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Epilepsia. 2020;61:1805–1817.
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1805
wileyonlinelibrary.com/journal/epi
Received: 16 April 2020
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Revised: 16 June 2020
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Accepted: 5 July 2020
DOI: 10.1111/epi.16630
CRITICAL REVIEW AND INVITED COMMENTARY
A new era in electroencephalographic monitoring? Subscalp
devices for ultra–long-term recordings
JonasDuun-Henriksen1,2
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MaximeBaud3,4
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Mark P.Richardson1
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MarkCook5,6
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GeorgeKouvas4
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John M.Heasman7
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DanielFriedman8
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JukkaPeltola9
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Ivan C.Zibrandtsen10
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Troels W.Kjaer10,11
1Department of Basic & Clinical Neuroscience, King’s College London, London, UK
2UNEEG medical, Lynge, Denmark
3Sleep-Wake-Epilepsy Center and Center for Experimental Neurology, Department of Neurology, Bern University Hospital, University of Bern, Bern,
Switzerland
4Wyss Center for Bio and Neuroengineering, Geneva, Switzerland
5Graeme Clark Institute, University of Melbourne, Melbourne, Victoria, Australia
6Epi-Minder, Melbourne, Victoria, Australia
7Cochlear, Sydney, New South Wales, Australia
8NYU Langone Comprehensive Epilepsy Center, New York, New York, USA
9Department of Neurology, Tampere University and Tampere University Hospital, Tampere, Finland
10Center of Neurophysiology, Department of Neurology, Zealand University Hospital, Roskilde, Denmark
11Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy
Correspondence
Jonas Duun-Henriksen, UNEEG Medical
A/S, Nymoellevej 6, 3540 Lynge, Denmark.
Email: jonas.duun-henriksen@kcl.ac.uk
Funding information
NH&MRC; Region Southern Denmark;
Engineering and Physical Sciences
Research Council; South London and
Maudsley NHS Foundation Trust;
Innovationsfonden; Health Science
Foundations of Region Zealand; Epilepsy
Foundation
Abstract
Inaccurate subjective seizure counting poses treatment and diagnostic challenges and
thus suboptimal quality in epilepsy management. The limitations of existing hospital-
and home-based monitoring solutions are motivating the development of minimally
invasive, subscalp, implantable electroencephalography (EEG) systems with accom-
panying cloud-based software. This new generation of ultra–long-term brain moni-
toring systems is setting expectations for a sea change in the field of clinical epilepsy.
From definitive diagnoses and reliable seizure logs to treatment optimization and
presurgical seizure foci localization, the clinical need for continuous monitoring of
brain electrophysiological activity in epilepsy patients is evident. Thispaper presents
the converging solutions developed independently by researchers and organizations
working at the forefront of next generation EEG monitoring. The immediate value
of these devices is discussed as well as the potential drivers and hurdles to adoption.
Additionally, this paper discusses what the expected value of ultra–long-term EEG
data might be in the future with respect to alarms for especially focal seizures, seizure
forecasting, and treatment personalization.
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1
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INTRODUCTION
The average accuracy of seizure diaries is <50%, and this
complicates diagnosis and management of epilepsy.1,2
Recent progress in the development of wearable electroen-
cephalography (EEG)3–6 and non-EEG seizure detection de-
vices was reviewed in a number of papers,3,7–10 all revealing
the unmet need for devices that could chronically monitor
epileptic brain activity. Implantable subscalp EEG devices
meet this need by detecting electrographic seizures, which
has been shown to be a robust objective measure that corre-
lates to clinical symptoms.11,12 In cardiology, the invention of
Holter electrocardiography (ECG) and the implantable loop
recorder provided a solution for the problem of monitoring
rare cardiac events.13,14 We anticipate a similar advance in
neurology with respect to long-term monitoring of brain ac-
tivity in epilepsy.
Currently, scalp EEG has several critical limitations
for long-term monitoring. Electrodes must be held fixed
to the skin either with a cap or an adhesive, such as collo-
dion, and the skin-electrode interface must be maintained
regularly to provide good recording quality. Despite in-
tense research on dry-electrode technology, the quality
attained so far is not sufficient to warrant broad appli-
cability. Moreover, scalp electrodes are generally accept-
able for periods of up to 1-2weeks at most, which might
be insufficient if seizures are infrequent, and surveys
show that esthetic appearance is an important variable
to determine patients' choice of a method for ambulatory
monitoring.15
Two commercially available intracranial devices enable
chronic EEG monitoring. The RNS System (NeuroPace)
continuously records counts of epileptic events per hour bin
and provides neurostimulation. However, only snippets of
raw data can be extracted, amounting to several minutes per
24 hours of monitoring. Percept PC (Medtronic) provides
neurostimulation treatment for symptoms associated with
movement disorders and obsessive-compulsive disorder as
well as epilepsy, where BrainSense technology can also pro-
vide a limited form of EEG monitoring (manually triggered
30-second EEG storage and bandpass average power every
10minutes). However, these are invasive intracranial systems
with a clear emphasis on therapeutic neurostimulation rather
than diagnostics.
With this gap in mind, a handful of researchers and or-
ganizations have individually pioneered the development
of subscalp EEG recording devices, reaching converging
technical solutions in recent years, and are currently work-
ing on translating the invention to the clinic and market. One
subscalp device has recently been launched in Europe (24/7
EEG SubQ, UNEEG Medical), and more are in development
at centers and companies around the world. In providing pre-
viously unobtainable data, these minimally invasive solutions
may lead to a paradigm shift in the management of epilepsy,
where clinical decisions will be based on objective brain ep-
ileptic activity, including seizure counts, sleep quality, and
vigilance.
This review describes the novel class of subscalp EEG
recording devices that can be implanted subcutaneously be-
tween the scalp and the cranium. A search on PubMed in
May 2020 for (((subcutaneous OR subgaleal OR subder-
mal OR subscalp OR epicranial OR epiosteal) AND EEG)
AND (epilepsy OR seizure)) resulted in 116 results, with
only a few of the systems mentioned in the current article
appearing. Given the sparse literature, we chose to perform
a knowledge-driven review of these EEG devices. The re-
view is based on information obtained from literature, con-
ferences, and personal correspondence as well as manually
reviewing references to articles mentioned in the literature
of the non-EEG and wearable EEG seizure detection de-
vices mentioned above.
We describe and provide an overview of current efforts for
subscalp EEG systems, commercially available or in devel-
opment, and discuss the utility of ultra–long-term monitoring
using subscalp devices in epilepsy and the advantages that
objective seizure counts can provide. We also speculate on
KEYWORDS
automatic seizure detection, chronotherapy, circadian rhythm, epilepsy monitoring and recording,
subcutaneous EEG
Key Points
• A new generation of subscalp, continuous brain
monitoring systems have the potential to advance
treatment and diagnosis in epilepsy
• First studies comparing subscalp recordings with
scalp EEG are favorable and show that seizures
can be documented electrographically
• Adoption of subscalp, ultra–long-term EEG moni-
toring may cause a shift from subjective seizure
reporting to objective seizure counting
• The true value of ultra–long-term EEG has yet to
be proven; more data collected over long periods
of time are essential to show the benefit
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DUUN-HENRIKSEN Et al.
TABLE 1 Overview and core characteristics of known subscalp EEG systems certified or currently in development
Device Channels/montage Recording modalities
EEG sampling
rate Battery
Wearable
companion
Continuous raw
data available Status
CE-approved devices
24/7 EEG SubQ 2 channels/unilateral EEG+3 axis accelerometry 207Hz External/24h
rechargeable
Yes Yes CE-marked by April
2019
Devices in validation phase
Minder 2 channels/bilateral EEG a External/24h
rechargeable
Yes Yes Clinical trial is
ongoing
EASEE 4 channel/unilateral
Laplacian
EEG a a Yes a Clinical trial is
ongoing
Epios 7 channels/temporal
OR 14 channels/
bitemporal OR 28
channels/full montage
EEG+ECG + audio+3
axis accelerometer
250Hz External/24h
rechargeable
Yes Yes Clinical trial to start
in 2020
Neuroview Technology 1 or 2 channels/
unilateral
EEG+3 axis accelerometry 256 Internal/1y No No; only relevant
epochs
Clinical trial to start
in 2020
UltimateEEG Up to 8 channels/
unilateral
a a a a a Clinical trial to start
in 2020
Abbreviation: EEG, electroencephalography.
aTo be decided or not yet disclosed.
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future possibilities of mechanistic insights into the epileptic
brain, seizure forecasting, and combination with non-EEG
modalities, and finally, we discuss current challenges and
limitations of the subscalp technology.
2
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SUBSCALP EEG AS A NEW
MODALITY
EEG is the most important paraclinical modality in diagnos-
ing epilepsy. In addition, it helps classify seizure types and
epilepsy syndromes.16 When routine outpatient EEG provides
insufficient information, long-term monitoring in a hospital-
based epilepsy monitoring unit (EMU) is the next classical
option. To mitigate the high costs of such inpatient investiga-
tions, many home-based solutions have been proposed, often
involving a few days of scalp EEG and a webcam placed in
the patient's house.17,18 Depending on the results of these in-
vestigations, surgical resection of the seizure focus may be
an option, and an additional intracranial EEG study is often
required.19
2.1
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Motivation for subscalp EEG
The development of subscalp EEG devices is motivated by
an unmet clinical need that neither scalp nor intracranial EEG
addresses: ultra–long-term (ie, >1month) EEG data collec-
tion in a home environment that can reveal temporal fluctua-
tions in patterns of seizures. This may have many advantages
for personalized epilepsy management in the context of rare
seizures, cycles of epileptic brain activity in a majority of pa-
tients, and alternating seizure localization in some individu-
als with multifocal epilepsies (eg, bitemporal epilepsy).20–24
Before discussing its potential for clinical practice in detail in
Section 3, a technical review of current solutions for subscalp
EEG follows.
2.2
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Key technical aspects
Technically, the electrodes are implanted subcutaneously
under the scalp but above the bone. Electrode location dif-
fers among devices and can be varied for some. The subscalp
placement removes the need for electrode care, avoids skin
abrasions, and secures a stable and low-impedance recording,
where several types of artifacts are attenuated.25–27 Modeling
studies show that subscalp electrodes provide more specific
and accurate measurements compared to scalp electrodes
but with lower spatial and temporal resolution than intracra-
nial electrodes.28 A comparison between subscalp and scalp
electrodes shows that the signal quality of the subscalp elec-
trodes were at least equally good during background activity
with closed and open eyes, and might be better during bodily
movements.29 Sleep recordings are also improved because
subscalp electrodes are less obtrusive than scalp electrodes
in the recumbent (sleeping) position. Many algorithms have
been proposed to remove noise from EEG30; however, espe-
cially for the modalities with only a few channels, this will be
challenging although not entirely impossible.31
Besides the implant, an external unit for power, data
storage, and transmission is needed. Five of six solutions
have opted for transmission of the data out of the implant
(see below). This requires an external battery that is simple
to recharge, easy to use, discreet, and unobtrusive. The sys-
tem should be able to function for prolonged monitoring for
>30 days and potentially for many months or years. Such
devices should also be connected to a secure, cloud-based
database supported by software applications to help organize
and analyze the recorded data. The same five solutions that
opted for external battery also provide continuous raw EEG
signals for later expert interpretation aided by detection al-
gorithms. Some solutions also include embedded software
for real-time EEG analysis, and some solutions are aiming
to enhance classification accuracy with multimodal detection
algorithms by including other physiological modalities such
as ECG, accelerometry, or voice recordings. Table1 gives an
overview of the different current subscalp EEG systems that
are described below.
2.3
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Overview of current subscalp
EEG systems
Different subscalp devices are proposed, and they vary with
respect to the number of channels (from two to 32), degree
of invasiveness (one incision under local anesthesia or up to
four incisions under local or general anesthesia), and main
application (seizure counting, alarming, forecasting, locali-
zation, neurofeedback, or neurostimulation). This section
provides an overview of the characteristics of different sub-
scalp EEG devices that are presented below in alphabetical
order. Figure1 gives an overview of several of the systems
described below as well as main application areas.
24/7 EEG SubQ from UNEEG Medical (Lynge, Denmark)
features two bipolar channels introduced under local anes-
thesia. The SubQ was used to record EEG in healthy sub-
jects29 as well as to detect clinically relevant electrographic
seizures in epilepsy patients, showing high reliability and
tolerance.32,33 The device comes with dedicated software for
automatic seizure detection and EEG visualization. The de-
vice is CE-marked, and multiple clinical trials are ongoing.34
The Epicranial Application of Stimulation Electrodes
for Epilepsy from Precisis (Heidelberg, Germany) uses five
subscalp platelet electrodes (four smaller electrodes arranged
around a larger center one). This arrangement is inspired
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DUUN-HENRIKSEN Et al.
by the surface Laplacian concept for improved stimulation
depth. It is meant to be implanted above a lesioned brain area
and/or epileptogenic focus and is capable of recording as well
as delivering neurostimulation at an individualized closed-
loop setting.35 A clinical trial is ongoing.
The Epios system from the Wyss Center for Bio and
Neuroengineering (Geneva, Switzerland) aims to offer flex-
ible configurations, from focal or bitemporal electrode lay-
outs to broad coverage transposing the locations of the full
10-20 scalp EEG montage to the subscalp compartment.
Implantation of the full montage is done under general an-
esthesia in <1 hour, through two to four small incisions
(<1 cm) using specialized epiosteal tunneling tools. With
lower coverage, implantation under mild sedation or nerve
blocking is being considered. EEG data are transferred wire-
lessly to a headpiece and on to a body-worn unit for power
and temporary storage.36 The body-worn unit also supports
multimodal coregistration (ECG, audio, accelerometry) that
is then transmitted to a secure cloud-based application de-
veloped to support long-term data visualization and analysis.
Preclinical trials are currently ongoing with the Epios im-
plant, and a clinical trial is expected to start in 2020.
Minder from Epi-Minder (Melbourne, Australia) is a
subscalp device that implants a multichannel electrode lead
across the skull using a tunneling procedure so that both
hemispheres are covered. Minder has the potential to provide
long-term and continuous measures of the EEG, which will
provide a platform to support improved diagnosis and man-
agement of epilepsy. A clinical trial is ongoing.
The Neuroview Technology Ally (Englewood, NJ) is
being developed as a fully implantable, subscalp EEG record-
ing system to quantify seizures and aid in the diagnosis of
infrequent paroxysmal episodes of altered consciousness or
convulsive activity.37 The fully implanted device can record
for 1 year of continuous use without the need to recharge.
Low-power, on-board algorithms identify epochs of subscalp
EEG activity suspicious for seizures and patient-identified
events. EEG epochs are transferred to a cloud platform via a
connected smartphone-based application for the neurologist
to review with the aid of cloud-based machine learning al-
gorithms to verify seizures and display and quantify seizure
activity between clinic visits. On-device detection algorithms
can subsequently be customized to improve the specificity of
seizure detection. Clinical trials are expected to commence
in 2020.
UltimateEEG from BrainCare Oy (Tampere, Finland)
uses platinum on silicon electrodes, with custom order sizes,
number of channels, and distance between electrodes. With
support for up to eight channels, the device offers mapping of
seizure propagation. The planar electrodes are directionally
focused toward the electrical sources to reduce electromyo-
graphic (EMG) noise. A clinical trial is expected to com-
mence in 2020.
2.4
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Other subscalp EEG systems
Several studies have helped clarify other aspects of subscalp
EEG recordings, but none of these seems to have evolved
into a commercial concept. Jochum et al38 experimented with
an implanted EEG system on a sheep and found a correlation
coefficient of 0.86-0.92 with simultaneous scalp EEG at the
same location. Ahmed et al39 investigated high-density sub-
dermal EEG probes subjected to artificial aging, compared
volume conduction simulations based on four-layered head
models, and found that recordings from the subdermal elec-
trodes were less attenuated at higher frequencies than scalp
EEG recordings. Do Valle et al40 investigated an eight-chan-
nel implanted EEG-recorder with electrode arrays projecting
FIGURE 1 Overview of different implantable parts of subscalp
devices as well as application areas. From lower left and up: 24/7
EEG SubQ from UNEEG medical, Denmark; the Epios system
from the Wyss Center for Bio and Neuroengineering, Switzerland;
UltimateEEG from BrainCare Oy, Finland; Minder from Epi-Minder,
Australia
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cranially in a fanlike pattern from behind the ear and used it
to test a seizure detection algorithm. Xu et al41 did a proof-
of-concept of subscalp EEG sensors that were comparatively
insensitive to motion-related artifacts that can be expected to
occur more often in daily life. In an intensive care unit set-
ting, low-maintenance subdermal wire electrodes have been
used, but although they are quick to set up, they can also be
dislodged easily, thus require additional fixation, and do not
appear to be practical for chronic monitoring in daily life.27
2.5
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Other modalities
Multimodal monitoring, combining measurements of two or
more different modalities, can be used to improve classifi-
cation accuracy above what can be achieved by using one
modality.10,42 Heart rate variability features are correlated
with para- and sympathetic activity, and this can be used
to detect focal seizures or added to EEG-based detection to
improve accuracy.42 Electrodermal activity exhibits changes
during generalized tonic-clonic seizures (GTCS) and focal
seizures43 and is positively correlated with longer duration
of postictal EEG suppression.44 Audio recording could be
useful to detect the initial vocalization or noise sometimes
occurring during a seizure (ictal cries) or noise that can be
characteristic of the postictal period.
Home video combined with ambulatory EEG has demon-
strated clinical utility, aiding in interpretation in 14 of 17 (82%)
cases in one study.17 Subscalp EEG recordings could be com-
bined with video or other modalities in a similar way. Video
quality in a home setting can be at the same level as in-hos-
pital video recordings, and a majority of patients would pre-
fer home monitoring. Cognitive and behavioral testing during
seizures matter for seizure classification and could possibly be
implemented in the home setting if online seizure detection al-
gorithms are sufficiently accurate, with low latency of detection
after onset. Standardized ictal test batteries have been proposed
and are feasible for all but very short seizures.45
2.6
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Tolerance and safety
A review of the literature on complication rates with similar
devices for deep brain neurostimulation and occipital nerve
stimulation revealed that expected complications include in-
fections (<2%), lead migration (~20%), fracture (~4%), and
skin erosion (~4%).46–49 Infections, a dreaded complication
with intracranial material, would here be limited to the sub-
scalp compartment, as the skull would act as an additional
protective barrier for the brain. Subscalp hematoma and scalp
fibrosis are expected to be very rare.
Prospective tolerance and safety data specific to sub-
scalp EEG come from a single trial.33 No serious adverse
device-related events occurred, and the patients generally
found the device easy to use, although this was only collected
anecdotally. Minor annoyances were reported, such as diffi-
culty with simultaneously wearing glasses, occasional nightly
disconnections, and the necessity of wearing clothes at night
to fix the external device. No participants felt constrained in
their ability to perform jobs or leisure activities, although six
of nine reported mild headache up to 1 week after surgery.
One participant reported uncommon mild headaches that
were tolerated without analgesics or other interventions.
In a study with a subdermal wire electrode partially im-
planted for 60days in the intensive care unit, no safety con-
cerns were noted.50
3
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UTILITY OF SUBSCALP EEG
RECORDING
It is estimated that 50% of seizures are unreported, par-
ticularly nocturnal seizures or focal seizures with impaired
awareness.2 The direct consequence is the inability to ascer-
tain therapeutic response; how often is epilepsy undertreated
when seizures are underreported, and are true changes in
seizure frequency overlooked? Patients may also misclassify
nonepileptic events as seizures in their diaries, potentially
causing overtreatment. Furthermore, the issue of comorbid
epileptic seizures and nonepileptic seizures is not uncom-
mon.51 In this section, we outline the most important aspects
and discuss the practical utility of subscalp EEG.
3.1
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The value of personal long data
Today, there is an ongoing debate on the importance of detect-
ing purely EEG seizures that patients are unaware of and do
not feel negatively affected by.52 This discussion is important
for subscalp EEG, as its ambulatory nature makes simultaneous
video unviable and thus difficult to classify seizures as clinical
or not. Neuroimaging studies in patients with temporal lobe ep-
ilepsy have identified widespread anatomical abnormalities,53
and longitudinal studies in patients with chronic epilepsy show
declines in memory and intelligence quotient,54 so it is possible
that repeated seizures have negative consequences, or perhaps
these results come from preferential sampling of the most se-
verely affected patients with chronic refractory epilepsy. In ei-
ther case, ultra–long-term monitoring technology will be useful
in clarifying this important question.
3.2
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The challenge of personal long data
With limited resources available for data review, a prereq-
uisite for ultra–long-term EEG systems is algorithms for
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DUUN-HENRIKSEN Et al.
analysis of the vast amount of recorded data. A trained EEG
technician can analyze 24 hours of two-channel EEG in
2-3hours. Use of trending tools alone can reduce the time
for analysis by a factor of 8-10. Whether the algorithms need
to be online or offline, simple or complex, and patient-spe-
cific or generic will very much depend on the application.
The actual time series will always be valuable to validate
the findings of the algorithms such that algorithms might be
considered a data reduction method, while the final valida-
tion is still made by expert EEG reviewers supported by the
algorithms. The right level of sensitivity must minimize the
number of false negatives, because going through a tractable
number of false-positive clips is highly feasible in daily clini-
cal routine. In addition to underlying algorithms, data visu-
alization is also an important issue; if a patient has worn the
system for 6 months, a way to obtain an overview of the sei-
zure frequency, seizure duration, periodicity, and time of day
would be crucial. With machine learning and big data analy-
sis, the prospects for automated detections are considerable.
3.3
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Objective seizure counting
Treatment decisions are informed by seizure counts, and
there have long been calls for more reliable measures than
what seizure diaries provide.1,2,55,56 Although wearables for
the detection of tonic-clonic seizures in particular are gaining
approval, the ability to automatically detect focal seizures,
particularly with impaired awareness or without major motor
features, remains unmet.57 Objective seizure counts may in-
form clinical decisions to avoid that an effective treatment
is abandoned because no discernible effect in self-reported
measures was apparent58 or that an inefficacious treatment
is maintained or initiated on the basis of nonepileptic events,
because nonseizure events (eg, antiepileptic drug [AED] side
effects, nonepileptic seizures) are incorrectly classified as
seizures by the patient.
Ultra–long-term EEG data have identified periodic pat-
terns in seizure and spike occurrences operating on different
timescales.22 Importantly, cycles appear to be stable within
individuals and thus potentially constitute interesting targets
for therapeutic intervention.22,59
3.4
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Initial epilepsy diagnosis
The differential diagnosis of epilepsy is broad; syncope and
nonepileptic seizures are commonly misdiagnosed as epi-
lepsy, and less commonly, hypoglycemia, paroxysmal disor-
ders of movement, sleep disorders, transient ischemic attack,
migraines with aura, and transitory global amnesia.51 On top
of that, there is also the risk of not being diagnosed with epi-
lepsy when recurring seizures are present but not identified.
Before establishing a definitive diagnosis of epilepsy, char-
acterization of the events is a key step. Inpatient video-EEG
monitoring is regularly successful but may not capture events
if they are too infrequent. Figure2 visualizes the cumulative
probability functions for seizure detection as a function of
monitoring duration assuming a constant seizure frequency
where each day can be conceived as a Bernoulli trial for a
seizure occurring. Many patients will have seizure frequen-
cies < 1/wk and are thus unlikely to have a seizure during a
standard EMU visit.
3.5
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Seizure localization
When seizures are refractory to medical treatment, surgery is
often indicated and has been increasingly used with improv-
ing results in the past decades.60 Presurgical workup regularly
requires the implantation of intracranial electrodes to refine
the localization of the seizure onset zone, sometimes in brain
areas inaccessible to scalp or subscalp EEG. However, sub-
scalp EEG that includes bilateral electrode coverage would
FIGURE 2 Cumulative probability functions for seizure detection as a function of monitoring duration
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DUUN-HENRIKSEN Et al.
enable lateralization of seizures. A study of outpatient after
inpatient intracranial EEG monitoring in 82 patients with me-
sial temporal lobe epilepsy of unknown laterality reclassified
16 (20%) as having unilateral or bilateral onset, which can
help evaluate candidates for epilepsy surgery.23,24
Subscalp EEG that offers broad head electrode coverage
could localize to a given cerebral lobe, although studies will
be needed to confirm this. Basing surgical decisions on doz-
ens to hundreds of electrographic seizures instead of a hand-
ful typically collected in hospital is a promising possibility
for the future. Subscalp EEG will improve the continuum
between optimization of medical treatment and presurgical
planning, and represents a bridge partially mitigating both the
critical lack of information in outpatient epileptology and the
somewhat artificial conditions imposed in the EMU.11
3.6
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Seizure alarming
A majority of patients and caregivers want some form of sei-
zure monitoring, either at night only or 24/7, to feel more safe
and less stigmatized.61 This is where subscalp EEG is most
likely to improve the everyday life of a person with epilepsy.
A large study on quality of life (QoL) in epilepsy describes
problems in terms of lower self-esteem, higher levels of anx-
iety and depression, social isolation, stigmatization, risk of
sudden unexpected death in epilepsy (SUDEP), and higher
rate of unemployment.62 Injuries (burns, head and dental in-
juries) increase with higher seizure frequency. Feelings of
stigmatization were common, and 48% worried about epi-
lepsy some or much of the time. Hopefully, a reliable online
alarm can alleviate such issues.
SUDEP is a major cause of anxiety and is one of the
primary motivations some people with epilepsy have for
wanting a seizure alarm. Death following a seizure may be
preceded by a critical interval, where an intervention could
potentially save lives.63 Because GTCS are the main risk
factor for SUDEP,63 the motivation for seizure alarming for
SUDEP prevention may be weaker for focal non–tonic-clonic
seizures. For a subscalp device to be relevant for SUDEP pre-
vention, it needs to provide at least equivalent performance to
wearables, or it could be part of a multimodal system that is
more robust. It could also be used to assess whether the risk
of SUDEP changes over time for a certain patient by esti-
mating changes in the postictal EEG, although this has to be
shown in a clinical trial.64–66
3.7
|
Seizure forecasting
When patients are asked directly about the impact of seizure
unpredictability, 66%-68% consider it an important or very
important aspect.67 Developing systems that can predict the
occurrence of a future seizure event with sufficient time to
act would be a game changer. Instead of a binary output,
the prediction could be expressed as elevated seizure risk,
referred to as seizure forecasting. One successful demonstra-
tion of seizure forecasting used intracranial EEG recordings
to provide visual feedback to patients minutes in advance
of seizures.68 Much effort has been put into developing so-
lutions for seizure prediction combining intracranial EEG
dataset and online competitions reaching classification ac-
curacies of 81%.69
However, as intracranial recordings are unlikely to be-
come widespread due to their invasiveness, it will be rele-
vant to test whether good forecasting performance can be
achieved on subscalp recordings. Although no prospective
study with good forecasting results on extracranial EEG has
yet been carried out, the authors are aware of several ongoing
studies that hopefully will shed new light on predictability
when ultra–long-term recordings are available. Such systems
should always be trained and tested on at least several months
of labeled data to cover natural physiological variation70 and
circadian and multidien cycles in epilepsy.22
3.8
|
Using subscalp EEG in the future
Ultra–long-term monitoring can be used both before and
after establishing a diagnosis of epilepsy. Long monitoring
durations are necessary to detect rare paroxysmal events, as
shown in Figure2. Routinely used solutions of drug taper-
ing, sleep deprivation, and other provocations may in some
cases induce events that differ from spontaneous seizures and
cloud the interpretation. Therefore, an outpatient-based so-
lution may under these circumstances outperform the EMU.
Currently, clinicians will estimate the underlying seizure fre-
quency before referring a patient to the EMU, but if ultra–
long-term EEG monitoring is an option, a probability plot as
in Figure2 could be informative when deciding the optimal
diagnostic strategy. Furthermore, having a subscalp EEG
implant does not prohibit an EMU stay for full video-EEG
characterization; on the contrary, given that multidien cycles
of seizures are highly prevalent among epilepsy patients,22
the hospital stay could be timed to take place during a period
of high likelihood of seizures.11
We envisage a toolkit, whereby subscalp devices for ultra–
long-term EEG monitoring can help detect focal or general-
ized seizures, and non-EEG modalities (EMG, ECG, others)
could be “added on” to the setup depending on the specific
circumstances. Furthermore, as a relationship between sleep
quality/duration and seizure risk has been suggested, the abil-
ity to record objective sleep quality and seizures is critical to
understanding whether strategies to improve sleep can help
seizure control. One study has even shown that two-channel
subscalp EEG is sufficient to do robust sleep staging.71,72
|
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DUUN-HENRIKSEN Et al.
4
|
READINESS FOR SUBSCALP
DEVICES
As no published studies have dealt with the usability of sub-
scalp devices, we must look into the readiness for wearables,
scalp EEG, and intracranial EEG.
4.1
|
Neurologist readiness
In a survey of 21 neurologists,73 16 agreed that current am-
bulatory recordings are diagnostically useful over traditional
inpatient recordings, and 18 agreed that there is a further
need for wearable EEG devices. Although the questionnaire
addresses standard ambulatory EEG, it does give a good indi-
cation that there is an unmet need that exceeds the 30-minute
routine EEG and 1- to 3-week EMU stay.
Surveys of medical doctors’ views on the usefulness of
seizure detection devices found that most considered alarms
with major motor seizures and seizures associated with fall
important, and 53% gave a 4 or 5 on a 0-5 scale of necessity
for alarms for impaired awareness during focal seizure and
absences.61
4.2
|
Patient readiness
Patients have heterogeneous expectations for the seizure
tracking device’s performance but describe desirable features
in medication reminders, water-proof design, real-time data
analysis, improved diagnostics, and seizure management.74
Surveys suggest that patients would accept devices for sei-
zure registrations provided that they have only a small nega-
tive effect on daily life,75 but patients are concerned about
appearance and visibility of sensors, so concealed sensors
could help increase user acceptance.15 Subscalp sensors are
concealed but may use an external device for power and/or
data storage that can be hidden under the user's clothing. The
majority (82%) of surveyed patients expected a seizure detec-
tion sensitivity of 90% or better.61
When asking the patients whether they would agree to
wear a device on a daily basis, the participants saw the pos-
sible benefits for improved treatment effect and valued this
benefit more than the possible inconvenience of wearing a
sensor.15 Most (90%) would prefer the size of a wristwatch
or smaller. Obviously, acceptance will vary on an individual
basis and depend on the tradeoff between perceived benefit
and the sum of inconveniences and potential side effects. It
must be kept in mind that the questionnaires mentioned deal
in hypotheticals regarding implantable devices, and what
patients might imagine when posed such questions may not
accurately reflect their reactions toward the real devices de-
tailed in this review. The implantable cardiac loop recorder
is well accepted, and so it seems likely that with sufficient
benefit for the recipient, implantable subscalp EEG devices
will also be well accepted.
Some surveys suggest that up to 45.8% of patients think
documentation of seizures is either an “important” or an “es-
sential” feature in a long-term seizure detection system.75
Seizure alarming can help to reduce anxiety and assist auton-
omy; 60.6% of caregivers found that the seizure alarm gave
them more freedom, and 30.3% believed that it gave the pa-
tients more autonomy.76
5
|
CHALLENGES AND
LIMITATIONS OF SUBSCALP EEG
RECORDERS
In this section, we outline proposed objectives in future tri-
als, considerations about low spatial resolution, logistical
considerations relating to implantation, data management,
and safety.
5.1
|
Future trials
Future trials involving ultra–long-term monitoring in epi-
lepsy using subscalp EEG will be required to explore the
value proposition of the technology. Although the first safety
and feasibility studies have been completed, evidence of
clinical usefulness of ultra–long-term EEG recordings is not
available at the current stage of development, although mul-
tiple studies are in preparation or have commenced.
Development of seizure detection algorithms should fol-
low the standards for reporting diagnostic accuracy proposed
in Beniczky and Ryvlin77 or Cohen.78 We should be moving
from small sample sizes and repeated training on retrospec-
tive data to prospective trials with larger samples and pre-
defined thresholds for the algorithm’s detection. It should
be clear whether the goal of the trial is seizure alarming or
counting. Detection of interictal abnormalities should also
adhere to published standards.4
Trials on seizure detection devices focus on reliable and
accurate seizure counting, which rapidly raises the question
of the clinical relevance of the many electrographic seizures
typically recorded with ultra–long-term EEG. This is an op-
portunity to improve the quality of how seizures are defined,
although the question is not trivial.52 More advanced trials
aimed at optimizing medical management, increasing the
ability to identify a change in seizure frequency, or inform-
ing epilepsy surgery will be necessary after this first step is
achieved. Using the classical patient-reported outcomes for
such trials (including seizure self-report) would defy the
purpose. Other impacts could be quantified in terms of QoL
scores, changes in level of disability, number of accidents,
1814
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DUUN-HENRIKSEN Et al.
and mortality, or simply whether the neurologist found a
treatment improvement or was aided in reaching his thera-
peutic decisions.
Without a full understanding of the real seizure burden,
outcomes of medication trials are often set for failure, pro-
longing patients suffering. Simulations based on self-re-
ported seizure events in the SeizureTracker database have
investigated factors that can reduce costs of randomized
clinical trials on AED efficacy without lowering statistical
power, but did not attempt to incorporate seizure event uncer-
tainty directly into the model.79 Simulations could be useful
in clarifying the impact of objective versus subjective seizure
counts in epilepsy for randomized controlled trials on AEDs
in advance of real data having been accumulated, which will
take many years.
5.2
|
Considerations regarding reduced
spatial resolution
One disadvantage of most suggested subscalp devices
except one compared to standard scalp EEG is reduced
spatial resolution. For focal abnormalities, this can re-
sult in lower sensitivity compared to standard scalp EEG,
but strategically selecting the location of the subscalp
electrodes (eg, guided by abnormality seen on standard
EEG or magnetic resonance imaging) might be useful
to inform placement in individual cases. Spikes in the
interictal EEG might inform implantation strategy, but
unilateral implantation will likely miss seizures confined
to the contralateral hemisphere, precluding a discovery
of bilateral seizure onset in such cases. In the absence
of interictal spikes and lateralizing semiology from the
patient history, but where a strong suspicion of epilepsy
is present, a bilateral implantation strategy could be
considered. One development has shown that it is pos-
sible to place electrodes according to the 10-20 system
in the subscalp space with minimally invasive surgery,
although it is done under general anesthesia. Importantly,
a major limitation of subscalp EEG as compared to in-
tracranial EEG is that it cannot monitor deep structures
of the brain and has in that sense the same “field of view”
as scalp EEG.
6
|
CONCLUSIONS
Subscalp EEG recording is an emergent technology. Studies
comparing subscalp recordings with scalp EEG are favorable
and show that seizures can be documented electrographically.
Different devices are being developed to offer a range of
subscalp electrode coverage, some with minimally invasive
implantation of just a few electrodes under local anesthesia,
others increasing coverage to the full head with general an-
esthesia. Some devices are fit for seizure counting, whereas
others aim at localization.
The true value of ultra–long-term EEG has yet to be estab-
lished. It could give novel insights into brain function and is
likely to open new avenues for biomarker discovery, person-
alized treatment, and population analytics, especially when
combined with other complementary information such as
movement and heart rate. Only when data have been collected
over long periods of time will the true value of algorithm de-
velopment for seizure prediction in patients be apparent.
Adoption of subscalp EEG for ultra–long-term mon-
itoring in epilepsy will cause a shift away from subjective
seizure reporting in favor of objective seizure counting, a
long-awaited change. This could have a broad impact on the
daily management of epilepsy and place patients at the center
of management of the disorder.
For clinical science, the technology will also facilitate
the collection of otherwise very rare ultra–long-term EEG
recordings that could not only provide novel insights into ep-
ilepsy and other brain diseases but also provide high tempo-
ral resolution of physiological short- and long-term rhythms
over time.
ACKNOWLEDGMENTS
M.P.R. is funded in part by MRC Centre for
Neurodevelopmental Disorders (MR/N026063/1), the
National Institute for Health Research Biomedical Research
Centre at South London and Maudsley National Health
Service Foundation Trust and the Epilepsy Foundation. M.C.
is funded by the Epilepsy Foundation and National Health
and Medical Research Council. T.W.K. is funded in part
by the health science foundations of Region of Zealand and
Region of Southern Denmark, as well as Innovation Fund
Denmark.
CONFLICT OF INTEREST
J.D.-H. is a full-time employee at UNEEG medical, a
company developing and producing a subscalp EEG de-
vice. M.B. is a part-time employee at Wyss Center for Bio
and Neuroengineering, a not-for-profit foundation, and
coinventor on an international patent application under
the Patent Cooperation Treaty number 62665486 entitled
“Neural Interface System.” M.P.R. holds research fund-
ing from Medical Research Council, National Institute
for Health Research, Wellcome, Epilepsy Research UK,
Epilepsy Foundation of America, European Commission,
and Canadian Institutes of Health Research. He is UK
Chief Investigator of a trial sponsored by Xenon Pharma
and has research collaborations with UNEEG, UCB,
ANT Neuro, J&J, and Seer Medical. He has been an ad-
visory board member for UNEEG medical. He holds pat-
ent WO2013182848A1. M.C. is CMO at Epi-Minder, as
|
1815
DUUN-HENRIKSEN Et al.
well as CMO at SEER Medical. G.K. is Chief Technology
Officer at the Wyss Center for Bio and Neuroengineering,
an independent, nonprofit research and development organ-
ization developing a subscalp EEG device. J.M.H. consults
for Epi-Minder, a company developing a subscalp EEG
device. D.F. is a cofounder of Neuroview Technology and
holds equity interests in the company. He also receives sal-
ary support for consulting and clinical trial–related activi-
ties performed on behalf of the Epilepsy Study Consortium,
a nonprofit organization. D.F. receives no personal income
for these activities. New York University receives a fixed
amount from the Epilepsy Study Consortium toward D.F.’s
salary. Within the past year, the Epilepsy Study Consortium
received payments for research services performed by
D.F. from Adamas, Axcella, Biogen, Crossject, CuroNZ,
Engage Pharmaceuticals, Eisai, GW Pharmaceuticals,
Pfizer, SK Life Science, Takeda, Xenon, and Zynerba. He
has also served as a paid consultant for Eisai. He has re-
ceived an honorarium from Neuropace. He has received
travel support from Medtronic, Eisai, and the Epilepsy
Foundation. He receivesresearch support from the Centers
for Disease Control and Prevention, The National Institute
of Neurological Disorders and Stroke, Epilepsy Foundation,
Empatica, Epitel, UCB, and Neuropace. He serves on the
scientific advisory board for Receptor Life Sciences and
holds equity interests in the company. J.P. has participated
in clinical trials for Eisai, UCB, and Bial; received research
grants from Eisai, Medtronic, UCB, and LivaNova; received
speaker honoraria from LivaNova, Eisai, Medtronic, Orion
Pharma, and UCB; received support for travel to congresses
from LivaNova, Eisai, Medtronic, and UCB; and partici-
pated in advisory boards for LivaNova, Eisai, Medtronic,
UCB, and Pfizer. He is a cofounder of Neuroeventlabs and
holds equity interest in the company. He is also medical
advisor to Braincare. I.C.Z. consults for UNEEG medical.
T.W.K. consults for UNEEG medical. We confirm that we
have read the Journal’s position on issues involved in ethi-
cal publication and affirm that this report is consistent with
those guidelines.
ORCID
Jonas Duun-Henriksen https://orcid.org/0000-0003-1558-8225
Maxime Baud https://orcid.org/0000-0002-8297-7696
Mark P. Richardson https://orcid.org/0000-0001-8925-3140
Mark Cook https://orcid.org/0000-0002-8875-4135
Daniel Friedman https://orcid.org/0000-0003-1068-1797
Ivan C. Zibrandtsen https://orcid.org/0000-0002-0529-0110
Troels W. Kjaer https://orcid.org/0000-0002-2105-6199
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How to cite this article: Duun-Henriksen J, Baud M,
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Available via license: CC BY 4.0
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