Clinical characteristics of symptomatic narcolepsy or hypersomnia: an analysis of 182 consecutive cases with neurological disorders associated with hypersomnolence
- 16 Downloads
Symptomatic narcolepsy is characterized as low orexin (hypocretin) levels (≤ 110 pg/ml) due to neurological diseases. However, we have experienced the cases that show symptoms similar to narcolepsy, complaining of pathological sleepiness even in cases with intermediate orexin levels (110–200 pg/ml). Therefore, we reevaluated the previously reported cases to make the concept of disease to the group in which the orexin concentration is intermediate.
Although orexin-deficient symptomatic narcolepsy has been reported worldwide, facilities that are capable of measuring orexin are still limited. Currently, our laboratory handles with almost all the CSF samples from Asian countries for determining orexin levels. We measured over 2500 cases including 182 cases suspected of symptomatic narcolepsy/hypersomnolence. Therefore, we subdivided these cases into three groups according to CSF orexin levels, low orexin group (≤ 110 pg/ml), intermediate orexin group (110–200 pg/ml), and normal orexin group (> 200 pg/ml). We defined “symptomatic hypersomnia” for hypersomnolence cases with intermediate CSF orexin levels. MSLT was recommended but not necessary. Short sleep latency (< 8 min) without SOREMPs should be observed on MSLT when performed. We compared symptoms (excessive daytime sleepiness and cataplexy) and objective measures (mean sleep latency and number of SOREMPs in MSLT) among the three groups, attempting to characterize the “symptomatic hypersomnia” group.
Among the 182 cases with clinical hypersomnolence, there were 32 cases of symptomatic narcolepsy (16%) and 14 cases of symptomatic hypersomnia (8%). Causative diseases of symptomatic narcolepsy cases consist of immune-mediated demyelinating disorders (34%) and neurodegenerations (19%), whereas those of symptomatic hypersomnia are immune-mediated demyelinating disorders (43%) and encephalopathies (14%). Significant differences were not found between orexin levels and the existence of cataplexy, SOREMPs, and short sleep latency among three hypersomnolence groups. From these results, we found that it is difficult to estimate orexin concentration from subjective symptoms and PSG/MSLT findings.
We identified that 32 symptomatic narcolepsy and 14 cases of symptomatic hypersomnolence with intermediate CSF orexin levels. We proposed these latter cases as a novel category of “symptomatic hypersomnia”. Currently, symptomatic hypersomnia cases with intermediate orexin levels or short sleep latency (< 8 min) without SOREMPs were not classified as a specific entity. However, symptomatic hypersomnia had similar severity of hypersomnolence symptoms to symptomatic narcolepsy. Therefore, these cases including equivalent pathophysiology are enough to make a comparable category as “symptomatic hypersomnia”. Since it is difficult to estimate the orexin concentration from subjective symptoms and physiological findings (PSG/MSLT), further studies for the characterization of “symptomatic hypersomnia” and understanding its pathophysiology are necessary.
KeywordsHypersomnolence Narcolepsy Hypersomnia Orexin Sleep disorder
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interests.
This study was approved by ethical committees at Akita University and it is conformed to the provisions of the Declaration of Helsinki.
Informed consent was obtained from all individual participants included in the study.
- 14.American Academy of Sleep Medicine. The international classification of sleep disorders diagnostic and coding manual, 2nd edn. Winchester: American Academy of Sleep Medicine; 2005.Google Scholar
- 15.American Academy of Sleep Medicine. The international classification of sleep disorders diagnostic and coding manual, 3rd edn. Winchester: American Academy of Sleep Medicine; 2014.Google Scholar
- 26.Kanbayashi T, Imanishi A, Ohmori Y, Sagawa Y, Takahashi Y, Omokawa M, Sato M, Hishikawa Y, Shimizu T, Nishino S. Symptomatic narcolepsy or hypersomnolence with and without hypocretin (orexin) deficiency chap. 9. In: Goswami M, Thorpy MJ, Pandi-Perumal SR, editors. Narcolepsy a clinical guide, 2nd edn. Amsterdam: Springer International Publishing; 2016, pp. 95–128.CrossRefGoogle Scholar
- 32.Nokura K, Kanbayashi T, Ozeki T, Koga H, Senda M, Zettsu T, et al. Hypersomnia secondary to hypothalamic damage and CSF orexin-A level in four cases. Sleep. 2004;27(suppl):A249.Google Scholar
- 34.Uchida T, Kanbayashi T, Tanabe R, Nagasawa K, Ishii M. A case of a 13 year old girl who was diagnosed as narcolepsy with hypersomnia after surgery on craniopharyngioma. No To Hattatsu. 2014;46:423.Google Scholar
- 35.Arii J, Kanbayashi T, Miyamoto H, Suzuki H, Kondo H, Ishii M. A case with post-trumatic hypersomnia and low hypocretin/orexin level. JSSR abstract. 2004:257.Google Scholar
- 37.Miyamoto T, Miyamoto M, Hirata K. Comparison of the three cases of nocturnal polysomnography in bilateral paramedian thalamic infarction. Jpn J Clin Neurophysiol. 2004;32(5):550.Google Scholar
- 38.Adachi T, Maeda H, Yoshimizu A, Iwata N, Yoshimura J, Sakai S, et al. A case with acute onset hypersomnolence. Mem Yamaguchi Med Soc. 2013;47:172.Google Scholar
- 39.Kashiwagi M, Tanabe T, Hara K, Suzuki S, Wakamiya E, Shimizu T, et al. Sleepiness due To Wernicke’s encephalopathy with bilateral hypothalamic lesion In A 5-year-old girl. Sleep. 2004;27:A315.Google Scholar
- 40.Yamato H, Tanozaki M, Seino Y, Wakasaya Y, Suda T, Baba M. A hypersomnia case due to limbic encephalitis with decreased orexin level. Rinsho Shinkeigaku Clin Neurol. 2004;44(7):482.Google Scholar
- 42.Mukaino A, Kinoshita I, Fukushima N, Otubo M, Kanbayashi T. A case of herpes simplex encephalitis with hypersomnia and low orexin level in the cerebrospinal fluid. Clin Neurol. 2014;54:207–11.Google Scholar
- 45.Teraoka H, Yasui K, Nomura T, IIto S, Watanabe Y, Kowa H, et al. A case of Parkinson’s disease with hypersomnia and low CSF orexin level. Rinsho Shinkeigaku. 2013;53(5):389.Google Scholar
- 47.Sugiura K, Kanbayashi T, Hattori N, Inoue Y. A case with narcolepsy which symptoms were exacerbated by comorbidity of progressive supranuclear palsy. Suimin Iryou. 2007;2(1):101–4.Google Scholar
- 51.Nozaki H, Katada S, Sato M, Tanaka K, Nishizawa M. A case with hypersomnia and paresthesia due to diffuse MS leisons from hypothalamus to spine. Rinsho Shinkeigaku Clin Neurol. 2004;44(1):59.Google Scholar
- 52.Nakamura M, Nishii M, Maki S, Nakamuara M, Suenaga T. A MS cses with EDS and bilateral hypothlamic lesions. Clin Neurol. 2005;45(2):187.Google Scholar
- 54.Sekiguchi T, Ishibashi T, Kubodera T, Yokota T, Mizusawa H. A 41 year old female with anti-AQP4 related encephalitis had narcolepsy and autonomic disturbance at onset. Rinsho Shinkeigaku Clin Neurol. 2011;51(7):516.Google Scholar
- 57.Suzuki K, Nakamura T, Hashimoto K, Miyamoto M, Komagamine T, Nagashima T, et al. Hypothermia, hypotension, hypersomnia, and obesity associated with hypothalamic lesions in a patient positive for the anti-aquaporin 4 antibody: a case report and literature review. Arch neurol. 2012;69(10):1355–9.CrossRefGoogle Scholar
- 58.Miyagawa S, Kitamura E, Uchino A, Kanbayashi T, Ogino M. A case of 27 year old woman who developed hypersomnia due to a large lesion of hypothalamus with anti-AQP4-antibody. Rinsho Shinkeigaku. 2013;53(2):169.Google Scholar
- 59.Sakai W, Matsui N, Fujita K, Izumi Y, Nishida Y, Takahashi T, et al. A case of neuromyelitis optica spectrum disorder associated with central pontine and extrapontine myelinolysis preceded by syndrome of inappropriate antidiuretic hormone secretion. Rinsho Shinkeigaku. 2014;54(7):556–60.CrossRefGoogle Scholar
- 60.Kume K, Deguchi K, Ikeda K, Takata T, Kokudo Y, Kamada M, et al. Neuromyelitis optica spectrum disorder presenting with repeated hypersomnia due to involvement of the hypothalamus and hypothalamus-amygdala linkage. Rinsho Shinkeigaku. 2014;54(4):364.Google Scholar
- 64.Yano T, Kanbayashi T, Sawaishi Y, Shimizu T, Takada G. An infant case of hypersomnia with acute disseminated encephalomyelitis due to hypothalamic dysfunction. Sleep. 2004;27(suppl):A238.Google Scholar
- 65.Mizuno K, Kiba Y, Yokoyama T, Tosho Y, Inoue M, Maeba H, et al. A case of ADEM with hypersomnolence associated with low CSF hypocretin-1 level. J Jpn Pediatr Soc. 2011;115(2):330.Google Scholar
- 68.Terashima H, Hoshino H, Ota S, Kashiwai H, Kubota M, Horikawa R, et al. A case of Prader-Willi Syndrome with temporary hypersomnic symptoms. No To Hattatsu. 2012;44(2):155.Google Scholar
- 71.Soda M, Kanno K, Oguchi H, Matsumoto J, Itagaki S, Kobayashi N, et al. A case of Niemann–Pick disease type C with epilepsy, autistic symptoms, and narcolepsy associated with low CSF orexin level. Fukushima J Med Sci. 2011;61(3):184.Google Scholar
- 72.Eto K, Ito Y, Nishikawa A, Saito K, Kanbayashi T, Inoue T, et al. Use of clomipramine for cataplexy associated with Niemann–Pick disease type C. 2015 (Submitting).Google Scholar
- 74.Omori Y, Kanbayashi T, Imanishi A, Tsutsui K, Sagawa Y, Kikuchi YS, Takeshima M, Yoshizawa K, Uemura S, Shimizu T. Orexin/hypocretin levels in the cerebrospinal fluid and characteristics of patients with myotonic dystrophy type 1 with excessive daytime sleepiness. Neuropsychiatr Dis Treat. 2018;14:451–7.CrossRefGoogle Scholar
- 75.Sato T, Muroya K, Kanbayashi T. Components of excessive daytime sleepiness in patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation. Pediatrics. http://pediatrics.aappublications.org/content/132/3/e788.long/reply-pediatrics_el_56631; 2014 (online).
- 76.Ito H, Ishimaru Y, Yatsuda K. A new onset and spontaneous remission case with Behcet’s disease during Infliximab treatment. Abstr Jpn Coll Rheumatol. 2007;51:412.Google Scholar
- 82.Imanishi A, Kawazoe T, Hamada Y, Ohmori Y, Omokawa M, Sagawa Y, Takahashi Y, Takahashi J, Tsutsui K, Kanbayashi T, Sakai N, Shimizu T. Cerebrospinal fluid orexin levels in symptomatic narcolepsy-cataprexy, Niemann–pick type C. Abstract of 29st Annual Meeting of the Associated Professional Sleep Societies, A270. 2015.Google Scholar