Objective EEG Bed Side Assessment of Impaired Conscious Awareness in Epilepsy
Conditions: Epilepsy, Absence
Sponsor: University Hospital Schleswig-Holstein

Study protocol, version 3, 08.04.2021 
Objective EEG Bed Side Assessment of Impaired Conscious Awareness in Epilepsy  
 
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ClinicalTrials.gov Identifier: NCT04799795 
Project:  Objective EEG Bed Side Assessment of Impaired Conscious 
Awareness in Epilepsy 
Version 2021/04/08 
 

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Objective EEG Bed Side Assessment of Impaired 
Conscious Awareness in Epilepsy 
 
 
 
 
 
 
 
 
 
Principal Investigator and Staff 
Principal Investigators:  
PD Dr. med. Helmut Laufs, PhD 1 
Dr. phil. Dipl.-Psych. Inken Tödt, 1 
Staff: 
Gesine Hermann 1 
 
1 Neurological Department, University Hospital Schleswig-Holstein, Campus Kiel, Christian-Albrechts-
University Kiel, Germany 
 

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1.) Aim of this study  
Recent studies were able to show that epileptic seizures with simultaneous loss of 
consciousness affect large parts of cortical and subcortical networks. This has consequences 
for people suffering from epilepsy. However, it is not possible to objectively measure 
consciousness in some kind of bedside test. This study’s aim is to develop a test that can 
measure and classify loss of consciousness using electroencephalography (EEG) close to the 
patient. 
In previous projects in Frankfurt within the same scientific research group, sleep was used as 
a model for loss of consciousness to identify spatial and temporal neural correlates via 
functional magnetic resonance imaging (fMRI). In this follow-up study, the investigation group 
tries to use these findings to determine neural signals of consciousness reduction using EEG 
alone. Afterwards, we want to develop and use a quantitative EEG analysis as a clinical test 
for the reduction of consciousness. 
2.) Preliminary work 
2.1 Epilepsy and reduced consciousness 
Epilepsy has a high prevalence and can sometimes go ahead with severe health restrictions in 
everyday life. These limitations also have socio-economic consequences that should not be 
underestimated (Newton & Garcia, 2012). Impairment of consciousness plays a major role in 
this. Especially in idiopathically generalized epilepsy (IGE) in children and adolescents as well 
as temporal lobe epilepsy (TLE) in adults, there is a decrease in consciousness (Blumenfeld, 
2011). This has a strong impact on the lives of patients and covers all areas of everyday life, 
such as work, social interactions and driving vehicles. The International League against 
Epilepsy (ILAE) already proposed a change of the guidelines in the classification of epilepsy in 
2014 in response to the increasing relevance of the topic and last implemented them directly 
in the guidelines (Blumenfeld & Meador, 2014; Fisher et al., 2017). Over the past years, 
pathophysiological issues of awareness loss have been studied and associated activity 
patterns of cortical and subcortical regions have been identified. 
2.2 This study’s relevance 
The cognitive limits of patients with epilepsy may differ in quality and strength, but also in 
appearance. Thus, several research groups have already shown that a reduction in 
consciousness can also occur interictal (Aarts, Binnie, Smit, & Wilkins, 1984; Berman et al., 
2010; Binnie, 2003; Blumenfeld, 2012; H Laufs & Duncan, 2007; Helmut Laufs, 2012; Helmut 
Laufs, Lengler, Hamandi, Kleinschmidt, & Krakow, 2006; Pressler, Robinson, Wilson, & Binnie, 
2005). The development of an objective test procedure, which could also be used in outpatient 
care, could be able to show cognitive impairment even interictal and therefore help to 
optimize the handling of the disease. Potential side effects due to drug treatment could be 
better evaluated and interpreted as part of a risk-benefit assessment. Furthermore, the 
planned test procedure could prevent focusing too much on a healthy EEG signal or the 

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number of epileptic seizures as a treatment target (Besag, 1995; Binnie, 2003). Accordingly, 
we would be able to improve the quality of life in epilepsy patients and possibly prevent 
further progression of the disease’s consequences (Bertram, 2007). Better assessment of 
driving ability would also be of relevance. Psychometric scales have already been proposed in 
the measurement of ictal consciousness, but these are based on retrospective self-assessment 
or the assessment of a third person (Nani & Cavanna, 2014). Unfortunately, these indirect 
measurements cannot guarantee unrestricted objectivity and reproducibility. The planned 
test procedure based on the physiological measurements of the EEG could solve this problem. 
3.) Hypotheses 
The aim of this study is the development of an objective and reproducible clinical test, which 
can quantify and classify consciousness based on EEG data. First, we want to develop an EEG-
based application for measuring impaired consciousness in wakefulness and sleep. This 
application should be developed based on the aforementioned previous fMRI-based study (E. 
Tagliazucchi et al., 2013). Our first hypothesis is that temporal integrity decreases from 
wakefulness to light sleep, as being a marker of consciousness and attention. This already has 
been shown in the previous studies using fMRI (E. Tagliazucchi et al., 2013; Enzo Tagliazucchi 
et al., 2013; Enzo Tagliazucchi, Crossley, Bullmore, & Laufs, 2016; Enzo Tagliazucchi & Laufs, 
2014). Processing a microstate analysis of the EEG data, we could display sequences in 
topographic maps and measure temporal integrity using appropriate parameters (Brodbeck 
et al., 2012; Kuhn et al., 2015). 
Furthermore, the planned EEG data sample will be compared to already given fMRI analysis 
data by source analysis. In this context it is hypothesized that EEG-modularity and temporal 
integrity will be higher comparing EEG data on wakefulness to the data during sleep. 
As an additional goal it is planned to apply the developed analysis / the findings from the 
aforementioned hypothesis (wakeful vs. sleep) on epilepsy patients as well as on non-sufferers 
(epilepsy vs. non-epilepsy). The microstate sequences, potentially showing an impaired 
temporal integrity – could be used as a marker for impaired consciousness in pathological 
circumstances. It is hypothesized that the temporal integrity of the microstate sequence will 
be decreased in patients with epilepsy and impairment of consciousness. 
In a third step the spatial and temporal analysis of our EEG data will be applied on the 
pathological EEGs, got from patients suffering from epilepsy. A higher modularity and a lower 
temporal autocorrelation in epilepsy patients compared to controls are expected. For the 
analysis EEG data which was acquired during a wakeful rest will be used. 

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4.) Study design 
Each participant will be studied like followed. 
Image 1: study design in „Objective bed side assessment of impaired conscious awareness in epilepsy”  
5.) Description  
5.1 Course 
After proving their suitability for participation in the study, participants will be informed about 
the aim, potential risks as well as about the time course and the scientific background of this 
project. Afterwards, demographic data will be collected and a neuropsychological assessment 
will be carried out. In addition to the neuropsychological test procedures, which register the 
cognitive domains of memory, attention, concentration and executive functions, clinical 
questionnaires and general psychosocial measures are collected (Table 1). 
All of the subsequently named tests will take place in a safe environment for patients and 
participants and will be conducted by a trained psychologist. A clinician scientist will always 
be there on demand. 
Afterwards, the EEG electrodes will be placed and prepared for the following recordings. The 
EEG will be conducted by trained staff. After finishing the recordings, the cap will be removed 
and participants will have the opportunity to wash and dry their hair as well as asking any 
questions about the procedure. After finishing the data collection financial compensation will 
be paid.  
Written informed Consent
Collection of demographical data
Neuropsychological Assessment
EEG Preparations
EEG
Removing the EEG cap, Questions?, 
Financial compensation

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Table 1: Psychological Tests  
Neuropsychological tests 
Clinical surveys 
Psychosocial disposition 
- 
Verbal learning- and 
memory test 
- 
Short term memory and 
visuo-constructive skills:  
Rey Complex Figure Test 
- 
Attention and executive 
functions: Test of 
Attentional Performance 
(TAP) 
- 
Working memory: 
Repeating Numbers from 
Wechsler Adult 
Intelligence Scale; Block-
Tapping-Test 
- 
Depression: Beck Depression 
Inventory-II 
- 
Anxiety and Depression: 
Hospital Anxiety and 
Depression Scale 
- 
Psychopathologies: 
Symptom checklist-90-S 
- 
Sleep Habits: The 
Pittsburgh Sleep Quality 
Index PSQI 
- 
Quality of Life: The 
German version of the 
Quality of Life in Epilepsy 
Inventory 
- 
Consciousness: 
retrospective 
quantitative 
consciousness 
assessment in epilepsy 
seizures: The Ictal 
Consciousness Inventory 
 
5.2 Potential risks and side effects of EEG measurement 
As a health risk to fetuses cannot be completely ruled out, women who could be pregnant will 
not take part in the study. 
In the context of EEG recordings, incidental pathological findings can occur, for example in the 
form of epilepsy-typical patterns. Therefore, the possibility of pathological findings is 
mentioned in the declaration of consent, which has to be read and signed by every participant. 
In the case of incidental findings, the participant will be informed and will have the 
opportunity of an appointment with a physician in our outpatient clinic. 
By using CE-certified electrode caps and devices from ‘Brainproducts’ as required, EEG 
recordings do not represent a risk for participants. 
While recording EEG, a medical doctor will be there on demand or will even stay during the 
measurement, even if there is no increased risk for epileptic seizures due to the data 
collection. 
6.) Ensuring security for participants 
6.1 Recruiting epilepsy patients 
The recruitment of study participants with IGE and TLE will take place in the outpatient 
department of the Department of Neurology (University Hospital) in Kiel. If the patients are 
suitable for participation in the study, the treating physicians will inform them about the study 
procedure. If patients are interested in participating, they can contact the investigation staff, 
ask further questions and potentially register to participate. Furthermore, resident 
neurologists will be informed about the study and will be asked to pass the study information 
on to suitable patients by giving them flyers. A third possibility of recruiting could be to contact 
the Group “Epilepsie Kiel e.V.”, who could publish information about this study on their 
website.  

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6.2 Recruiting the control group 
Participants will be informed about the study by postings / flyers, laid out in the Christian-
Albrechts University in Kiel, the University Hospital Schleswig-Holstein in Kiel, the polytechnic 
Kiel as well as in the adult education center. For the control group we would like to expand 
the recruiting about a posting in eBay Kleinanzeigen. 
 
6.3 In- and exclusion criteria  
In the group of epilepsy patients, severe secondary diseases lead to exclusion from the study. 
For the control group, only healthy, age-adjusted subjects will be included. Further exclusion 
criteria are systemic diseases of the central nervous system, addictions and other serious 
psychiatric illnesses. An existing pregnancy also leads to exclusion from the study. 
6.4 Termination criteria 
Upon request, the examination can be paused or terminated at any time. Furthermore, the 
attending physician can stop the continuation of the examination if the subject is at risk. If the 
subject stops the participation, no explanation is required and there will not be any 
disadvantages. 
7.) Sample size calculation 
The planned sample size is mainly based on the abovementioned EEG-fMRI study (Tagliazucchi 
et al., 2013). There, 63 healthy subjects were surveyed and divided into 4 groups according to 
sleep stages. Due to possible technical problems and artifacts, individual subjects can be 
excluded, especially in the group of patients. In order to achieve a sufficient effect, 30 subjects 
per group will be collected (IGE, TLE, healthy controls). 
8.) Time course 
Data acquisition will take about 20 months with 2 to 3 appointments per week. For the 
following analysis 16 months are planned.   
9.) Analysis 
Before the statistical analysis of the data, EEG raw data will be preprocessed. The programs 
MatLab®, Cartool and BrainVision Analyzer for which licenses are not necessary or already 
available at the institute, will be used for this. The data from the psychological testing, 
questionnaires and, demographical data will be analyzed in R statistics or / and Jupyter 
Notebooks. 
10.) Data acquisition, transfer and storage  
The data acquisition takes place in the abovementioned institute. The long-term storage of 
the data takes place on an external storage medium that is stored under lock in the institute. 
Personal data and the provided pseudonymized data are stored separately from one each 

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other, so that an assignment to one another is only possible via a key list that is only known 
to the project manager and the involved staff. The original survey material is also archived 
under lock and without the possibility of personal identification. The data is archived for 10 
years in accordance with current regulations. 
 
 

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Literature 
Aarts, J. H. P., Binnie, C. D., Smit, A. M., & Wilkins, A. J. (1984). Selective cognitive impairment during 
focal and generalized epileptiform eeg activity. Brain, 107(1), 293–308. 
https://doi.org/10.1093/brain/107.1.293 
Berman, R., Negishi, M., Vestal, M., Spann, M., Chung, M. H., Bai, X., … Blumenfeld, H. (2010). 
Simultaneous EEG, fMRI, and behavior in typical childhood absence seizures. Epilepsia, 51(10), 
2011–2022. https://doi.org/10.1111/j.1528-1167.2010.02652.x 
Bertram, E. (2007). The relevance of kindling for human epilepsy. Epilepsia. 
https://doi.org/10.1111/j.1528-1167.2007.01068.x 
Besag, F. M. C. (1995). The therapeutic dilemma: Treating subtle seizures or indulging in 
electroencephalogram cosmetics? Seminars in Pediatric Neurology, 2(4), 261–268. 
https://doi.org/10.1016/S1071-9091(95)80005-0 
Binnie, C. D. (2003). Cognitive impairment during epileptiform discharges: Is it ever justifiable to treat 
the EEG? Lancet Neurology. https://doi.org/10.1016/S1474-4422(03)00584-2 
Blumenfeld, H. (2011). Epilepsy and the Consciousness System: Transient Vegetative State? 
Neurologic Clinics. https://doi.org/10.1016/j.ncl.2011.07.014 
Blumenfeld, H. (2012). Impaired consciousness in epilepsy. The Lancet Neurology. 
https://doi.org/10.1016/S1474-4422(12)70188-6 
Blumenfeld, H., & Meador, K. J. (2014). Consciousness as a useful concept in epilepsy classification. 
Epilepsia, 55(8), 1145–1150. https://doi.org/10.1111/epi.12588 
Brodbeck, V., Kuhn, A., von Wegner, F., Morzelewski, A., Tagliazucchi, E., Borisov, S., … Laufs, H. 
(2012). EEG microstates of wakefulness and NREM sleep. NeuroImage, 62(3), 2129–2139. 
https://doi.org/10.1016/j.neuroimage.2012.05.060 
Fisher, R. S., Cross, J. H., French, J. A., Higurashi, N., Hirsch, E., Jansen, F. E., … Zuberi, S. M. (2017). 
Operational classification of seizure types by the International League Against Epilepsy: Position 
Paper of the ILAE Commission for Classification and Terminology. Epilepsia, 58(4), 522–530. 
https://doi.org/10.1111/epi.13670 
Kuhn, A., Brodbeck, V., Tagliazucchi, E., Morzelewski, A., von Wegner, F., & Laufs, H. (2015). 
Narcoleptic Patients Show Fragmented EEG-Microstructure During Early NREM Sleep. Brain 
Topography, 28(4), 619–635. https://doi.org/10.1007/s10548-014-0387-1 
Laufs, H. (2012). Functional imaging of seizures and epilepsy: evolution from zones to networks. 
Current Opinion in Neurology, 25(2), 194–200. 
https://doi.org/10.1097/WCO.0b013e3283515db9 
Laufs, H., & Duncan, J. S. (2007). Electroencephalography/functional MRI in human epilepsy: what it 
currently can and cannot do. Curr Opin Neurol, 20(4), 417–423. 
https://doi.org/10.1097/WCO.0b013e3282202b92 
Laufs, H., Lengler, U., Hamandi, K., Kleinschmidt, A., & Krakow, K. (2006). Linking generalized spike-
and-wave discharges and resting state brain activity by using EEG/fMRI in a patient with 
absence seizures. Epilepsia, 47(2), 444–448. https://doi.org/10.1111/j.1528-1167.2006.00443.x 
Nani, A., & Cavanna, A. E. (2014). The quantitative measurement of consciousness during epileptic 

Study protocol, version 3, 08.04.2021 
Objective EEG Bed Side Assessment of Impaired Conscious Awareness in Epilepsy  
 
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seizures. Epilepsy and Behavior. https://doi.org/10.1016/j.yebeh.2013.09.007 
Newton, C. R., & Garcia, H. H. (2012). Epilepsy in poor regions of the world. The Lancet, 380(9848), 
1193–1201. https://doi.org/10.1016/S0140-6736(12)61381-6 
Pressler, R. M., Robinson, R. O., Wilson, G. A., & Binnie, C. D. (2005). Treatment of interictal 
epileptiform discharges can improve behavior in children with behavioral problems and 
epilepsy. The Journal of Pediatrics, 146(1), 112–7. https://doi.org/10.1016/j.jpeds.2004.08.084 
Tagliazucchi, E., Crossley, N., Bullmore, E. T., & Laufs, H. (2016). Deep sleep divides the cortex into 
opposite modes of anatomical–functional coupling. Brain Structure and Function, 221(8), 4221– 
4234. https://doi.org/10.1007/s00429-015-1162-0 
Tagliazucchi, E., & Laufs, H. (2014). Decoding Wakefulness Levels from Typical fMRI Resting-State 
Data Reveals Reliable Drifts between Wakefulness and Sleep. Neuron, 82(3), 695–708. 
https://doi.org/10.1016/j.neuron.2014.03.020 
Tagliazucchi, E., von Wegner, F., Morzelewski, A., Brodbeck, V., Borisov, S., Jahnke, K., & Laufs, H. 
(2013). Large-scale brain functional modularity is reflected in slow electroencephalographic 
rhythms across the human non-rapid eye movement sleep cycle. NeuroImage, 70, 327–339. 
https://doi.org/10.1016/j.neuroimage.2012.12.073 
Tagliazucchi, E., von Wegner, F., Morzelewski, A., Brodbeck, V., Jahnke, K., & Laufs, H. (2013). 
Breakdown of long-range temporal dependence in default mode and attention networks during 
deep sleep. Proceedings of the National Academy of Sciences, 110(38), 15419–15424. 
https://doi.org/10.1073/pnas.1312848110