,40].

CONCLUSION

As such, the MSLT has limitations in diagnosing NT2 and inconsistencies in follow-up tests. Precise diagnosis of NT2 requires careful attention to diagnostic complications and appropriate test conditions. It is highly recommended to repeat the MSLT and further develop more accurate diagnostic methods to reduce unwanted diagnostic shifts. The differential diagnosis of NT2 and idiopathic hypersomnia solely relying on MSLT should also be improved, as it could undermine the diagnostic classification of narcolepsy and hinder the accurate research of narcolepsy.

NOTES

Availability of Data and Material
Data sharing not applicable to this article as no datasets were generated or analyzed during the study.
Authors’ Contribution
Conceptualization: Seung-Chul Hong. Investigation: Seung-Chul Hong, Tae-Won Kim. Methodology: Seung-Chul Hong. Project administration: Seung-Chul Hong, Tae-Won Kim. Visualization: Young-Chan Kim. Writing—original draft: Seung-Chul Hong, Young-Chan Kim, Ji Hyun Song. Writing—review & editing: Seung-Chul Hong, Ji Hyun Song.
Conflicts of Interest
Seung-Chul Hong, a contributing editor of the Sleep Medicine Research, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest.
Funding Statement
None.

REFERENCES

1. Baumann CR, Bassetti CL, Scammell TE. Narcolepsy: pathophysiology, diagnosis, and treatment. New York: Springer Science & Business Media 2011.

2. Roth B, Broughton RJ. Narcolepsy and hypersomnia. Basel: Karger 1980.

3. Mignot E. Excessive daytime sleepiness: population and etiology versus nosology. Sleep Med Rev 2008;12:87-94.
crossref pmid
4. American Academy of Sleep Medicine. International classification of sleep disorders (ICSD-3). 3rd ed. Darien: American Academy of Sleep Medicine 2014.

5. Anderson KN, Pilsworth S, Sharples LD, Smith IE, Shneerson JM. Idiopathic hypersomnia: a study of 77 cases. Sleep 2007;30:1274-81.
crossref pmid pmc
6. Dauvilliers Y, Siegel JM, Lopez R, Torontali ZA, Peever JH. Cataplexy--clinical aspects, pathophysiology and management strategy. Nat Rev Neurol 2014;10:386-95.
crossref pmid pmc
7. Baumann CR, Mignot E, Lammers GJ, Overeem S, Arnulf I, Rye D, et al. Challenges in diagnosing narcolepsy without cataplexy: a consensus statement. Sleep 2014;37:1035-42.
crossref pmid pmc
8. Zhang M, Inocente CO, Villanueva C, Lecendreux M, Dauvilliers Y, Lin JS, et al. Narcolepsy with cataplexy: does age at diagnosis change the clinical picture? CNS Neurosci Ther 2020;26:1092-102.
crossref pmid pmc
9. Almeneessier AS, Alballa NS, Alsalman BH, Aleissi S, Olaish AH, Ba-Hammam AS. A 10-year longitudinal observational study of cataplexy in a cohort of narcolepsy type 1 patients. Nat Sci Sleep 2019;11:231-9.
pmid pmc
10. Lavault S, Dauvilliers Y, Drouot X, Leu-Semenescu S, Golmard JL, Lecendreux M, et al. Benefit and risk of modafinil in idiopathic hypersomnia vs. narcolepsy with cataplexy. Sleep Med 2011;12:550-6.
crossref pmid
11. Huang YS, Tafti M, Guilleminault C. Daytime sleepiness with and without cataplexy in Chinese-Taiwanese patients. Sleep Med 2006;7:454-7.
crossref pmid
12. Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet 2007;369:499-511.
crossref pmid
13. Chen L, Fong SY, Lam CW, Tang NL, Ng MH, Li AM, et al. The familial risk and HLA susceptibility among narcolepsy patients in Hong Kong Chinese. Sleep 2007;30:851-8.
crossref pmid pmc
14. Bassetti CLA, Adamantidis A, Burdakov D, Han F, Gay S, Kallweit U, et al. Narcolepsy—clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nat Rev Neurol 2019;15:519-39.
crossref pmid
15. Bassetti C, Gugger M, Bischof M, Mathis J, Sturzenegger C, Werth E, et al. The narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A). Sleep Med 2003;4:7-12.
crossref pmid
16. Andlauer O, Moore H, Jouhier L, Drake C, Peppard PE, Han F, et al. Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA Neurol 2013;70:891-902.
crossref pmid pmc
17. Andlauer O, Moore H 4th, Hong SC, Dauvilliers Y, Kanbayashi T, Nishino S, et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep 2012;35:1247-55.
crossref pmid pmc
18. Nakamura M, Kanbayashi T, Sugiura T, Inoue Y. Relationship between clinical characteristics of narcolepsy and CSF orexin-A levels. J Sleep Res 2011;20(1 Pt 1):45-9.
crossref pmid
19. Hong SC, Lin L, Jeong JH, Shin YK, Han JH, Lee JH, et al. A study of the diagnostic utility of HLA typing, CSF hypocretin-1 measurements, and MSLT testing for the diagnosis of narcolepsy in 163 Korean patients with unexplained excessive daytime sleepiness. Sleep 2006;29:1429-38.
crossref pmid
20. Heier MS, Evsiukova T, Vilming S, Gjerstad MD, Schrader H, Gautvik K. CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in Norway. Sleep 2007;30:969-73.
crossref pmid pmc
21. Dauvilliers Y, Baumann CR, Carlander B, Bischof M, Blatter T, Lecendreux M, et al. CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry 2003;74:1667-73.
crossref pmid pmc
22. Büchele F, Baumann CR, Poryazova R, Werth E, Valko PO. Remitting narcolepsy? Longitudinal observations in a hypocretin-deficient cohort. Sleep 2018;41:zsy118.

23. Pizza F, Moghadam KK, Vandi S, Detto S, Poli F, Mignot E, et al. Daytime continuous polysomnography predicts MSLT results in hypersomnias of central origin. J Sleep Res 2013;22:32-40.
crossref pmid
24. Pizza F, Vandi S, Detto S, Poli F, Franceschini C, Montagna P, et al. Different sleep onset criteria at the multiple sleep latency test (MSLT): an additional marker to differentiate central nervous system (CNS) hypersomnias. J Sleep Res 2011;20(1 Pt 2):250-6.
crossref pmid
25. Goldbart A, Peppard P, Finn L, Ruoff CM, Barnet J, Young T, et al. Narcolepsy and predictors of positive MSLTs in the Wisconsin Sleep Cohort. Sleep 2014;37:1043-51.
crossref pmid pmc
26. Zwyghuizen-Doorenbos A, Roehrs T, Schaefer M, Roth T. Test-retest reliability of the MSLT. Sleep 1988;11:562-5.
crossref pmid
27. Roehrs TA, Randall S, Harris E, Maan R, Roth T. MSLT in primary insomnia: stability and relation to nocturnal sleep. Sleep 2011;34:1647-52.
crossref pmid pmc
28. Coelho FM, Georgsson H, Murray BJ. Benefit of repeat multiple sleep latency testing in confirming a possible narcolepsy diagnosis. J Clin Neurophysiol 2011;28:412-4.
crossref pmid
29. Amira SA, Johnson TS, Logowitz NB. Diagnosis of narcolepsy using the multiple sleep latency test: analysis of current laboratory criteria. Sleep 1985;8:325-31.
crossref pmid
30. Dietmann A, Gallino C, Wenz E, Mathis J, Bassetti CLA. Multiple sleep latency test and polysomnography in patients with central disorders of hypersomnolence. Sleep Med 2021;79:6-10.
crossref pmid
31. Drake CL, Rice MF, Roehrs TA, Rosenthal L, Guido P, Roth T. Scoring reliability of the multiple sleep latency test in a clinical population. Sleep 2000;23:911-3.
pmid
32. Pizza F, Barateau L, Jaussent I, Vandi S, Antelmi E, Mignot E, et al. Validation of multiple sleep latency test for the diagnosis of pediatric narcolepsy type 1. Neurology 2019;93:e1034-44.
crossref pmid
33. Bonnet MH. ACNS clinical controversy: MSLT and MWT have limited clinical utility. J Clin Neurophysiol 2006;23:50-8.
crossref pmid
34. Ruoff C, Pizza F, Trotti LM, Sonka K, Vandi S, Cheung J, et al. The MSLT is repeatable in narcolepsy type 1 but not narcolepsy type 2: a retrospective patient study. J Clin Sleep Med 2018;14:65-74.
crossref pmid pmc
35. Huang YS, Guilleminault C, Lin CH, Chen CH, Chin WC, Chen TS. Multiple sleep latency test in narcolepsy type 1 and narcolepsy type 2: a 5-year follow-up study. J Sleep Res 2018;27:e12700.
crossref pmid
36. Lopez R, Doukkali A, Barateau L, Evangelista E, Chenini S, Jaussent I, et al. Test–retest reliability of the multiple sleep latency test in central disorders of hypersomnolence. Sleep 2017;40:zsx164.
crossref
37. Trotti LM, Staab BA, Rye DB. Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J Clin Sleep Med 2013;9:789-95.
crossref pmid pmc
38. Seong MJ, Choi SJ, Hong SB, Joo EY. Test-retest reliability of multiple sleep latency test in diagnosis of narcolepsy. J Sleep Med 2020;17:175-80.
crossref
39. Kwon Y, Kazaglis L, Cho Y, Howell MJ, Mahowald MW. Test-retest reliability of two consecutive mean sleep latency tests in patients with hypersomnia. Sleep Biol Rhythms 2017;15:337-9.
crossref pmid pmc
40. Chun HS, Kim SM, Kim TW, Um YH, Jeong JH, Seo HJ, et al. Different course of narcolepsy diagnosed by multiple sleep latency test: a single center experience. Sleep Med Res 2022;13:153-7.
crossref
41. Han SJ, Joo EY, Cho JW, Hong SB. The usefulness of repeated multiple sleep latency test for the diagnosis of narcolepsy. J Korean Sleep Res Soc 2008;5:39-42.
crossref
42. Chen L, Ho CK, Lam VK, Fong SY, Li AM, Lam SP, et al. Interrater and intrarater reliability in multiple sleep latency test. J Clin Neurophysiol 2008;25:218-21.
crossref pmid

Table 1.
Changed diagnoses on retesting of NT1 and NT2 patients
Study Trotti et al., 2013 [37] Ruoff et al., 2018 [34] Seong et al., 2020 [38] Chun et al., 2022 [40]
First diagnosis NT2 (n = 15) NT1 (n = 53) NT2 (n = 30) NT1 (n = 29) NT2 (n = 31) NT1 (n = 58) NT2 (n = 16)
Interval (yr) 4.2 2.9 2.7 4.0 3.7 8.48 7.05
Hypersomnia 3 - - 7 9 3 5
REM dysregulation 3 - - 0 4 0 0
Normal 4 - - 0 7 1 3
Changed diagnosis, n (%) 10 (66.7) 10 (18.9) 21 (70) 7 (24.1) 20 (64.5) 4 (6.9) 8 (50)

NT1, narcolepsy type 1; NT2, narcolepsy type 2; REM, rapid eye movement.