Sleep disturbances are common in patients with autoimmune encephalitis

  • Margaret S. Blattner
  • Gabriela S. de Bruin
  • Robert C. Bucelli
  • Gregory S. DayEmail author
Original Communication



Autoimmune encephalitis (AE) is increasingly recognized as an important cause of subacute cognitive decline, seizures, and encephalopathy, with an ever-broadening clinical phenotype. Sleep disturbances are reported in AE patients, including rapid eye movement sleep behavior disorder, hypersomnia, fragmented sleep, and sleep-disordered breathing; however, the prevalence of sleep disturbances and contributions to outcomes in AE patients remain unknown. There is a need to determine the prevalence of sleep disturbances in AE patients, and to clarify the relationship between specific autoantibodies and disruptions in sleep.


Clinical history, results of serum and cerebrospinal fluid testing, electroencephalography, and neuroimaging were reviewed from 26 AE patients diagnosed and managed at our tertiary care hospital. Polysomnography was performed in patients with clinical indications, yielding data from 12 patients.


The median age of AE patients was 53 years (range 18–83). Autoantibodies against intracellular antigens (including Ma and Hu autoantibodies) were identified in 6/26 (23%) patients, while autoantibodies against cell-surface neuronal antigens (including NMDAR and LGI1) were identified in 20/26 (77%) patients. New sleep complaints were reported by 19/26 (73%) AE patients, including gasping or snoring (9/19, 47%), dream enactment behavior (6/19, 32%), insomnia (5/19, 29%), hypersomnia (4/19, 21%), other parasomnias (4/19, 21%), and dream-wake confusional states (2/19, 11%). Dream enactment behaviors were particularly common in AE associated with LGI1 autoantibodies, reported in 4/7 (57%) patients. Polysomnography showed reduced total sleep time, stage 3 and rapid eye movement sleep, and prominent sleep fragmentation.


Sleep disturbances are common in AE, warranting active surveillance in affected patients. Improved identification and treatment of sleep disorders may reduce morbidity associated with AE and improve long-term outcomes.


Autoimmune encephalitis NMDAR encephalitis LGI1 autoantibodies REM behavior disorder Restless legs Sleep apnea Polysomnography 



American Academy of Sleep Medicine


Autoimmune encephalitis


Apnea-hypopnea index


Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid


Collapsin response-mediator protein-5


Cerebrospinal fluid




Gamma-aminobutyric acid


Type 1 anti-neuronal nuclear antibody


Leucine-rich glioma-inactivated protein 1


Magnetic resonance imaging


Stage I sleep


Stage II sleep


Stage III sleep


N-Methyl-d-aspartate receptor




Rapid eye movement


Restless legs syndrome


Voltage-gated calcium channel


Purkinje cell cytoplasmic antibody type 1



Funding was provided by the American Academy of Neurology/American Brain Foundation (Clinical Research Training Fellowship to GSD), and via philanthropic contributions from patients and family members to promote research and education into Autoimmune Encephalitis (GSD).

Compliance with ethical standards

Ethical standards

All the procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all the individual participants included in the study.

Conflicts of interest

On behalf of all the authors, the corresponding author states that there are no conflicts of interest. Dr. Blattner has no disclosures to report. Dr. de Bruin has equity in Neuroquestions, LLC. Dr. Bucelli receives an annual gift from a patient’s family for Parsonage-Turner research; served on an advisory board for MT Pharma; and has equity in Neuroquestions, LLC. Dr. Day has served as a topic editor on dementia for DynaMed Plus (EBSCO Industries, Inc) and as clinical director for the Anti-NMDA Receptor Encephalitis Foundation (uncompensated). He receives research/grant support from The American Academy of Neurology/American Brain Foundation, Avid Radiopharmaceuticals, the Foundation for Barnes Jewish Hospital, and the National Institutes of Health (P01AG03991, R56AG057195, U01AG057195) and holds stock in ANI Pharmaceuticals, Inc. Dr. Day has provided record review and expert medical testimony on legal cases pertaining to the management of Wernicke encephalopathy.

Supplementary material

415_2019_9230_MOESM1_ESM.docx (30 kb)
Supplementary material 1 (DOCX 30 KB)


  1. 1.
    Dalmau J, Graus F (2018) Antibody-mediated encephalitis. N Engl J Med 378:840–851Google Scholar
  2. 2.
    Dubey D, Pittock SJ, Kelly CR, McKeon A, Lopez-Chiriboga AS, Lennon VA, Gadoth A, Smith CY, Bryant SC, Klein CJ, Aksamit AJ, Toledano M, Boeve BF, Tillema JM, Flanagan EP (2018) Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 83:166–177Google Scholar
  3. 3.
    Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Hoftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Pruss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostasy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15:391–404Google Scholar
  4. 4.
    McKeon A (2016) Autoimmune encephalopathies and dementias. Continuum (Minneap Minn) 22:538–558Google Scholar
  5. 5.
    Finke C, Pruss H, Heine J, Reuter S, Kopp UA, Wegner F, Then Bergh F, Koch S, Jansen O, Munte T, Deuschl G, Ruprecht K, Stocker W, Wandinger KP, Paul F, Bartsch T (2017) Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol 74:50–59Google Scholar
  6. 6.
    Gadoth A, Pittock SJ, Dubey D, McKeon A, Britton JW, Schmeling JE, Smith A, Kotsenas AL, Watson RE, Lachance DH, Flanagan EP, Lennon VA, Klein CJ (2017) Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients. Ann Neurol 82:79–92Google Scholar
  7. 7.
    Hebert J, Day GS, Steriade C, Wennberg RA, Tang-Wai DF (2018) Long-term cognitive outcomes in patients with autoimmune encephalitis. Can J Neurol Sci 45:540–544Google Scholar
  8. 8.
    Long JM, Day GS (2018) Autoimmune dementia. Semin Neurol 38:303–315Google Scholar
  9. 9.
    Peer M, Pruss H, Ben-Dayan I, Paul F, Arzy S, Finke C (2017) Functional connectivity of large-scale brain networks in patients with anti-NMDA receptor encephalitis: an observational study. Lancet Psychiatry 4:768–774Google Scholar
  10. 10.
    Titulaer MJ, McCracken L, Gabilondo I, Armangue T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12:157–165Google Scholar
  11. 11.
    Barone DA, Krieger AC (2016) Sleep disturbances in voltage-gated potassium channel antibody syndrome. Sleep Med 21:171–173Google Scholar
  12. 12.
    Cornelius JR, Pittock SJ, McKeon A, Lennon VA, Aston PA, Josephs KA, Tippmann-Peikert M, Silber MH (2011) Sleep manifestations of voltage-gated potassium channel complex autoimmunity. Arch Neurol 68:733–738Google Scholar
  13. 13.
    Iranzo A, Graus F, Clover L, Morera J, Bruna J, Vilar C, Martinez-Rodriguez JE, Vincent A, Santamaria J (2006) Rapid eye movement sleep behavior disorder and potassium channel antibody-associated limbic encephalitis. Ann Neurol 59:178–181Google Scholar
  14. 14.
    Kawamura N, Kawajiri M, Ohyagi Y, Minohara M, Murai H, Kira J (2005) A patient with paraneoplastic limbic encephalitis induced by breast cancer presenting with hypersomnia. Rinsho Shinkeigaku 45:575–578Google Scholar
  15. 15.
    Tobin WO, Lennon VA, Komorowski L, Probst C, Clardy SL, Aksamit AJ, Appendino JP, Lucchinetti CF, Matsumoto JY, Pittock SJ, Sandroni P, Tippmann-Peikert M, Wirrell EC, McKeon A (2014) DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. Neurology 83:1797–1803Google Scholar
  16. 16.
    Gaig C, Graus F, Compta Y, Hogl B, Bataller L, Bruggemann N, Giordana C, Heidbreder A, Kotschet K, Lewerenz J, Macher S, Marti MJ, Montojo T, Perez-Perez J, Puertas I, Seitz C, Simabukuro M, Tellez N, Wandinger KP, Iranzo A, Ercilla G, Sabater L, Santamaria J, Dalmau J (2017) Clinical manifestations of the anti-IgLON5 disease. Neurology 88:1736–1743Google Scholar
  17. 17.
    Anderson KN, Kelly TP, Griffiths TD (2013) Primary sleep disorders can cause long-term sleep disturbance in patients with autoimmune mediated limbic encephalitis. Clin Neurol Neurosurg 115:1079–1082Google Scholar
  18. 18.
    Allen R, Picchietti D, Garcia-Borreguero D, Ondo W, Walters A, Winkelman J, Zucconi M, Ferri R, Trenkwalder C, Lee H, Group IRLSS (2014) Restless legs syndrome/Willis–Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med 15:860–873Google Scholar
  19. 19.
    Berry RB, Brooks R, Gamaldo CE, et al. for the American Academy of Sleep Medicine (2012). The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications, Version 2.0. American Academy of Sleep Medicine, Darien, ILGoogle Scholar
  20. 20.
    Berry RB, Brooks R, Gamaldo CE, et al. for the American Academy of Sleep Medicine (2016) The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications, Version 2.3. American Academy of Sleep Medicine, Darien, ILGoogle Scholar
  21. 21.
    Mitterling T, Hogl B, Schonwald SV, Hackner H, Gabelia D, Biermayr M, Frauscher B (2015) Sleep and respiration in 100 healthy caucasian sleepers—a polysomnographic study according to American Academy of Sleep Medicine standards. Sleep 38:867–875Google Scholar
  22. 22.
    Kim AE, Kang P, Bucelli RC, Ferguson CJ, Schmidt RE, Varadhachary AS, Day GS (2018) Autoimmune encephalitis with multiple autoantibodies: a diagnostic and therapeutic challenge. Neurologist 23:55–59Google Scholar
  23. 23.
    Laurido-Soto O, Brier MR, Simon LE, McCullough A, Bucelli RC, Day GS (2019) Patient characteristics and outcome associations in AMPA receptor encephalitis. J Neurol 266(2):450–460Google Scholar
  24. 24.
    Dauvilliers Y, Bauer J, Rigau V, Lalloyer N, Labauge P, Carlander B, Liblau R, Peyron C, Lassmann H (2013) Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy. JAMA Neurol 70:1305–1310Google Scholar
  25. 25.
    Overeem S, Dalmau J, Bataller L, Nishino S, Mignot E, Verschuuren J, Lammers GJ (2004) Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. Neurology 62:138–140Google Scholar
  26. 26.
    Hars B, Hennevin E (1987) Impairment of learning by cueing during postlearning slow-wave sleep in rats. Neurosci Lett 79:290–294Google Scholar
  27. 27.
    Molle M, Eschenko O, Gais S, Sara SJ, Born J (2009) The influence of learning on sleep slow oscillations and associated spindles and ripples in humans and rats. Eur J Neurosci 29:1071–1081Google Scholar
  28. 28.
    Barnes DC, Wilson DA (2014) Slow-wave sleep-imposed replay modulates both strength and precision of memory. J Neurosci 34:5134–5142Google Scholar
  29. 29.
    Cairney SA, Ashton JE, Roshchupkina AA, Sobczak JM (2015) A dual role for sleep spindles in sleep-dependent memory consolidation? J Neurosci 35:12328–12330Google Scholar
  30. 30.
    Saxvig IW, Lundervold AJ, Gronli J, Ursin R, Bjorvatn B, Portas CM (2008) The effect of a REM sleep deprivation procedure on different aspects of memory function in humans. Psychophysiology 45:309–317Google Scholar
  31. 31.
    Ju YS, Ooms SJ, Sutphen C, Macauley SL, Zangrilli MA, Jerome G, Fagan AM, Mignot E, Zempel JM, Claassen J, Holtzman DM (2017) Slow wave sleep disruption increases cerebrospinal fluid amyloid-beta levels. Brain 140:2104–2111Google Scholar
  32. 32.
    Lucey BP, McCullough A, Landsness EC, Toedebusch CD, McLeland JS, Zaza AM, Fagan AM, McCue L, Xiong C, Morris JC, Benzinger TLS, Holtzman DM (2019) Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease. Sci Transl Med. Google Scholar
  33. 33.
    Musiek ES, Xiong DD, Holtzman DM (2015) Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp Mol Med 47:e148Google Scholar
  34. 34.
    Fyfe I (2015) Sleep disorder deficits suggest signature for early Parkinson disease. Nat Rev Neurol 12:3–3Google Scholar
  35. 35.
    Louter M, Aarden WC, Lion J, Bloem BR, Overeem S (2012) Recognition and diagnosis of sleep disorders in Parkinson’s disease. J Neurol 259:2031–2040Google Scholar
  36. 36.
    Kang P, de Bruin GS, Wang LH, Ward BA, Ances BM, Lim MM, Bucelli RC (2016) Sleep pathology in Creutzfeldt–Jakob disease. J Clin Sleep Med 12:1033–1039Google Scholar
  37. 37.
    McKeon GL, Robinson GA, Ryan AE, Blum S, Gillis D, Finke C, Scott JG (2018) Cognitive outcomes following anti-N-methyl-d-aspartate receptor encephalitis: a systematic review. J Clin Exp Neuropsychol 40:234–252Google Scholar
  38. 38.
    Yeshokumar AK, Gordon-Lipkin E, Arenivas A, Cohen J, Venkatesan A, Saylor D, Probasco JC (2017) Neurobehavioral outcomes in autoimmune encephalitis. J Neuroimmunol 312:8–14Google Scholar
  39. 39.
    Verstraeten E (2007) Neurocognitive effects of obstructive sleep apnea syndrome. Curr Neurol Neurosci Rep 7:161–166Google Scholar
  40. 40.
    Lee CH, Khoo SM, Tai BC, Chong EY, Lau C, Than Y, Shi DX, Lee LC, Kailasam A, Low AF, Teo SG, Tan HC (2009) Obstructive sleep apnea in patients admitted for acute myocardial infarction. Prevalence, predictors, and effect on microvascular perfusion. Chest 135:1488–1495Google Scholar
  41. 41.
    Marin JM, Carrizo SJ, Vicente E, Agusti AGN (2005) Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 365:1046–1053Google Scholar
  42. 42.
    Peppard PE, Young T, Palta M, Skatrud J (2000) Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342:1378–1384Google Scholar
  43. 43.
    Sivathamboo S, Farrand S, Chen Z, White EJ, Pattichis AA, Hollis C, Carino J, Roberts CJ, Minogue T, Jones NC, Yerra R, French C, Perucca P, Kwan P, Velakoulis D, O’Brien TJ, Goldin J (2019) Sleep-disordered breathing among patients admitted for inpatient video-EEG monitoring. Neurology 92:e194–e204Google Scholar
  44. 44.
    Olson EJ, Boeve BF, Silber MH (2000) Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 123:331–339Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Margaret S. Blattner
    • 1
  • Gabriela S. de Bruin
    • 1
  • Robert C. Bucelli
    • 1
  • Gregory S. Day
    • 1
    • 2
    Email author
  1. 1.Department of NeurologyWashington University School of MedicineSaint LouisUSA
  2. 2.The Charles F. and Joanne Knight Alzheimer Disease Research CenterWashington University School of MedicineSaint LouisUSA

Personalised recommendations