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Brief Communication
Seizure occurrence and the circadian rhythm of cortisol:
a systematic review
Jolien S. van Campen
a,b,
⁎,FlorisA.Valentijn
a
,FloorE.Jansen
a
,MarianJoëls
b
,KeesP.J.Braun
a
a
Department of Pediatric Neurology, University Medical Center Utrecht, The Netherlands
b
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands
abstractarticle info
Article history:
Received 31 December 2014
Revised 5 April 2015
Accepted 29 April 2015
Available online 14 May 2015
Keywords:
Epilepsy
Stress
Hormones
Diurnal
Chronobiology
Purpose: Stress is the seizure precipitant most often reported by patients with epilepsy or their caregivers. The
relation between stress and seizures is presumably mediated by stress hormones such as cortisol, affecting neu-
ronal excitability. Endogenous cortisol is released in a circadian pattern.To gain insight into the relation between
the circadian rhythm of cortisol and seizure occurrence, we systematically reviewed studies on the diurnal dis-
tribution of epileptic seizures in children and adults and linked the results to the circadian rhythm of cortisol.
Methods: A structured literature search was conducted to identify relevant articles, combining the terms ‘epilepsy’
and ‘circadian seizure distribution’, plus synonyms. Articles were screened using predefined selection criteria. Data
on 24-hour seizure occurrence were extracted, combined, and related to a standard circadian rhythm of cortisol.
Results: Fifteen relevant articles were identified of which twelve could be used for data aggregation. Overall, seizure
occurrence showed a sharp rise in the early morning, followed by a gradual decline, similar to cortisol rhythmicity.
The occurrence of generalized seizures and focal seizures originating from the parietal lobe in particular followed
the circadian rhythm of cortisol.
Conclusions: The diurnal occurrence of epileptic seizures shows similarities to the circadian rhythm of cortisol. These
results support the hypothesis that circadian fluctuations in stress hormone level influence the occurrence of
epileptic seizures.
© 2015 Elsevier Inc. All rights reserved.
1. Introduction
The majority of patients with epilepsy report seizures triggered or pro-
voked by endogenous or exogenous factors. The seizure precipitant most
often reported is stress [1–7]. The relation between stress and seizures
is expected to be mediated by stress hormones like corticotrophin-
releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and
cortisol, affecting neuronal excitability and seizure threshold [8,9].
Under physiological conditions, cortisol —the ‘end product’of the
hypothalamic–pituitary–adrenal axis —is released in a distinct circadian
pattern [10,11]. These circadian changes in cortisol concentration
are likely to affect many important homeostatic processes in the body,
including the balance between neuronal excitability and inhibition
[12–14]. However, the relationship between circadian fluctuations in
cortisol levels and seizure susceptibility is unknown. To provide a first
step in exploring this possible relationship, we systematically reviewed
the currentliterature on circadian seizure occurrence in children as well
as adults and compared this to the rhythm of cortisol release.
2. Methods
2.1. Search strategy
To identify studies describing the full 24-hour seizure distribution of
seizures in children as well as adults, a literature search was conducted
in PubMed and EMBASE on the 30th of July 2014, combining the term
‘epilepsy’plus synonyms with a term describing the occurrence of
seizures during the day (see supplementary Table 1).
2.2. Article selection
After the exclusion of double publications, titles or abstracts were
screened and excluded when no English abstract was available; the
study did not report on humans, epilepsy or the circadian occurrence
of epileptic seizures; the study did not present original patient data; or
when no full text was available. Full texts of the remaining articles
were screened and excluded when additional information revealed a
conflict with these criteria or seizure occurrence was reported for less
than 24 h. References of the remaining articles and articles citing the
remaining articles were identified using Web of Science and screened
using the same criteria. Only studies reporting results of (video-) scalp
electroencephalographic (EEG) or electrocorticographic (ECoG) monitoring
Epilepsy & Behavior 47 (2015) 132–137
⁎Corresponding author at: Department of Pediatric Neurology KC03.063.0, University
Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands. Tel.: +31 6
19 784 051.
E-mail address: J.S.vanCampen@gmail.com (J.S. van Campen).
http://dx.doi.org/10.1016/j.yebeh.2015.04.071
1525-5050/© 2015 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
Epilepsy & Behavior
journal homepage: www.elsevier.com/locate/yebeh
were included in data aggregation to avoid inaccuracy caused by
reporting bias in diary studies. In case of overlapping patient
populations, multiple inclusions of data from a single seizure were
avoided by excluding one of the two overlapping studies, in favor
of the one with the largest patient population.
2.3. Data analysis
Seizure data (i.e., time of occurrence, seizure classification, and local-
ization of the epileptogenic focus) were extracted from the selected ar-
ticles. Secondary generalized seizures were classified as focal. Data were
analyzed for the overall population, as well as for children and adults
separately when possible, where the threshold for ‘children’cor-
responded with the threshold used in each individual publication.
Data of different studies were combined by calculating the total number
of seizures observed in a specific time window. As the time bins in
which seizures were measured varied between studies, all results
were recalculated into the number of seizures per hour, by dividing
the number of seizures observed within a certain time bin by the num-
ber of hours in that time window (if time bins comprised two or more
hours, seizure frequency in these hours was kept constant).
None of the selected studies measured cortisol in study subjects.
Therefore, circadiandistribution of epileptic seizures could only be visu-
ally compared to a standard circadian cortisol concentration curve in
humans. The circadian cortisol rhythm in children develops between
1 month and 2 years of age [15–26]. Although interindividual variability
in cortisol levels has been related to age or pubertal status [24,27,28],
the overall circadian pattern is very robust [25,29]. Therefore, data of
children and adults were compared to the same cortisol curve obtained
from Weitzman et al. [30].
3. Results
Initially, our searchresulted in 2533 titles and abstracts, of which 15
articlesfulfilled selection criteria. Reference screening identified one ad-
ditional article, which did not lead to modification of the query because
a term describing circadian seizure distribution in title and abstract was
lacking (for a flow chart, see supplementary Fig. 1). Results of the select-
ed studies are described in Table 1.
One study was excluded from data aggregation because seizure oc-
currence was only reported in a seizure diary [31], as opposed to EEG
or ECoG in the other studies. Of the 14 studies remaining, seven focused
on children, one on adults, two described results for children and adults
separately, and four provided resultswithout this distinction. All studies
that provided separate data for adults focused on focal seizures. For two
of the studies, only data for specific generalized seizure types could be
included in our analysis, because of possible overlap in patient popula-
tions with other studies of the same research group [32,33]. Epileptic
seizures were monitored by scalp EEG in 12 studies and intracranial
ECoG in two. The numberof recorded seizures per study varied between
80 and 1350, within a period ranging from 24 h to 16 days. Information
on the number of seizures per patient was only reported in eight of the
original articles. Combined data resulted in a total of 5700 seizures, of
which 2074 could specifically be attributed to children, 1393 to adults,
and the other 2233 were reported in studies not distinguishing between
adults and children.
3.1. Circadian seizure distribution
Circadian seizure distribution varied between studies (Table 1).
Most of the original studies described an increased seizure occurrence
in the (early) morning compared to the rest of the day, both in epilepsy
populations of all ages [31,34,35] and in cohorts including children
[32,33,36–39] or adults separately [40]. Many also reported a peak at
varying times in the afternoon or the evening [32–37,39–45].
The aggregated seizure data showed a steep increase in seizure
occurrence in the early morning, starting around 4h (military time),
following the rise in plasma cortisol with a time lag of roughly 1 to 2 h
(see Fig. 1). The seizure occurrence reached a plateau level around 6h,
approximately the moment in time when plasma cortisol showed its
awakening response. During the next 3 h, seizure occurrence and corti-
sol both stayed high. During the day, additional peaks were observed in
seizure occurrence (11–12h and 15–17h), that were not observed in
cortisol level. At the end of the day, both seizure occurrence and cortisol
levels dropped to reach a nightly quiescence. Few differences were
observed in seizure occurrence between children and adults (Fig. 1).
Seizure occurrence in children follows the same pattern as overall sei-
zure occurrence, with an additional increase in the evening (21–22h).
In adults, from whom only data on focal seizures were available, an ad-
ditional increase in seizure occurrence can be observed between 13 and
17h, followed by a steady decrease during the evening and early night.
3.2. Specific localizations and seizure types
Circadian seizure distribution varied with localization of the epilep-
tic focus in patients with focal seizures and between seizure types
(Fig. 2). Bothseizures with a focal (n = 3783) and primarily generalized
(n = 575) onset showed a clear increase in occurrence in the early
morning (4–7h resp. 6–8h), after a nightly quiescence. Where focal sei-
zures showed an additional peak in the afternoon, occurrence of gener-
alized seizures gradually declined throughout the day, following the
circadian rhythm of cortisol (Fig. 2A). Although no EEG based data on
seizures with a generalized onset were available for adults, a diary
study by Le et al. [31] also reported these seizures to mainly occur in
the morning.
Subdivision of focal seizures based on the localization of the epileptic
focus showed that associations with the circadian rhythm of cortisol
existed especially for seizures with a parietal onset (n = 250)
(Fig. 2B). These seizures showed a clear peak in occurrence in the
early morning and an afternoon decline, although an additional
peak was observed in the evening. While the occurrence of seizures
with a frontal onset (n = 752) and seizures with a temporal onset
(n = 2008) showed the least circadian variation, both showed an in-
crease in seizure frequency in the early morning, with an additional
peak in the afternoon. Seizures from the occipital lobe showed a strong
afternoon preference. Some studies suggested differences in circadian
seizure occurrence between neocortical temporal lobe epilepsy and me-
sial temporal lobe epilepsy, with a morning peak especially for mesial
temporal lobe seizures [34,40].
Subdivision of generalized seizures based on seizure type showed
that seizure occurrence increased in the early morning (resembling the
rising phase in the circadian cortisol rhythm) for myoclonic (n = 89),
clonic (n = 297), tonic (n = 201), and atonic (n = 55) seizures
(Fig. 2C). Most of these seizure types showed a morning peak, except
for atonic seizures that peaked in the early afternoon. Although tonic–
clonic seizures (n = 230) also often occurred in the early morning, sim-
ilarity to the cortisol rhythm was less striking because their occurrence
was already high during the night and showed a downward trend during
the day. Absences (n = 47) and epileptic spasms (n = 299) showed a
different rhythm.
4. Discussion
This review summarized the circadian rhythmicity of seizure
occurrence by pooling the data of previous studies and enabled visual
comparison with circadian cortisol rhythmicity. The overall circadian
occurrence of epileptic seizures resembles the circadian rhythm of
cortisol, especially the increase in seizure occurrence in the early morn-
ing and the state of quiescence at night. This similarity was observed
both in children and adults but varied between different seizure types
and localizations of the epileptic focus.
133J.S. van Campen et al. / Epilepsy & Behavior 47 (2015) 132–137
The similarity between the circadian rhythms of seizures and corti-
sol could be explained by the proconvulsive effects of stress hormones,
that were suggested by human studies reportingstress as a seizure pre-
cipitant (reviewed by van Campen et al. [9]) and animal studies show-
ing that stress hormones, such as CRH [46–50] and corticosteroids
[51–54],caninfluence neuronal excitability and seizure threshold.
Besides absolute levels of cortisol, its rise and decline might also play a
role. Cortisol is released in ultradian pulses, occurring once every 1 to
2 h. In humans, pulse amplitudes are high early in the morning and
gradually decline during the day, thus, contributing to the overall circa-
dian pattern [12,14]. When averaging cortisol concentration curves of
multiple patients, individual pulses are no longer discernible, but the
Table 1
Studies describing 24-hour seizure occurrence.
n
(seizures/
patients)
Seizures
per patient
Age
(years)
Type of
seizures
Localization Method of
seizure
monitoring
Time
bin (h)
Time of reported peaks in seizure occurrence
General population
Pavlova et al. [35] 129/44 1–81–92 All All EEG: 1–3 d 4 Frontal seizures occurred mainly at
05:15–07:30h; temporal lobe seizures at
18:45–23:56h.
Le et al. [31]
a
25,720/1877 –29.9 ± 16.0 All All Seizure diary 1 Significantly different distribution in timing
of focal and generalized seizures.
Generalized seizures mainly occurred in the
morning (34% 5–11h), whereas focal
seizures were fairly evenly distributed
throughout the day and evening.
Karafin et al. [34] 694/60 10.5 ± 7.9 35.9 ± 9.2 Focal MTLE EEG: 2–16 d 1 Bimodal pattern with peaks at 6–8h and
15–17h.
Pavlova et al. [43] 90/26 –35.5 ± 11 Focal Focal
(TLE vs. XTLE)
EEG: ≥24 h 4 Differences in the patterns between TLE and
XTLE, with significant peaks for TLE at
15–19h and for XTLE at 19–23h.
Quigg et al. [42] 1350/96 –30.9 ± 10.2 Focal Focal EEG: 3–14 d 1 Random seizure patterns in LTLE and XTLE.
Peak at 15h for MTLE.
Children
Sanchez Fernandez
et al. [33]
b
866/215 1–13 0–21 Seizures with multiple
semiology phases
All EEG: ≥24 h 3 Clonic seizures peaked at 0–3h and 6–9h;
tonic seizures at 21–12h.
Ramgopal et al. [38] 219/51 1–13 0–21 Epileptic spasms All EEG: 1–30 d 3 Seizures peaked at 9–12h and 15–18h. For
children b3 years, peaks at 9–12h and
15–18h; for children N3 years, a peak at
6–9h and a nonsignificant peak at 15–18h.
Ramgopal et al. [39] 223/71 –0–21 (Secondary)
generalized
tonic–clonic
All EEG: 1–10 d 3 Peaks for focal seizures with tonic–clonic
evolution at 00–03h and 6–9h. Primarily
generalized tonic–clonic seizures peaked at
9–12h.
Kaleyias et al. [36] 259/66 1–77 2–18 Focal Focal
(lesional)
EEG: 3–10 d 3 Temporal seizures peaked at 9–12h and
15–18h; extratemporal seizures at 6–9h.
Zarowski et al. [32]
b
316/77 1–12 0–21 Generalized Generalized EEG: 1–8 d 3 Peaks for clonic seizures at 6–9h and
12–15h, absence seizures at 9–12h and
18–0h, atonic seizures at 12–18h, and
epileptic spasms at 6–9h and 15–18h.
Loddenkemper
et al. [37]
1008/225 1–13 0–21 All All EEG: 1–10 d 3 Generalized seizures peaked at 6–12h,
temporal seizures at 21–9h, frontal seizures
at 0–6h, parietal seizures at 6–9h, and
occipital seizures at 9–12h and 15–18h.
Hofstra et al. [44] 396/76 –1–15 Focal Focal
(TLE vs. XTLE)
EEG: 22 h–7 d 6 Overall seizures and extratemporal seizures
peaked at daytime (11–17h).
Hofstra et al. [45] 138/7 –
c
5–15 Focal Focal ECoG: 2–8 d 6 Only frontal seizures could be analyzed
reliably. Fewer frontal seizures occurred
between 5 and 11h compared to the rest of
the day.
Plouin et al. [41] 80/16 ––(infants) Infantile spasms All EEG: 24 h 2 Seizure clusters were most frequently
observed at 14–20h, with a peak at 19–20h.
Isolated spasms were most frequent at
18–24h with a peak at 20–22h.
Adults
Durazzo et al. [40] 669/131 2–8 29.6 ± 10.9 Focal Focal ECoG: 9–10 d 3 Frontal and parietal lobe seizures peaked at
4–7h, occipital seizures at 16–19h, mesial
temporal seizures at 7–10h and 16–19h, and
neocortical temporal seizures at 13–16h.
Hofstra et al. [44] 412/100 –16–65 Focal + secondary
generalized
Focal
(TLE vs. XTLE)
EEG: 1–7 d 6 Overall seizures and temporal seizures
peaked at daytime (11–17h).
Hofstra et al. [45] 312/26 –
c
17–45 Focal Focal ECoG: 3–9 d 6 Temporal seizures peaked at 11–17h, frontal
seizures at 23–05h, and parietal seizures at
17–23h.
n: number, EEG: scalp electroencephalography, ECoG: intracranial electrocorticography, h: hours (time windows are displayed in military time [0–24h]), d: days, TLE: temporal lobe
epilepsy, XTLE: extratemporal lobe epilepsy, MTLE: mesiotemporal lobe epilepsy, general population: no restrictions in inclusion criteria, –: not specified.
a
Excluded from data aggregation because seizure occurrence was measured by seizure diary only.
b
Excluded from overall data aggregation because of possible overlap in patient populations.
c
Maximum of 15 seizures per patient per time bin.
134 J.S. van Campen et al. / Epilepsy & Behavior 47 (2015) 132–137
rapid changes in cortisol concentration associated especially with the
high morning peaks might have large effects on signal transduction
and seizure susceptibility [12–14]. The reported similarity between
the morning rise in cortisol and seizure occurrence is striking, and the
time delay, where an increase in cortisol levels precedes the increase
in seizure occurrence, supports the possibility of a causal relation.
When interpreting the presented data, it is important to keep in mind
that circadian seizure occurrence is also influenced by other variables
than cortisol. Various types of seizures are differentially affected by
sleep patterns. For example, in juvenile myoclonic epilepsy, myoclonic
seizure frequency increases in the first hours after awakening [55,56].
The studies reviewed here do report differences in seizure occurrence be-
tween sleep and wake, but no information is provided on seizure occur-
rence with respect to the timing of awakening. Although awakening
might be considered to confound the relation between cortisol and
seizure occurrence, the pathophysiological mechanisms behind the
seizure-precipitating effects of awakening are yet unresolved, and it
could well be hypothesized that the peak levels in cortisol just before
and after awakening play a causal role in this. In addition to the sleep–
wake cycle, fluctuations in the concentration of antiepileptic drugs
(AEDs), related to dosage intervals [57–59], could contribute to the in-
creased seizure occurrence in the early morning. Both factors might
also explain some of the differences observed between children and
adults, as daytime naps in young children can influence sleep-related
seizure occurrence, and for many AEDs, children show an increased clear-
ance and therefore higher fluctuations in blood levels compared to adults
[60–62]. In addition, children below the age of two years might not yet
have developed circadian cortisol rhythmicity, while they are included
in the majority of pediatric studies. Epileptic spasms mainly occur espe-
cially in infants, which might explain the dissimilarity between their
circadian occurrence and the displayed cortisol curve. For these reasons,
the chronobiological distribution of epileptic seizures can never be
expected to exclusively depend on cortisol concentration but is rather a
result of the interaction of many circadian and exogenous processes
influencing neuronal excitability, including cortisol and other stress hor-
mones. This is emphasized by the large differences in circadian seizure
occurrence between different seizure types and localizations of the sei-
zure focus, where generalized seizures and focal seizures originating
from the parietal lobe in particular followed the circadian rhythm of cor-
tisol. Theoretically, this might be explained by (1) differences in stress
sensitivity of the specific brain regions, determined by, for example, the
density of stress hormone receptors and connectivity to other brain
Fig. 1. Circadian seizure distribution and cortisol rhythmicity. Combined seizure occur-
rence over a 24-hour period, displayed on top of a standard curve of the plasma cortisol
concentration (adapted from Weitzman et al. [30]) to enable visual comparison. Time:
military time (0–24h). Total: seizure data forchildren, adults andunspecified age groups;
h: hours.
Fig. 2. Circadian seizuredistribution for focal and generalized seizures separately. Combined seizureoccurrence over a 24-hour period,displayed on top of a standard concentrationcurve
of the plasma cortisol concentration (gray) to enable visual comparison. A. Seizures with a focal versus generalized seizure onset; B. Focal seizures per lobe of origin. C1/2. Various
generalized seizures and epileptic spasms. Time: military time (0–24h); h: hours.
135J.S. van Campen et al. / Epilepsy & Behavior 47 (2015) 132–137
regions; or (2) sensitivity of the specific brain regions to other seizure-
precipitating variables with a circadian rhythm, that might blunt the
association with stress hormone levels. As stress hormone receptors are
especially abundant in limbic regions and the prefrontal cortex [63–65],
the high resemblance of parietal and generalized seizure occurrences
with cortisol levels points towards the second hypothesis. Further studies
need to resolve the mechanisms behind the differences in circadian
seizure occurrence between seizure types and localizations.
In this systematic literature review, data of multiple studies on
24-hour occurrence of epileptic seizures were pooled. Data subdivi-
sions were restricted to those shown in the original articles with
respect to age limits, time bins, seizure classification, or localization,
as individual patient data were not available. Also, the exact number
of patients in which seizures of specific localizations or seizure types
were recorded was not reported in the majority of articles. Minimal
overlap in seizure data between different studies cannot be completely
excluded but was mitigated as much as possible by excluding data from
studies describing the same patient population [32,33]. Furthermore,
none of the selected studies measured cortisol during seizure registra-
tion. Also,temporal distribution of seizure occurrence, as well as cortisol
levels, in inpatient epilepsy monitoring units might differ from the daily
life situation. Therefore, this review can only provide indirect evidence
for a relation between cortisol concentration and seizure occurrence.
4.1. Conclusion and implications
We conclude that the circadian occurrence of epileptic seizures
shows similarities to the circadian rhythm of cortisol. These results are
compatible with the hypothesis that stress hormones influence the
occurrence of epileptic seizures. Prospective studies, measuring endog-
enous cortisol levels or applying exogenous cortisol in patients with ep-
ilepsy during EEG —preferably with high time resolution —are needed
to further unravel the effects of the circadian cortisol variability and
ultradian cortisol variability on epileptic activity. Increased knowledge
on the relation between stress, stress hormones, and epilepsy may pro-
vide insight in the mechanisms underlying stress sensitivity of seizures
and ictogenesis, in general, and contribute to improvements of the
treatment and care of patients with epilepsy.
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.yebeh.2015.04.071.
Disclosure
None of the authors has any conflict of interest to disclose. We
confirm that we have read the Journal's position on issues involved in
ethical publication and affirm that this report is consistent with those
guidelines.
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