Hypersomnia and excessive daytime sleepiness in ischemic stroke

A number of studies have demonstrated a high incidence of sleep disturbances in patients with stroke. The paper reviews the variants of wakefulness disorders observed in ischemic stroke, taking into account the current terminology, as well as methods for their diagnosis. Currently, the origin of post-stroke hypersomnolence and its pathophysiology remain debatable. Various mechanisms including orexin ligand deficiency, degeneration of orexin neurons, as well as disruption of the links between the histaminergic and orexinergic systems are considered as links in the pathogenesis of hypersomnolence caused by ischemic stroke. The paper discusses the pathophysiology of hypersomnia and excessive daytime sleepiness in patients with ischemic stroke, demonstrates various points of view on the relationship of these pathological phenomena with ischemic stroke. A hypothesis on the compensatory nature of hypersomnia and excessive daytime sleepiness in acute ischemic stroke and their possible neuroprotective effect on the brain in patients with stroke is presented.

1. Krishnamurthi RV, Feigin VL, Forouzanfar MH, Mensah GA, Connor M, Bennett DA et al. Global and regional burden of firstever ischaemic and haemorrhagic stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet Glob Health. 2013;1(5):259–81. doi:10.1016/S2214-109X(13)70089-5

2. Ding Q, Whittemore R, Redeker N. Excessive daytime sleepiness in stroke survivors: an integrative review. Biol Res Nurs. 2016;18(4):420–431. doi:10.1177/1099800415625285

3. Chen X, Bi H, Zhang M, Liu H, Wang X, Zu R. Research of sleep disorders in patients with acute cerebral infarction. J Stroke Cerebrovasc Dis. 2015;24(11):2508–13. doi:10.1016/j.jstrokecerebrovasdis.2015.06.033

4. Katzan IL, Thompson NR, Walia HK, Moul DE, FoldvarySchaefer N. Sleep-related symptoms in patients with mild stroke. J Clin Sleep Med. 2020;16(1):55–64. doi:10.5664/jcsm.8122

5. Pasic Z, Smajlovic D, Dostovic Z, Kojic B, Selmanovic S. Incidence and types of sleep disorders in patients with stroke. Med Arh. 2011;65(4):225–7. doi:10.5455/medarh.2011.65.225–227

6. Leppävuori A, Pohjasvaara T, Vataja R, Kaste M, Erkinjuntti T. Insomnia in ischemic stroke patients. Cerebrovasc Dis. 2002;14(2):90–7. doi:10.1159/000064737

7. Ferre A, Ribó M, Rodríguez-Luna D, Romero O, Sampol G, Molina CA, et al. Strokes and their relationship with sleep and sleep disorders. Neurologia. 2013;28(2):103–18. English, Spanish. doi:10.1016/j.nrl.2010.09.016

8. Gasanov RL. Brain functioning in the cycle “wakefulness–sleep” in patients with cerebral stroke: Doctoral Thesis. M., 2000. In Russian.

9. Johns MW. A new perspective on sleepiness. Sleep and biological rhythms. 2010;8(3):170–179. doi:10.1111/j.1479-8425.2010.00450.x

10. Shahid A, Shen J, Shapiro CM. Measurements of sleepiness and fatigue. J Psychosom Res. 2010;69(1):81–89. doi:10.1016/j.jpsychores.2010.04.001

11. Goel N, Basner M, Rao H, Dinges DF. Circadian rhythms, sleep deprivation, and human performance. Prog Mol Biol Transl Sci. 2013;119:155–90. doi:10.1016/B978-0-12-396971-2.00007-5

12. Scammell TE, Nishino S, Mignot E, Saper CB. Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke. Neurology. 2001;56(12):1751–3. doi:10.1212/wnl.56.12.1751

13. Falconer M, Walsh S, Harbison JA. Estimated prevalence of fatigue following stroke and transient ischemic attack is dependent on terminology used and patient gender. J Stroke Cerebrovasc Dis. 2010;19(6):431–4. doi:10.1016/j.jstrokecerebrovasdis.2009.07.017

14. Lammers GJ, Bassetti CLA, Dolenc-Groselj L, Jennum PJ, Kallweit U, Khatami R et al. Diagnosis of central disorders of hypersomnolence: A reappraisal by European experts. Sleep Med Rev. 2020;52:101306. doi:10.1016/j.smrv.2020.101306

15. American Academy of Sleep Medicine. International classification of sleep disorders, 3rd ed. Darien, IL: American Academy of Sleep Medicine, 2014.

16. Iber C, Ancoli-Israel S, Chessonn A, et al, for the American Academy of Sleep Medicine. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.

17. Belova AN. Scales, tests and questionnaires in neurology and neurosurgery, 3rd ed. M.: Prakticheskaya Meditsina, 2018. 696 p. In Russian.

18. Ibáñez V, Silva J, Cauli O. A survey on sleep questionnaires and diaries. Sleep Med. 2018;42:90–96. doi:10.1016/j.sleep.2017.08.026

19. Carney CE, Buysse DJ, Ancoli-Israel S, Edinger JD, Krystal AD, Lichstein KL et al. The consensus sleep diary: standardizing prospective sleep self-monitoring. Sleep. 2012;35(2): 287–302. doi:10.5665/sleep.1642

20. Fekedulegn D, Andrew ME, Shi M, Violanti JM, Knox S, Innes KE. Actigraphy-Based Assessment of Sleep Parameters. Ann Work Expo Health. 2020;64(4):350–367. doi:10.1093/annweh/wxaa007

21. Bochkarev MV, Korostovtseva LS, Medvedeva EA, Sviryaev YuV. Actigraphy for estimation of the characteristics of sleep and sleep-wake rhythm. Profilakticheskaya medicina = The Russian Journal of Preventive Medicine. 2019;22(2):95–100. In Russian.

22. Montgomery-Downs HE, Insana SP, Bond JA. Movement toward a novel activity monitoring device. Sleep and Breathing. 2012;16(3):913–917. doi:10.1007/s11325-011-0585-y

23. Agnew HW Jr, Webb WB, Williams RL. The first night effect: an EEG study of sleep. Psychophysiology. 1966;2(3):263–266. doi:10.1111/j.1469-8986.1966.tb02650.x

24. Babkina OV, Poluektov MG, Levin OS. Diagnostic of daytime sleepiness. Effektivnaya Farmakoterapiya= Effective pharmacotherapy. 2016;(19):80–5. In Russian.

25. Sagaspe P, Micoulaud-Franchi JA, Coste O, Léger D, Espié S, Davenne D et al. Maintenance of wakefulness test, real and simulated driving in patients with narcolepsy/hypersomnia. Sleep Med. 2019;55:1–5. doi:10.1016/j.sleep.2018.02.009

26. Jang SH, Chang CH, Jung YJ, Seo JP. Post-stroke hypersomnia. Int J Stroke. 2016;11(1): NP5–6. doi:10.1177/1747493015607502

27. Arpa J, Rodríguez-Albariño A, Izal E, Sarriá J, Lara M, Barreiro P. Hypersomnia after tegmental pontine hematoma: case report. Neurologia. 1995;10(3):140–4.

28. Hermann DM, Siccoli M, Brugger P, Wachter K, Mathis J, Achermann P et al. Evolution of neurological, neuropsychological and sleep-wake disturbances after paramedian thalamic stroke. Stroke. 2008;39(1):62–8. doi:10.1161/STROKEAHA.107.494955

29. Façon E, Steriade M, Wertheim N. Hypersomnie prolongée engendrée par des lésions bilatérales du système activateur médial; le syndrome thrombotique de la bifurcation du tronc basilaire [Prolonged hypersomnia caused by bilateral lesions of the medial activator system; thrombotic syndrome of the bifurcation of the basilar trunk]. Rev Neurol (Paris). 1958;98(2):117–33. French.

30. Rivera VM, Meyer JS, Hata T, Ishikawa Y, Imai A. Narcolepsy following cerebral hypoxic ischemia. Ann Neurol. 1986; 19(5):505–8. doi:10.1002/ana.410190516

31. Drake ME Jr. Kleine-Levin syndrome after multiple cerebral infarctions. Psychosomatics. 1987;28(6):329–30. doi:10.1016/s0033-3182(87)72524-9

32. Bollu PC, Manjamalai S, Thakkar M, Sahota P. Hypersomnia. Mo Med. 2018;115(1):85–91.

33. Jones BE. Basic mechanisms of sleep-wake states. In: Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. Philadelphia: Elsevier Saunders; 2005. p. 136–53.

34. Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T, Scammell TE. Behavioral state instability in orexin knock-out mice. J Neurosci. 2004;24(28):6291–300. doi:10.1523/JNEUROSCI.0586-04.2004

35. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27(3):469–74. doi:10.1016/s0896-6273(00)00058-1

36. Vanni-Mercier G, Sakai K, Lin JS, Jouvet M. Mapping of cholinoceptive brainstem structures responsible for the generation of paradoxical sleep in the cat. Arch Ital Biol. 1989;127(3):133–64.

37. Steininger TL, Alam MN, Gong H, Szymusiak R, McGinty D. Sleep-waking discharge of neurons in the posterior lateral hypothalamus of the albino rat. Brain Res. 1999;840(1–2):138–47. doi:10.1016/s0006-8993(99)01648-0

38. Bliwise DL, Rye DB, Dihenia B, Gurecki P. Greater daytime sleepiness in subcortical stroke relative to Parkinson’s disease and Alzheimer’s disease. J Geriatr Psychiatry Neurol. 2002;15(2):61–7. doi:10.1177/089198870201500202

39. Bassetti CL. Sleep and stroke. Semin Neurol. 2005;25(1): 19–32. doi:10.1055/s‑2005-867073

40. Sterr A, Herron K, Dijk DJ, Ellis J. Time to wake-up: sleep problems and daytime sleepiness in long-term stroke survivors. Brain Inj. 2008;22(7–8):575–9. doi:10.1080/02699050802189727

41. Schuiling WJ, Rinkel GJ, Walchenbach R, de Weerd AW. Disorders of sleep and wake in patients after subarachnoid hemorrhage. Stroke. 2005;36(3):578–82. doi:10.1161/01.STR.0000154862.33213.73

42. Herron K, Dijk DJ, Dean P, Seiss E, Sterr A. Quantitative electroencephalography and behavioural correlates of daytime sleepiness in chronic stroke. Biomed Res Int. 2014;2014:794086. doi:10.1155/2014/794086

43. Happe S. Excessive daytime sleepiness and sleep disturbances in patients with neurological diseases: epidemiology and management. Drugs. 2003;63(24):2725–37. doi:10.2165/00003495-200363240-00003

44. Nishino S, Taheri S, Black J, Nofzinger E, Mignot E. The neurobiology of sleep in relation to mental illness. In: Charney DS, Nestler EJ, editors. Neurobiology of mental illness. New York: Oxford University Press; 2004. p. 1160–79.

45. Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol. 1997;52(1):27–78. doi:10.1016/s0301-0082(96)00070-6

46. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257–63. doi:10.1038/nature04284

47. John J, Wu MF, Boehmer LN, Siegel JM. Cataplexyactive neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron. 2004;42(4):619–34. doi:10.1016/s0896-6273(04)00247-8

48. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573–85. doi:10.1016/s0092-8674(00)80949-6

49. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A. 1998;95(1):322–7. doi:10.1073/pnas.95.1.322

50. Siegel JM. Hypocretin (orexin): role in normal behavior and neuropathology. Annu Rev Psychol. 2004;55:125–48. doi:10.1146/annurev.psych.55.090902.141545

51. Autret A, Laffont F, de Toffol B, Cathala HP. A syndrome of REM and non-REM sleep reduction and lateral gaze paresis after medial tegmental pontine stroke. Computed tomographic scans and anatomical correlations in four patients. Arch Neurol. 1988;45(11):1236–42. doi:10.1001/archneur.1988.00520350074019

52. Kovalzon VM. Orexin/MCH system and narcolepsy. In: VM Kovalzon. The basics of somnology: physiology and neurochemistry of cycle “wakefulness–sleep”. M.: BINOM; Laboratoriya znanii, 2011. P. 44–68. In Russian.

53. Nishino S, Sakurai E, Nevsimalova S, Yoshida Y, Watanabe T, Yanai K et al. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin‑1 in comparison to healthy controls. Sleep. 2009;32(2):175–80. doi:10.1093/sleep/32.2.175

54. Kanbayashi T, Kodama T, Kondo H, Satoh S, Inoue Y, Chiba S et al. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep. 2009;32(2):181–7. doi:10.1093/sleep/32.2.181

55. Ayerbe L, Ayis S, Wolfe CD, Rudd AG. Natural history, predictors and outcomes of depression after stroke: systematic review and meta-analysis. Br J Psychiatry. 2013;202(1):14–21. doi:10.1192/bjp.bp.111.107664

56. Hackett ML, Pickles K. Part I: frequency of depression after stroke: an updated systematic review and meta-analysis of observational studies. Int J Stroke. 2014;9(8):1017–25. doi:10.1111/ijs.12357

57. Mitchell AJ, Sheth B, Gill J, Yadegarfar M, Stubbs B, Yadegarfar M et al. Prevalence and predictors of post-stroke mood disorders: A meta-analysis and meta-regression of depression, anxiety and adjustment disorder. Gen Hosp Psychiatry. 2017;47:48–60. doi:10.1016/j.genhosppsych.2017.04.001

58. Winward C, Sackley C, Metha Z, Rothwell PM. A population-based study of the prevalence of fatigue after transient ischemic attack and minor stroke. Stroke. 2009;40(3):757–61. doi:10.1161/STROKEAHA.108.527101

59. Frank MG. The mystery of sleep function: current perspectives and future directions. Rev Neurosci. 2006;17(4):375–92. doi:10.1515/revneuro.2006.17.4.375

60. Strygin KN, Poluektov MG. Current views on stress and the protective role of sleep. Meditsinskiy Sovet = Medical Council. 2015;(5):70–77. In Russian.

61. Mensen A, Pigorini A, Facchin L, Schöne C, D’Ambrosio S, Jendoubi J et al. Sleep as a model to understand neuroplasticity and recovery after stroke: observational, perturbational and interventional approaches. J Neurosci Methods. 2019;313:37–43. doi:10.1016/j.jneumeth.2018.12.011

62. Facchin L, Schöne C, Mensen A, Bandarabadi M, Pilotto F, Saxena S et al. Slow waves promote sleep-dependent plasticity and functional recovery after stroke. J Neurosci. 2020;40(45):8637–8651. doi:10.1523/JNEUROSCI.0373-20.2020

63. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111. doi:10.1126/scitranslmed.3003748

64. Nakada T. Virchow-Robin space and aquaporin‑4: new insights on an old friend. Croat Med J. 2014;55(4):328–36. doi:10.3325/cmj.2014.55.328

65. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373–7. doi:10.1126/science.1241224