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Reduced REM sleep: a potential biomarker for epilepsy – a retrospective case-control study

      Highlights

      • Determining a correct diagnosis in individuals with suspected epilepsy is challenging, if seizures and epileptic discharges are not recorded
      • Our aim was to assess whether the percentage of REM sleep (REM%) could discriminate between individuals with epilepsy and with differential diagnoses
      • We performed a retrospective, monocentric study with 128 individuals admitted to the EMU for diagnostic purposes
      • We found that REM% was significantly lower in individuals with the diagnosis of epilepsy and had a good predictive performance
      • Reduced REM% could be a supplementary biomarker for epilepsy in challenging diagnostic settings

      Abstract

      Objective

      Establishing the diagnosis of epilepsy can be challenging if interictal epileptic discharges (IEDs) or seizures are undetectable. Many individuals with epilepsy experience sleep disturbances. A reduced percentage of REM sleep (REM%) has been observed following seizures. We aimed to assess differences of REM% in individuals with epilepsy in comparison with differential diagnoses.

      Methods

      We performed a retrospective, monocentric, two-armed case-control study with 128 age-matched individuals who underwent ≥72 hours of continuous video-EEG monitoring at our epilepsy monitoring unit (EMU) for diagnostic evaluation. We assessed REM% on the first and last night of EMU admission. Logistic regressions models were used to evaluate the predictive value of REM%.

      Results

      We included 64 individuals diagnosed with epilepsy and 64 with a differential diagnosis. REM% in the epilepsy group was significantly lower [12.2% (±4.7) vs. 17.2% (±5.2), p<0.001]. We found no significant influence of sex, age, anti-seizure, or other medications. A REM%-based and an IED and seizure-based regression model were not significantly different [area under the curve (AUC) 0.791 (95% confidence interval (CI): 0.713-0.870) vs. 0.853 (95% CI: 0.788-0.919), p=0.23]. A combined model, based on IEDs, seizures, and REM%, was superior to the IED model alone [0.933 (0.891-0.975), p<0.01].

      Interpretation

      Our study shows significantly reduced REM% in individuals with epilepsy. REM%-based models show a good predictive performance. REM% assessment could improve diagnostic accuracy – especially for challenging cases, e.g., when IEDs or seizures are absent and patient history and semiology appear ambiguous. REM% as a biomarker should be evaluated in prospective, multicentric trials.

      Keywords

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      References

        • van Donselaar CA
        • Stroink H
        • Arts WF
        Dutch Study Group of Epilepsy in C. How confident are we of the diagnosis of epilepsy?.
        Epilepsia. 2006; 47 (Suppl): 9-13
        • Salinsky M
        • Kanter R
        • Dasheiff RM.
        Effectiveness of multiple EEGs in supporting the diagnosis of epilepsy: an operational curve.
        Epilepsia. 1987; 28: 331-334
        • Werhahn KJ
        • Hartl E
        • Hamann K
        • Breimhorst M
        • Noachtar S.
        Latency of interictal epileptiform discharges in long-term EEG recordings in epilepsy patients.
        Seizure. 2015; 29: 20-25
        • Basiri R
        • Shariatzadeh A
        • Wiebe S
        • Aghakhani Y.
        Focal epilepsy without interictal spikes on scalp EEG: A common finding of uncertain significance.
        Epilepsy Res. 2019; 150: 1-6
        • Moore JL
        • Carvalho DZ
        • St Louis EK
        • Bazil C
        Sleep and Epilepsy: a Focused Review of Pathophysiology, Clinical Syndromes, Co-morbidities, and Therapy.
        Neurotherapeutics. 2021; 18: 170-180
        • de Weerd A
        • de Haas S
        • Otte A
        • et al.
        Subjective sleep disturbance in patients with partial epilepsy: a questionnaire-based study on prevalence and impact on quality of life.
        Epilepsia. 2004; 45: 1397-1404
        • Jain SV
        • Glauser TA.
        Effects of epilepsy treatments on sleep architecture and daytime sleepiness: an evidence-based review of objective sleep metrics.
        Epilepsia. 2014; 55: 26-37
        • Vendrame M
        • Jackson S
        • Syed S
        • Kothare SV
        • Auerbach SH.
        Central sleep apnea and complex sleep apnea in patients with epilepsy.
        Sleep Breath. 2014; 18: 119-124
        • Malow BA
        • Levy K
        • Maturen K
        • Bowes R.
        Obstructive sleep apnea is common in medically refractory epilepsy patients.
        Neurology. 2000; 55: 1002-1007
        • Janz D.
        The grand mal epilepsies and the sleeping-waking cycle.
        Epilepsia. 1962; 3: 69-109
        • Malow BA.
        Sleep deprivation and epilepsy.
        Epilepsy Curr. 2004; 4: 193-195
        • Fountain NB
        • Kim JS
        • Lee SI.
        Sleep Deprivation Activates Epileptiform Discharges Independent of the Activating Effects of Sleep.
        Journal of Clinical Neurophysiology. 1998; 15: 69-75
        • Glick TH.
        The sleep-deprived electroencephalogram: evidence and practice.
        Arch Neurol. 2002; 59: 1235-1239
        • Ohayon MM
        • Carskadon MA
        • Guilleminault C
        • Vitiello MV.
        Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan.
        Sleep. 2004; 27: 1255-1273
        • Malow BA
        • Selwa LM
        • Ross D
        • Aldrich MS
        Lateralizing value of interictal spikes on overnight sleep-EEG studies in temporal lobe epilepsy.
        Epilepsia. 1999; 40: 1587-1592
        • Ng M
        • Pavlova M.
        Why are seizures rare in rapid eye movement sleep? Review of the frequency of seizures in different sleep stages.
        Epilepsy Res Treat. 2013; 2013932790
        • Kumar P
        • Raju TR.
        Seizure susceptibility decreases with enhancement of rapid eye movement sleep.
        Brain Res. 2001; 922: 299-304
        • Shouse MN
        • Siegel JM
        • Wu MF
        • Szymusiak R
        • Morrison AR.
        Mechanisms of seizure suppression during rapid-eye-movement (REM) sleep in cats.
        Brain Res. 1989; 505: 271-282
        • Bazil CW
        • Castro LH
        • Walczak TS.
        Reduction of rapid eye movement sleep by diurnal and nocturnal seizures in temporal lobe epilepsy.
        Arch Neurol. 2000; 57: 363-368
        • Cicchetti DV.
        Guidelines, criteria, and rules of thumb for evaluating normed and standardized assessment instruments in psychology.
        Psychological Assessment. 1994; 6: 284-290
        • Pavlova MK
        • Ng M
        • Allen RM
        • et al.
        Proceedings of the Sleep and Epilepsy Workgroup: Section 2 Comorbidities: Sleep Related Comorbidities of Epilepsy.
        Epilepsy Curr. 2021; (15357597211004549)
        • Manni R
        • Terzaghi M.
        Comorbidity between epilepsy and sleep disorders.
        Epilepsy Res. 2010; 90: 171-177
        • Clemens Z
        • Janszky J
        • Szucs A
        • Bekesy M
        • Clemens B
        • Halasz P.
        Interictal epileptic spiking during sleep and wakefulness in mesial temporal lobe epilepsy: a comparative study of scalp and foramen ovale electrodes.
        Epilepsia. 2003; 44: 186-192
        • Sammaritano M
        • Gigli GL
        • Gotman J.
        Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy.
        Neurology. 1991; 41 (2 (Pt 1): 290-297
        • McLeod GA
        • Ghassemi A
        • Ng MC.
        Can REM Sleep Localize the Epileptogenic Zone?.
        A Systematic Review and Analysis. Front Neurol. 2020; 11: 584
        • Li J
        • Vitiello MV
        • Gooneratne NS.
        Sleep in Normal Aging.
        Sleep Med Clin. 2018; 13: 1-11
        • Agnew Jr, HW
        • Webb WB
        • Williams RL
        The first night effect: an EEG study of sleep.
        Psychophysiology. 1966; 2: 263-266
        • Peever J
        • Fuller PM.
        The Biology of REM Sleep.
        Curr Biol. 2017; 27: R1237-R1R48
        • Dumoulin Bridi MC
        • Aton SJ
        • Seibt J
        • Renouard L
        • Coleman T
        • Frank MG
        Rapid eye movement sleep promotes cortical plasticity in the developing brain.
        Sci Adv. 2015; 1e1500105
        • Llewellyn S.
        Such stuff as dreams are made on? Elaborative encoding, the ancient art of memory, and the hippocampus.
        Behav Brain Sci. 2013; 36: 589-607
        • Poe GR
        • Nitz DA
        • McNaughton BL
        • Barnes CA.
        Experience-dependent phase-reversal of hippocampal neuron firing during REM sleep.
        Brain Research. 2000; 855 (2000/02/07/): 176-180
        • Liu X
        • Forbes EE
        • Ryan ND
        • Rofey D
        • Hannon TS
        • Dahl RE.
        Rapid eye movement sleep in relation to overweight in children and adolescents.
        Arch Gen Psychiatry. 2008; 65: 924-932
        • Mellman TA
        • Pigeon WR
        • Nowell PD
        • Nolan B.
        Relationships between REM sleep findings and PTSD symptoms during the early aftermath of trauma.
        J Trauma Stress. 2007; 20: 893-901
        • Wang YQ
        • Li R
        • Zhang MQ
        • Zhang Z
        • Qu WM
        • Huang ZL.
        The Neurobiological Mechanisms and Treatments of REM Sleep Disturbances in Depression.
        Curr Neuropharmacol. 2015; 13: 543-553
        • Dell KL
        • Payne DE
        • Kremen V
        • et al.
        Seizure likelihood varies with day-to-day variations in sleep duration in patients with refractory focal epilepsy: A longitudinal electroencephalography investigation.
        EClinicalMedicine, 2022
        • Friedman DE
        • Hirsch LJ.
        How long does it take to make an accurate diagnosis in an epilepsy monitoring unit?.
        J Clin Neurophysiol. 2009; 26: 213-217
        • LaFrance Jr., WC
        • Baker GA
        • Duncan R
        • Goldstein LH
        • Reuber M
        Minimum requirements for the diagnosis of psychogenic nonepileptic seizures: a staged approach: a report from the International League Against Epilepsy Nonepileptic Seizures Task Force.
        Epilepsia. 2013; 54: 2005-2018
      1. Kellinghaus C, Luders HO. Frontal lobe epilepsy. Epileptic Disord. 2004 Dec;6(4):223-39.

        • Kutlubaev MA
        • Xu Y
        • Hackett ML
        • Stone J.
        Dual diagnosis of epilepsy and psychogenic nonepileptic seizures: Systematic review and meta-analysis of frequency, correlates, and outcomes.
        Epilepsy Behav. 2018; 89: 70-78
        • Smith D
        • Defalla BA
        • Chadwick DW.
        The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic.
        QJM. 1999; 92: 15-23
        • Placidi F
        • Marciani MG
        • Diomedi M
        • et al.
        Effects of lamotrigine on nocturnal sleep, daytime somnolence and cognitive functions in focal epilepsy.
        Acta Neurol Scand. 2000; 102: 81-86
        • Foldvary N
        • Perry M
        • Lee J
        • Dinner D
        • Morris HH.
        The effects of lamotrigine on sleep in patients with epilepsy.
        Epilepsia. 2001; 42: 1569-1573