The role of sleep state and time of day in modulating breathing in epilepsy: implications for sudden unexpected death in epilepsy

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death among patients with refractory epilepsy. While the exact etiology of SUDEP is unknown, mounting evidence implicates respiratory dysfunction as a precipitating factor in cases of seizure-induced death. Dysregulation of breathing can occur in epilepsy patients during and after seizures as well as interictally, with many epilepsy patients exhibiting sleep-disordered breathing (SDB), such as obstructive sleep apnea (OSA). The majority of SUDEP cases occur during the night, with the victim found prone in or near a bed. As breathing is modulated in both a time-of-day and sleep state-dependent manner, it is relevant to examine the added burden of nocturnal seizures on respiratory function. This review explores the current state of understanding of the relationship between respiratory function, sleep state and time of day, and epilepsy. We highlight sleep as a particularly vulnerable period for individuals with epilepsy and press that this topic warrants further investigation in order to develop therapeutic interventions to mitigate the risk of SUDEP.

Full text

TYPE Review
PUBLISHED 23 August 2022
DOI 10.3389/fncir.2022.983211
OPEN ACCESS
EDITED BY
Christina Gross,
Cincinnati Children’s Hospital Medical
Center, United States
REVIEWED BY
Cameron S. Metcalf,
The University of Utah, United States
Stefano Bastianini,
University of Bologna, Italy
*CORRESPONDENCE
Gordon F. Buchanan
Gordon-buchanan@uiowa.edu
RECEIVED 30 June 2022
ACCEPTED 25 July 2022
PUBLISHED 23 August 2022
CITATION
Joyal KG, Kreitlow BL and
Buchanan GF (2022) The role of sleep
state and time of day in modulating
breathing in epilepsy: implications for
sudden unexpected death in eliepsy.
Front. Neural Circuits 16:983211.
doi: 10.3389/fncir.2022.983211
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The role of sleep state and time
of day in modulating breathing
in epilepsy: implications for
sudden unexpected death in
epilepsy
Katelyn G. Joyal1,2,3, Benjamin L. Kreitlow 1,2,3,4
and Gordon F. Buchanan1,2,3,4*
1Interdisciplinary Graduate Program in Neuroscience, Carver College of Medicine, University of
Iowa, Iowa City, IA, United States, 2Department of Neurology, Carver College of Medicine,
University of Iowa, Iowa City, IA, United States, 3Iowa Neuroscience Institute, Carver College of
Medicine, University of Iowa, Iowa City, IA, United States, 4Medical Scientist Training Program,
Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of
death among patients with refractory epilepsy. While the exact etiology of
SUDEP is unknown, mounting evidence implicates respiratory dysfunction
as a precipitating factor in cases of seizure-induced death. Dysregulation of
breathing can occur in epilepsy patients during and after seizures as well as
interictally, with many epilepsy patients exhibiting sleep-disordered breathing
(SDB), such as obstructive sleep apnea (OSA). The majority of SUDEP cases
occur during the night, with the victim found prone in or near a bed. As
breathing is modulated in both a time-of-day and sleep state-dependent
manner, it is relevant to examine the added burden of nocturnal seizures on
respiratory function. This review explores the current state of understanding of
the relationship between respiratory function, sleep state and time of day, and
epilepsy. We highlight sleep as a particularly vulnerable period for individuals
with epilepsy and press that this topic warrants further investigation in order
to develop therapeutic interventions to mitigate the risk of SUDEP.
KEYWORDS
epilepsy, SUDEP, sleep, circadian, breathing
Introduction
Epilepsy is one of the most common neurological disorders.
One in 26 Americans will develop epilepsy during their lifetime
(Kotsopoulos et al., 2002 ;Hesdorffer et al., 2011). Despite
its prevalence, approximately 35% of patients will not achieve
seizure freedom with medical treatment (Kwan and Brodie, 2000;
Chen et al., 2018). Though there has been continued expansion
in the availability of anti-seizure medications (ASM), patients
who exhibit an inadequate response to initial ASM treatment are
likely to have medically refractory epilepsy (Kwan and Brodie,
2000). The leading cause of death among these individuals with
poor seizure control is sudden unexpected death in epilepsy
or SUDEP (Devinsky et al., 2016). SUDEP is defined as the
“sudden, unexpected, witnessed or unwitnessed, nontraumatic
and nondrowning death in patients with epilepsy, with or
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Joyal et al. 10.3389/fncir.2022.983211
without evidence for a seizure and excluding documented
status epilepticus, in which postmortem examination does not
reveal a toxicologic or anatomic cause of death” (Nashef et al.,
1998). While by definition SUDEP does not have to follow a
seizure, there is strong evidence to suggest it is a seizure-related
phenomenon, with its agonal mechanisms beginning during or
in the immediate aftermath of a seizure (Nashef et al., 1998;
Nilsson et al., 1999; Surges et al., 2009; Surges and Sander, 2012;
Bozorgi and Lhatoo, 2013). There is a slight predominance of
SUDEP cases in males compared to females (Tennis et al., 1995;
Nilsson et al., 1999; Shankar et al., 2013).
Despite the tremendous burden of SUDEP, its underlying
pathological mechanisms are poorly understood. However,
evidence is accumulating that implicates seizure-related
respiratory failure as a major factor in this deadly phenomenon
(Ryvlin et al., 2013; Buchanan et al., 2014; Kim et al., 2018;
Dhaibar et al., 2019). In SUDEP cases that were captured in
epilepsy monitoring units (EMU), terminal apnea preceded
terminal asystole in every case (Ryvlin et al., 2013). Further,
mechanical ventilation has been found to greatly reduce seizure-
induced mortality, both in human patients and animal models
(Tupal and Faingold, 2006; Ryvlin et al., 2013; Buchanan et al.,
2014). Thus, further investigation into respiratory dysfunction
in epilepsy is critical to untangle the underlying mechanisms of
SUDEP, as well as to assist clinicians in developing respiratory-
focused interventions.
Another consistent observation is that SUDEP cases
predominantly occur during the night (Nobili et al., 2011;
Lamberts et al., 2012; Sveinsson et al., 2018). Around 95%
of SUDEP cases occur inside the victim’s residence, with the
majority of victims found in or near a bed in a prone position
(Opeskin and Berkovic, 2003; Zhuo et al., 2012; Ali et al., 2017;
Sveinsson et al., 2018). Despite occurring so close to home, the
vast majority of these cases are unwitnessed (Lamberts et al.,
2012; Zhuo et al., 2012; Rugg-Gunn et al., 2016; Purnell et al.,
2018). Patients who die of SUDEP are twice as likely to have a
history of nocturnal seizures, and thus the presence of nocturnal
seizures are considered a risk factor for SUDEP (Lamberts et al.,
2012; Shankar et al., 2013; Sveinsson et al., 2018; Van Der Lende
et al., 2018). Seizures and epileptiform discharges occur more
frequently during non-rapid eye movement (NREM) sleep in
both human patients and animal models (Bazil and Walczak,
1997; Malow et al., 1998). Sleep state can influence the frequency,
severity, and duration of seizures (Bazil and Walczak, 1997; Ng
and Pavlova, 2013). Seizures occurring during sleep tend to be
longer and are more likely to evolve into focal and bilateral tonic-
clonic seizures (Bazil and Walczak, 1997).
As humans tend to consolidate their sleep during the night,
many investigations of and conclusions about SUDEP risk
factors conflate sleep-state and nighttime as one in the same.
In reality, sleep and circadian rhythmicity can independently
alter physiological processes, including respiratory and cardiac
function (Snyder et al., 1964; Browne et al., 1983; Spengler
et al., 2000; Mortola, 2004; Buchanan, 2013). The major
influence of sleep and circadian timing on respiration makes
this a salient point of examination when considering SUDEP
pathophysiology. The aim of this review is to examine the
distinct influences of sleep and circadian rhythms on respiration
both in a healthy brain and in patients with epilepsy (Figure 1).
We hope to not only highlight the factors that make nocturnal
seizures more deadly, but to better differentiate between sleep-
state and time-of-day influences on breathing, so that clinicians
can develop specific preventative strategies for fatal seizure-
induced respiratory dysfunction.
Influence of sleep on breathing
It has long been appreciated that breathing is regulated in
a sleep state-dependent manner (Snyder et al., 1964; Spengler
et al., 2000; Haxhiu et al., 2003; Mortola, 2004; Malik et al.,
2012; Buchanan, 2013). Inspiratory drive is lower during NREM
sleep and lowest during rapid-eye movement (REM) sleep,
with tidal volume (VT) being reduced to 73% of its level
during wakefulness (Douglas et al., 1982a;Figure 2A). Within
NREM sleep, the nadir of minute ventilation (VE) occurs during
NREM stage 3 (N3) sleep—although this is likely driven by the
reduction in VT. This results in an end-tidal carbon dioxide
(ETCO2) concentration that is 1–2 torr higher than waking
levels (Krieger, 2005). This drop in VTand VEis likely due to
decreased chemosensitivity during the onset of sleep (Bulow,
1963; Douglas et al., 1982b,c). During sleep there is a decrease
in the respiratory response to hypercapnia (Reed and Kellogg,
1958; Birchfield et al., 1959; Cherniack, 1981; Douglas et al.,
1982c; Berthon-Jones and Sullivan, 1984;Figure 3A) as well
as hypoxia (Berthon-Jones and Sullivan, 1982; Douglas et al.,
1982b; Malik et al., 2012). Like inspiratory drive, there is
an even larger decrease in the hypoxia-induced respiratory
drive during REM compared to NREM sleep (Berthon-Jones
and Sullivan, 1984; Malik et al., 2012). There are sex-specific
differences in the response to hypercapnia, with males exhibiting
a 50% decrease in the hypercapnic ventilatory response (HCVR)
compared to wakefulness, while females exhibit a reduced
HCVR during wakefulness compared to males but have less
apparent reductions in the response during sleep (Berthon-Jones
and Sullivan, 1984). Progesterone has been found to stimulate
breathing during sleep, including increasing hypoxic and
hypercapnic respiratory responses (Javaheri and Guerra, 1990;
Saaresranta et al., 1999). Progesterone oscillates in a circadian
fashion, with its zenith at around midnight (Junkermann
et al., 1982; Gharib et al., 2018). No sex-specific differences in
respiratory responses to hypoxia have been identified (Malik
et al., 2012).
Breathing during NREM sleep has a more regular pattern
compared to breathing during wakefulness, without altering
mean breathing frequency (Malik et al., 2012). Conversely,
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FIGURE 1
Potential risk factors associated with seizures emerging from sleep vs. nocturnal seizures and how they may facilitate SUDEP by modulating
epilepsy, seizures, and respiration as well as seizure-induced death itself.
during REM sleep there is more variability in respiratory
patterns, including increased frequency, decreased regularity,
and brief periods of central apnea (Aserinsky and Kleitman,
1953; Cherniack, 1981; Malik et al., 2012). There is some
evidence that indicates this irregular breathing is a response
to cortical inputs that reflect the content of the individual’s
dream (Oudiette et al., 2018). Periodic breathing, which is
characterized as clusters of breaths separated by intervals of
central apnea or near apnea, also sometimes occurs during sleep.
Although previously thought to arise from a severe neurological
or cardiovascular condition, it now found that periodic breathing
can occur in healthy individuals, especially during hypoxia
(Berssenbrugge et al., 1983; Cherniack, 1999; Ainslie et al.,
2013). During intervals of periodic breathing, cyclic changes
in ventilation as well as the partial pressures of carbon dioxide
(CO2) and oxygen (O2) can trigger oscillations in heart rate,
blood pressure, autonomic nervous system activity, and upper-
airway resistance. This may create a feedback loop whereby these
oscillations in turn affect ventilation and increase the length
and symmetry of these periodic breathing cycles (Cherniack,
1999). Males tend to exhibit periodic breathing in response
to hypoxia more frequently than females (Pramsohler et al.,
2019). Breathing patterns are heavily dependent on the pre-
Bötzinger complex (pre-BötC; Smith et al., 1991; Buchanan,
2013; Del Negro et al., 2018; Muñoz-Ortiz et al., 2019). When
neurons expressing neurokinin-1 receptors (NK1R) in the pre-
BötC complex were bilaterally ablated in adult rats there was
a progressive and irreversible disruption in breathing stability,
which initially occurred only during sleep, but eventually
led to ataxic breathing during wakefulness as well (Mckay
and Feldman, 2008). When these pre-BötC NK1R-expressing
neurons were unilaterally ablated, there was a disruption in
respiratory pattern and increase in the frequency of central sleep
apnea and hypopneas solely during sleep, particularly during
REM sleep, which never developed during wakefulness (Mckay
and Feldman, 2008).
During sleep there is a reduction in upper airway patency
and an increase in respiratory resistance. This is caused by
a preferential reduction in tone of laryngeal and pharyngeal
muscles that help to maintain the structure of the upper airway
(Cherniack, 1981; Haxhiu et al., 1987; Buchanan, 2013; Kubin,
2016). This reduced patency and can be especially problematic
during REM sleep, when breathing is particularly unstable
(Cherniack, 1981). Upper airway tone is controlled by inputs
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FIGURE 2
Circadian and sleep state-dependent effects on ventilation. (A)
72-h traces of average minute ventilation (top), tidal volume
(middle) and breathing frequency (bottom) in adult male rats
housed under a 12:12 h light:dark cycle and receiving room air
(21% O2, balance N2). Solid horizontal bars at the bottom indicate
periods where lights were off. (B) 24-h trace of average minute
ventilation in rats during wake, non-rapid eye movement (NREM)
sleep, and rapid-eye movement (REM) sleep as indicated. All
animals housed in a 12:12 h light:dark cycle. (A) Redrawn with
permission from Seifert and Mortola (2002).(B) Redrawn with
permission from Stephenson et al. (2001).
from trigeminal (CN V), facial (CN VII), and hypoglossal (CN
XII) motor neurons (Buchanan, 2013). The genioglossus muscle,
which is innervated by hypoglossal motor neurons, is the largest
and most extensively studied of the airway dilator muscles. It has
been suggested that decreased serotonergic and noradrenergic
inputs to hypoglossal motor neurons during REM sleep causes
atonia of the genioglossus (Fenik et al., 2005). The genioglossus
and other muscles of the upper airway require both tonic and
phasic inspiratory activation in order to protect against collapse
(Kubin, 2016). When the tone of these airway-dilating muscles
can no longer oppose the negative inspiratory pressure, the
result is obstructive sleep apnea (OSA), which features recurrent
episodes of hypopneas and apneas (Remmers et al., 1978; Kubin,
2016). While these obstructive apneas only occur during sleep,
frequent sleep apnea and hypoventilation can result in breathing
abnormalities during wakefulness (Simonds, 1994).
Changes in several non-centrally mediated respiratory
mechanisms are also associated with the onset of sleep.
During NREM sleep, the activity of the intercostal muscles
is increased compared to wakefulness (Malik et al., 2012).
This may be indicative of increased contribution of the chest
wall to respiration in order to compensate for decreased
central inspiratory drive. During REM sleep, there is a loss
of tonic activity in the intercostals and diaphragm (Tusiewicz
et al., 1977; Bryan and Muller, 1980; Malik et al., 2012).
Chest wall compliance is also increased during this time,
and, in conjunction with decreased intercostal tone, can cause
paradoxical collapse of the chest during inspiration (Malik et al.,
2012). Lastly, the pulmonary stretch receptor reflex and irritant
receptor reflex are suppressed during sleep—thus, coughing in
response to apnea only occurs after arousal (Douglas, 2000). In
summary, sleep is a period where many facets of breathing are
suppressed—thus rendering it a particularly vulnerable period
for further insults to the respiratory system.
Circadian influences on breathing
Early studies of time-of-day variability in mammalian (adult
rat) breathing physiology revealed time-of-day differences in
breathing; however, the effect was limited to CO2production
and the mean inspiratory air flow (Peever and Stephenson,
1997). Under hypercapnic conditions, breathing frequency and
VEalso appeared to be time-of-day dependent. Unfortunately,
these studies only involved two time-points, limiting the
resolution of a daily rhythm, which may have been masked by
higher frequency ultradian variation in breathing (Stupfel and
Pletan, 1983; Stupfel et al., 1985).
The first clear evidence that respiratory function
demonstrated daily oscillations came from Seifert et al.
(2000). Adult rats were housed in 10 L barometric chambers
with carefully controlled in-flow and out-flow of gas, allowing
for measurement of breathing physiology over the course
of several days. Clear time-of-day differences in frequency,
VTand VEwere observed. The highest levels were observed
during the dark phase, coinciding with elevated temperature
and activity. These findings were further expanded in a later
study, demonstrating that O2consumption (a measure of
metabolic activity), inspiratory time, and expiratory time also
varied across the day (Seifert and Mortola, 2002;Figure 2B).
Interestingly, controlling for level of activity did not eliminate
the effect of time of day on VE, VT, frequency of breathing, or
O2consumption. The authors conclude that the daily variability
observed in breathing (specifically ventilation) is likely driven
by other physiological variables oscillating throughout the day,
such as temperature and oxygen consumption.
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FIGURE 3
Circadian and sleep state-dependent effects on the hypercapnic ventilatory response (HCVR). (A) 48-h trace of circadian variations in HCVR
in adult humans. (B) Sleep state-dependent differences in HCVR in adult males. (A) Redrawn with permission from Spengler et al. (2000).(B)
Redrawn with permission from Bulow (1963).
Using similar methods to Seifert et al., 2000, long-term
respiratory monitoring in non-human primates has also been
performed (Iizuka et al., 2010). Whole body plethysmography
was performed in 11 unrestrained, unanesthetized male
cynomolgus monkeys. Like findings from adult rats, multiple
respiratory parameters, including respiratory rate, VT, and VE
were shown to vary depending on the time of day. However,
recordings were only obtained hourly, and it is unclear if sleep-
state was controlled for.
Time-of-day variability in a number of respiratory
parameters has also been demonstrated in humans (Spengler
and Shea, 2000; Spengler et al., 2000). In a carefully controlled
laboratory setting, which included the removal of external
time cues (except for lighting), a constant environmental
temperature, controlled dietary intake, and carefully controlled
sleep schedules. Temporal variation in rectal temperature and
plasma cortisol were used as endogenous circadian markers.
ETCO2, O2consumption, and CO2production were all shown
to oscillate throughout the 24 h day, with highest levels in the
morning. Interestingly, there was also time-of-day variability in
HCVR magnitude, a finding previously demonstrated in awake,
adult rats (Peever and Stephenson, 1997;Figure 3B), suggesting
respiration-influencing chemosensitivity may also be under
circadian regulation. Sensitivity to isocapnic hypoxic challenge
has some evidence of time-of-day dependence; however, the
effect is far less pronounced (Siekierka et al., 2007).
While the studies described above in rats, monkeys,
and humans demonstrate temporal variation in breathing
physiology, they did not control for the rhythmic effect of light.
Therefore, whether this variability is due to the effect of an
external time cue or that of an endogenous circadian rhythm
cannot be concluded. The first study of time-of-day dependent
on breathing physiology that accounted for the influence of
light was performed in garter snakes (Hicks and Riedesel, 1983).
Animals were housed in either a 14:10 light-dark cycle or
constant darkness environment. Under these conditions, it was
revealed that time-of-day variability in oxygen consumption,
breathing frequency, VT, and VEpersisted in constant darkness,
suggesting endogenous regulation of these breathing parameters.
This time-of-day dependent variation in breathing has been
shown to be endogenously circadian in mice and mediated by the
body’s central circadian pacemaker, the suprachiasmatic nucleus
(Purnell and Buchanan, 2020). C57BL/6J mice were housed
in either 12:12 light-dark or constant darkness environments,
and running wheels were used to assess active phase onset
for the determination of individual free-running locomotive
rhythms. As sleep-state has been shown to influence breathing
(as described in detail earlier above), measurements of breathing
were only performed while the animals were awake. Time-
of-day variability in the frequency of breathing and VE, but
not VT, was observed. Both frequency and VEwere highest
during the dark phase of the day. This time-of-day rhythm was
shown to be circadian, as these two rhythms persisted when
animals were housed in constant darkness. Electrolytic lesioning
of the suprachiasmatic nucleus eliminated these breathing
rhythms, suggesting that the circadian variation in breathing was
controlled by the suprachiasmatic nucleus.
Although the suprachiasmatic nucleus is frequently referred
to as the master circadian oscillator, nuclei outside of the
suprachiasmatic nucleus and peripheral tissues may contain
autonomous circadian clocks (Mohawk et al., 2012). Such
peripheral clocks have been described in brainstem and spinal
cord neurons involved in the coordination and output necessary
to maintain normal respiration. Through the measurement
of molecular clock gene transcripts, such as Clock,Bmal1,
and Per1/2, researchers have identified robust molecular
clock gene rhythms in the nucleus tractus solitarius (Kaneko
et al., 2009; Chrobok et al., 2020), phrenic motor nucleus
(Kelly et al., 2020), and laryngeal, tracheal, bronchial, and
lung tissues within the airway (Bando et al., 2007). Bando
et al. (2007) demonstrated that the peripheral clock of
the airway tissues could be rendered arrhythmic following
electrolytic lesioning of the suprachiasmatic nucleus. Similarly,
genetically arrhythmic Clock 1/Clock2 knock-out mice did not
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demonstrate peripheral rhythmicity of clock gene expression
in airway tissues. In conclusion, circadian phase exerts
its own powerful influences on breathing, irrespective of
vigilance state.
Effect of seizures/epilepsy on
breathing
Some patients with epilepsy experience breathing
abnormalities at baseline which may be further compromised
during a seizure. Sainju et al. found a blunted hypercapnic
ventilatory response in a subset of patients with epilepsy, placing
them at greater risk for peri-ictal hypoventilation (Sainju et al.,
2019). Patients with Dravet syndrome (DS) similarly exhibit
a decreased ventilatory response to CO2(Kim et al., 2018).
Several animal models of epilepsy present with respiratory
dysregulation, even in the absence of a seizure. The Kcna1-null
mutant model exhibits progressive respiratory dysfunction
with age (Simeone et al., 2018). Like their human counterparts,
the Scn1aR1407X/+ human knock-in mouse model of DS has
a diminished ventilatory response to CO2, as well as baseline
hypoventilation and apnea (Kuo et al., 2019). A similar loss of
the hypercapnic ventilatory response has been found in animals
that have undergone amygdala kindling (Totola et al., 2019).
Hajek and Buchanan (2016) found that mice with increased
respiratory rate variability at baseline are more likely to die
following a maximal electroshock (MES) seizure. These findings
support the idea that interictal respiratory dysfunction may
serve as a biomarker for those at greater risk for SUDEP.
Seizures themselves can cause profound alterations in
respiration, including coughing, apnea, hyperventilation,
bronchial spasms, increased pulmonary vascular pressure,
laryngospasm, and pulmonary edema (Bayne and Simon,
1981; Kennedy et al., 2015; Nakase et al., 2016; Rugg-Gunn
et al., 2016). Seizures appear to cause varying degrees of
respiratory dysregulation depending on seizure type and origin
(Bateman et al., 2008; Blum, 2009). Longer duration of seizures
is associated with a greater degree of dysfunction, particularly
in regard to hypercapnia, pulmonary pressure, and pulmonary
edema (Bayne and Simon, 1981; Bateman et al., 2008; Seyal
et al., 2010; Kennedy et al., 2015).
Hypoventilation during a seizure may occur due to airway
obstruction or dysregulation of the brain’s respiratory centers
and usually results in hypercapnia and hypoxemia (Rugg-
Gunn et al., 2016). Dravet syndrome patients in particular
demonstrate peri-ictal hypoventilation, which precedes the onset
of bradycardia (Kim et al., 2018). Hypoventilation can lead
to secondary cardiac failure, especially during seizures where
oxygen saturation (SaO2) drops below 90% (Seyal et al., 2011). A
cause of some ictal hypoventilation is central apnea. Ictal central
apnea (ICA) is a relatively frequent occurrence during seizures,
especially ones with bihemispheric involvement (Nashef et al.,
1996; Rugg-Gunn et al., 2016). ICA occurs exclusively in focal
epilepsy, emerging during 33–50% of focal seizures (Lacuey
et al., 2018; Vilella et al., 2019; Tio et al., 2020). ICA can precede
electrographic seizure activity as well as clinical seizure onset
by up to 7–10 s (Nishimura et al., 2015; Tio et al., 2020).
These apneas tend to be brief and do not substantially impact
O2saturation (Bateman et al., 2008). A multivariate analysis
indicated that contralateral seizure spread and seizure duration
mutually contribute to increased ETCO2that follows ICA (Seyal
et al., 2010). Several animal models of epilepsy and SUDEP
exhibit ICA, including Scn1aR1407X/+ mice, in which mechanical
ventilation can prevent fatal seizure-induced respiratory arrest
(Kim et al., 2018). Additionally, a model of status epilepticus
induced in sheep features ICA and hypoventilation in 100%
of the animals, with some resulting in death (Johnston et al.,
1997). Post-convulsive central apnea (PCCA), in contrast, occurs
in both focal and generalized epilepsies, suggesting a separate
pathophysiology from ICA (Vilella et al., 2019). PCCA is less
common than ICA—occurring during only 18% of generalized
seizures. However, PCCA may be much more dangerous than
ICA. PCCA is associated with a longer recovery time from
hypoxemia, and it is considered by some to be a biomarker for
SUDEP (Jin et al., 2017; Vilella et al., 2019).
Seizures may impair a person’s ability to autoresuscitate
after central apnea. Autoresuscitation is a spontaneous protective
cardiorespiratory phenomenon which promotes the recovery of
normal breathing and heart rate after primary apnea by initiating
a gasping reflex (Adolph, 1969; Guntheroth and Kawabori,
1975). Failure to autoresuscitate has been documented in infant
deaths that were eventually classified as sudden infant death
syndrome (SIDS; Meny et al., 1994; Sridhar et al., 2003). There
are numerous parallels between SIDS and SUDEP, including
normal autopsy, prone position, predominance during the
nighttime, predicted respiratory mechanism, and evidence of
serotonergic system dysfunction (Richerson and Buchanan,
2011; Buchanan, 2019).
Obstructive apnea, or laryngospasm, is another seizure-
associated phenomenon that can result in death (Stewart, 2018).
DBA/2 mice, which display lethal audiogenic seizures, have
a significantly reduced mortality rate following seizures after
being implanted with a tracheal T-tube as a surrogate airway
(Irizarry et al., 2020). Seizures induced via kainic acid in rats
have been documented to cause partial or complete glottic
closure and subsequent death (Nakase et al., 2016; Budde et al.,
2018; Jefferys et al., 2019). It has been postulated that fatal
obstructive apnea is a consequence of bronchial spasms or
hypotonia of the muscles involved in respiration (Stöllberger and
Finsterer, 2004). Nakase et al. proposed that ictal laryngospasm
is caused by the spread of a seizure via autonomic medullary
motor regions to the laryngeal branches of the vagus nerve
(Nakase et al., 2016).
Spreading depolarization (SD) may be one of the underlying
mechanisms behind cardiorespiratory failure in SUDEP. In
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Cacna1aS218L mutant mice, which carry a gain of function
mutation in the Cav2.1 voltage-gated calcium channel,
brainstem SD occurs during all spontaneous fatal seizures,
as well as a subset of nonfatal seizures (Jansen et al., 2019).
Additionally, seizure-related SD in the ventrolateral medulla
is correlated with the incidence of respiratory suppression
(Jansen et al., 2019). Chemically induced seizures in Kcna1 and
Scn1a mutant mice cause a wave of SD in the dorsal medulla,
which may temporarily silence the cells that would serve to
reoxygenate the brain following a seizure (Aiba and Noebels,
2015). This depolarizing blockade may cause a positive feedback
loop in which the brain cannot reoxygenate following a seizure
during which oxygen saturation has dropped dramatically,
potentially leading to complete cardiorespiratory arrest (Aiba
and Noebels, 2015).
Numerous other potential mechanisms underlying ictal
respiratory dysfunction and failure have been proposed. A
leading hypothesis is that seizures activate inhibitory subcortical
projections to brainstem respiratory centers (Dlouhy et al., 2015;
Lacuey et al., 2017). It has also been found that central apnea
occurs in human patients when seizures spread to the amygdala
(Dlouhy et al., 2015; Rhone et al., 2020). Similarly, stimulation
of the amygdala as well as the hippocampus produces central
apnea that patients are not aware of (Dlouhy et al., 2015;
Lacuey et al., 2017; Nobis et al., 2018), and they are able to
voluntarily initiate inspiration when prompted (Dlouhy et al.,
2015). Further studies revealed that stimulation of the basal
amygdala in particular (including the basomedial and basolateral
nuclei) was particularly likely to cause apnea, while stimulation
of more lateral regions produced fewer apneas (Rhone et al.,
2020). In DBA/1 mice, unilateral lesions to the amygdala was
sufficient to suppress seizure-induced respiratory arrest (S-IRA)
(Marincovich et al., 2021). This suggests that apnea is due to the
loss of involuntary ventilatory drive rather than an issue with the
respiratory motor output pathways or musculature.
Despite the implications of both respiratory and cardiac
dysfunction contributing to SUDEP, recent evidence has
surfaced suggesting respiratory failure precedes cardiac failure
during instances of seizure-induced death. In 2013, a multi-
center MORTality in EMUs Study (MORTEMUS) of SUDEP
incidents in EMUs found that all recorded cases of SUDEP
featured terminal respiratory arrest prior to terminal asystole
(Ryvlin et al., 2013). Similar results have been found in the
Kcna1-null mouse model (Dhaibar et al., 2019) and in an
MES model (Buchanan et al., 2014). Another indicator of
respiratory failure’s pivotal role in SUDEP is that mechanical
ventilation, if administered immediately, can greatly reduce
mortality in both human patients and animal models (Tupal
and Faingold, 2006; Ryvlin et al., 2013; Buchanan et al., 2014).
In a similar vein, oxygenation prior to seizure induction can
prevent fatal audiogenic seizures in several strains of audiogenic
mice, without impacting seizure incidence or severity (Venit
et al., 2004). To summarize, seizures cause profound alterations
in breathing which may directly contribute to seizure-induced
death.
Sleep and circadian effects of
seizures/epilepsy on breathing
Approximately 10–15% of epilepsy patients have seizures
solely or primarily during sleep (Grigg-Damberger and
Foldvary-Schaefer, 2021). Seizures occurring during sleep
tend to be longer and are more likely to evolve into focal and
bilateral tonic-clonic seizures (Bazil and Walczak, 1997). As
mentioned above, longer convulsive seizures are associated
with an increased degree of respiratory dysfunction (Bayne and
Simon, 1981; Bateman et al., 2008; Seyal et al., 2010; Kennedy
et al., 2015). Seizures emerging from sleep are also more likely
to be associated with the presence of post-ictal generalized
EEG suppression (PGES) and greater oxygen desaturation
(Latreille et al., 2017). A clinical study in 20 patients with
epilepsy found that 44% of nocturnal seizures are associated
with ICA, and although the difference did not reach significance,
a smaller fraction of wake-related seizures were accompanied
by ICA (28%; Latreille et al., 2017). MES seizures in mice
that are induced during NREM sleep are also associated with
greater respiratory dysfunction than those induced during
wakefulness (Hajek and Buchanan, 2016). When factoring
in time of day, MES seizures that were induced during the
day, the rodent inactive phase, resulted in a greater degree
of postictal respiratory and EEG suppression than those
induced during the nighttime. This effect was even greater
when the seizures were induced during this time while the
animal was in NREM sleep (Purnell et al., 2017). When
DBA/1 mouse model of audiogenic seizures were exposed to
an audiogenic stimulus during the day, the ensuing seizures
resulted in death during 21.7% of trials. Conversely, seizures
induced during the night resulted in seizure-induced death
in 46.7% of trials (Purnell et al., 2021b;Figure 4A). The
same study used mice living in constant darkness to access
circadian influence on seizure-induced death in the MES mouse
model. They found that during the subjective night there
was a decrease in postictal ventilation and an increase in the
probability of seizure-induced death without altering seizure
severity (Purnell et al., 2021b;Figure 4B). Kv1.1 potassium
channel knockout (KO) mice and SCN1AR1407X/+mice,
which experience progressive breathing dysregulation (Kim
et al., 2018; Kuo et al., 2019; Iyer et al., 2020), also experience
seizure-induced death more commonly during the nighttime
(Figures 4C,D).
Because humans typically sleep during the night, nighttime
seizures are often unwitnessed (Lamberts et al., 2012; Zhuo et al.,
2012; Rugg-Gunn et al., 2016; Purnell et al., 2018). Lamberts
et al. (2012) reported that 86% of SUDEP cases are unwitnessed.
It is hypothesized that being unaccompanied during a nocturnal
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Joyal et al. 10.3389/fncir.2022.983211
FIGURE 4
Time-of-day and circadian probability of seizure-induced death in mouse models of epilepsy. Temporal distribution of spontaneous seizure-
induced death in (C) SCN1AR1407X/+ and (D) Kv1.1 knockout mice housed in a 12:12 h light:dark cycle. (A) Percentage of audiogenic seizures
resulting in death in DBA/1 mice housed in a 12:12 h light:dark cycle. (B) Percentage of maximal electroshock (MES) seizures resulting in death in
mice housed in constant darkness. Redrawn with permission from (C) Teran et al. (2019),(D) Moore et al. (2014),(A,B) Purnell et al. (2021b).
seizure may carry even more risk than the severity of sleep-
related respiratory dysfunction or PGES duration (Peng et al.,
2017; Sveinsson et al., 2020). The presence of someone who
could intervene and administer lifesaving resuscitative measures
may mean the difference between a case of near SUDEP
and actual SUDEP (Nashef et al., 1998; Langan et al., 2005;
Lamberts et al., 2012). Increasing nocturnal supervision through
the use of monitoring devices, checkups, or having another
person asleep in the same room is associated with decreased
SUDEP risk (Langan et al., 2005; Ryvlin et al., 2006; Harden et al.,
2017). The majority of SUDEP victims are found prone in or
near a bed (Opeskin and Berkovic, 2003; Sowers et al., 2013; Ali
et al., 2017; Sveinsson et al., 2018). Many generalized seizures
are followed by a period of PGES where the patient is more
likely to be immobile, unresponsive, and require resuscitative
measures (Semmelroch et al., 2012; Kuo et al., 2016). If a patient
is unresponsive after a seizure that renders them prone, their
nose and mouth may become obstructed by bedding. This may
result in upper airway occlusion or asphyxiation against the
surface the patient is positioned on. Outside of total airway
occlusion, ending a seizure in the prone position on bedding
may impairing postictal breathing by increasing inspiratory
resistance and causing the patient to rebreathe trapped air (Kemp
et al., 1994; Tao et al., 2010, 2015; Rugg-Gunn et al., 2016).
This would cause an acute rise in CO2in the blood, potentially
leading to severe acidosis, which would potentiate the postictal
immobility and further prolong the respiratory dysfunction until
terminal apnea and asystole develop (Peng et al., 2017; Purnell
et al., 2018).
Clock genes
Although seizures are frequently thought to be unpredictable
phenomenon, patients often display time-of-day-specific timing
of seizure onset. In a recent study of patients implanted with
responsive neurostimulators, it was shown that nearly 90% of
patients with focal epilepsy had circadian timing of seizure
onset (Leguia et al., 2021). Interestingly, circadian risk of
seizure onset could be clustered into five general times of day,
with seizures more likely to occur during the morning, mid-
afternoon, evening, early night, or late night.
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The circadian influence on seizures may be due in part
to the bi-directional relationship of epilepsy and clock genes.
Alterations in clock mechanisms increase the susceptibility
for epilepsy, while seizures have the potential to disrupt the
internal clock (Re et al., 2020). A significantly higher current
is required to induce both maximal and generalized seizures in
wild type (WT) mice during the dark phase of their diurnal cycle
compared to the light phase. This rhythm is abolished in Bmal1
KO mice, who also exhibit significantly lower seizure thresholds
at all times compared to their WT counterparts (Gerstner
et al., 2014). Similarly, conditional KO of Bmal1 in neurons in
the dentate gyrus increased the susceptibility to pilocarpine-
induced seizures in mice (Wu et al., 2021). Hippocampal
BMAL1 expression is reduced overtime in pilocarpine-treated
rats as they begin to develop spontaneous seizures—suggesting
that BMAL1 also plays a role in epileptogenesis (Matos et al.,
2018). Levels of BMAL1 protein have been found to be decreased
in the dentate gyrus and CA1 of mice with TLE (Wu et al., 2021).
Mutations in the RAR related orphan receptor alpha (RORA)
gene, which encodes for an activator of Bmal1 transcription,
have been linked to intellectual developmental disorder with
or without epilepsy or cerebellar ataxia (IDDECA) (Guissart
et al., 2018). Deletion of the gene Clock in cortical pyramidal
neurons in mice results in epileptiform discharges in excitatory
neurons as well as a decreased seizure threshold (Li et al.,
2017). Real-time quantitative PCR (qPCR) analysis has revealed
a loss in the rhythmic expression of CLOCK and decreased
levels of its transcript in a post-status epilepticus rat model
(Santos et al., 2015). Clock RNA and protein are similarly
downregulated in brain tissue resected from patients with
TLE (Li et al., 2017). Another oscillating clock gene, Per1, is
upregulated in the hippocampus following electrical and kainic
acid-induced seizures in mice (Eun et al., 2011). One study found
an alteration in the rhythmic expression of PER1, PER2, and
PER3 in a rat model of pilocarpine-induced seizures (Santos
et al., 2015). However, a subsequent study found that an increase
in PER1 expression and a decrease in PER2 expression prior to
the development of spontaneous seizures, while PER3 expression
was unaltered (Matos et al., 2018). To conclude, sleep and
circadian phase have direct effects on periictal breathing and
potentially the development of epilepsy itself.
Sleep impairment, sleep-disordered
breathing (SDB), and epilepsy
Sleep deprivation/sleep disorders
Apart from nocturnal seizures, patients with epilepsy also
have a greater prevalence of sleep disorders compared to healthy
individuals (Vaughn and D’cruz, 2004). A myriad of studies
over the past 30 years have repeatedly found that adults with
epilepsy are 2–3 times more likely to have a sleep/wake disorder
compared to the general population (Grigg-Damberger and
Foldvary-Schaefer, 2021). Patients with temporal lobe epilepsy
exhibit reduced sleep efficiency and more arousals compared to
those with frontal lobe epilepsy (Crespel et al., 2000). In addition,
amygdala kindling decreases REM sleep in experimental
animals, and selective REM sleep deprivation accelerates the
kindling process (Cohen and Dement, 1970; Tanaka and Naquet,
1975). The Scn1aR1407X/+ mouse shows impairments in circadian
sleep regulation, including a fragmented rhythm of NREM sleep
and an elongated circadian period of sleep (Sanchez et al., 2019).
Sleep deprivation caused by sleep disorders of frequent
nocturnal seizures can result in sleep deprivation. Sleep
deprivation itself can induce seizures and interictal spiking
(Mattson et al., 1965; Pratt et al., 1968; Malow et al., 2000b;
Konduru et al., 2021). In amygdala kindled cats, acute sleep
deprivation reduces seizure and after discharge threshold
(Shouse and Sterman, 1982). However, more prolonged sleep
deprivation increases their susceptibility to both kindled and
penicillin-induced seizures, regardless of sleep state (Shouse,
1988). Additionally, when kindled rats were administered a
microinjection of a cholinergic agonist into the pontine reticular
formation to enhance REM sleep, the result was a significant
increase in the current threshold needed to elicit afterdischarge
spiking in the amygdala (Kumar et al., 2007). Sleep deprivation
studies in healthy individuals have shown hypertension and
increased sympathetic nervous system activity after nights where
sleep was less than 5 h (Lusardi et al., 1996; Tochikubo et al.,
1996; Gangwisch et al., 2006). Thus, sleep deprivation may not
only worsen seizures themselves, but also leave patients more
vulnerable to seizure-induced autonomic insults.
SDB
Up to 9–11% of adult patients with epilepsy exhibit SDB
(Vendrame et al., 2014; Popkirov et al., 2019). This number
jumps up to 40% when looking at children with epilepsy
(Kaleyias et al., 2008). A recent case study highlighted a male
patient with a history of secondary generalized tonic/clonic
seizures who displayed paroxysmal nocturnal breathing. The
patient experienced periods of breathing arrest in conjunction
with an odd expiratory noise—primarily during REM sleep or
the transition between REM and NREM—despite being seizure
free for a year (Künstler et al., 2022).
OSA is a relatively common form of SDB, in which the upper
airway collapses, preventing ventilation. The ensuing apnea
provokes an arousal response which allows for re-positioning
and recovery of gas exchange (Butler et al., 2015). The precise
occurrence of OSA in people with epilepsy has yet to reach a
consensus. Popkirov et al. estimates that 7% of epilepsy patients
have mild-to-moderate OSA (Popkirov et al., 2019). A separate
polysomnography study postulates that one-third of patients
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with medically refractory epilepsy who were candidates for
epilepsy surgery have concomitant OSA (Malow et al., 2000b).
This is also closer to an estimate produced from a meta-analysis
in 2017, which determined the prevalence of mild-to-severe
OSA in patients with epilepsy to be 33.4%—2.4 times more
likely than healthy comparisons (Lin et al., 2017). This same
meta-analysis found that the prevalence of OSA in patients with
refractory epilepsy was not greater than the overall prevalence
of OSA in patients with epilepsy (Lin et al., 2017). Patients with
generalized epilepsy experience more severe OSA than those
with focal epilepsy. Both populations reported similar degrees
of abnormal daytime sleepiness. Older age, higher body mass
index (BMI), and a history of hypertension are also associated
with more severe OSA (Scharf et al., 2020). The incidence of
OSA apnea in individuals without epilepsy is higher in males
than in females (4% in men, 2% in women) (Block et al., 1979;
Young et al., 1993). Men are also much more likely to experience
O2desaturation during apnea compared to women (Block et al.,
1979). In patients with epilepsy, males are roughly three times
more susceptible to OSA compared to females (Lin et al., 2017).
The length of obstructive apneas tends to increase over the
course of a night’s sleep (Montserrat et al., 1996; Butler et al.,
2015). It is suggested that this is due to a blunting of the CO2
arousal response over the course of the night, leading to longer
periods of hypercapnia before arousal occurs (Montserrat et al.,
1996). It is possible that this increase in OSA in epilepsy patients
is due to an inherent blunting of chemosensitivity in an epileptic
brain. Obese adolescents with OSA have an increased HCVR
during wakefulness and a blunted HCVR during sleep (Yuan
et al., 2012). There are also endogenous circadian components
to the prolongation of respiratory events across the night. At
circadian phases that correspond to the early morning, the
duration of apnea and hypopneas are typically longer, but
apnea/hypopnea index (AHI), a measurement of OSA severity,
is low. In contrast, during the late afternoon to early evening,
event durations were short and AHI was high. Events during
REM sleep also tended to be 14% longer than those emerging
from NREM sleep (Butler et al., 2015).
Comorbidity of epilepsy with OSA can increase the
incidence of arrhythmias and increase the patient’s risk
for sudden cardiac death (Gami and Somers, 2008; Gami
et al., 2013). Patients with OSA experience disruption of the
autonomic system during sleep (Adlakha and Shepard, 1998),
which may be further imbalanced by seizures. While no direct
correlation between OSA and SUDEP has been identified,
higher revised SUDEP-7 scores [presence of seizures in the
past 12 months—especially generalized tonic clonic seizures
(GTCS), longer duration of epilepsy, increased number of ASMs,
and lower IQ/more cognitive impairment]—are associated with
probable SUDEP (Phabphal et al., 2021). OSA decreases the
amount of time a person spends asleep each night, potentially
leading to further sleep deprivation. Sleep deprivation is
particularly dangerous for those with epilepsy as it can have
an epileptogenic effect (Nobili et al., 2011; Popkirov et al.,
2019). It follows then that when epilepsy patients with OSA
were treated with continuous positive airway pressure (CPAP)
they exhibited better seizure control than their untreated peers
(Lin et al., 2017).
Vagus nerve stimulation (VNS) is a technique used to
treat refractory epilepsy via a neurostimulation device. While
these devices have been found to lessen seizure frequency and
severity, there is a lack of conclusive evidence indicating that
VNS lessens SUDEP risk (Annegers et al., 1998; Ryvlin et al.,
2018). There is, however; evidence that VNS activation during
sleep can induce mild OSA or exacerbate preexisting OSA.
VNS activation during sleep is similarly linked to decreased VT
and SaO2, increased respiratory rate and AHI, and excessive
daytime somnolence (Malow et al., 2000a; Holmes et al., 2003;
Marzec et al., 2003; Zambrelli et al., 2016; Somboon et al.,
2019; Kim et al., 2022). A recent study has also indicated
HCVR slope is attenuated in patients with an active VNS
(Sainju et al., 2021). Evidence suggests the exacerbation of OSA
after VNS is due to reduction of the glottal space or lack of
laryngeal–respiratory coordination (Zambrelli et al., 2016). This
is notable as patients with refractory epilepsy are at higher risk
for SUDEP and are more likely to opt for VNS as a method
of seizure control. To summarize, individuals with epilepsy
are more likely to experience sleep disorders and SDB, which
may directly influence seizure frequency. Moreover, a common
treatment for refractory epilepsy appears to aggravate SDB in
these patients.
Neurotransmitter mechanisms
While the underlying mechanisms behind the sleep
and circadian effects on breathing in epilepsy are still
not fully understood, numerous neurotransmitters and
signaling molecules have been implicated. For instance, the
monoaminergic neurotransmitter serotonin (5-HT) plays an
important role in sleep-wake regulation and respiration (Jouvet,
1999; Richerson, 2004; Hodges et al., 2009; Ptak et al., 2009;
Hodges and Richerson, 2010; Depuy et al., 2011; Buchanan,
2013; Iwasaki et al., 2018; Smith et al., 2018). It is also heavily
implicated in epilepsy and SUDEP pathophysiology (Bagdy
et al., 2007; Richerson and Buchanan, 2011; Richerson, 2013;
Feng and Faingold, 2017; Li and Buchanan, 2019; Petrucci et al.,
2020). Serotonergic tone is modulated in both a sleep state and
circadian phase-dependent manner, with the nadir occurring
during the nighttime and during sleep (Mcginty and Harper,
1976; Rosenwasser et al., 1985; Agren et al., 1986; Rao et al., 1994;
Sakai and Crochet, 2001; Mateos et al., 2009; Sakai, 2011; Purnell
et al., 2018). 5-HT neurons in both the midbrain and medullary
raphe have been demonstrated to be robustly chemosensitive
(Larnicol et al., 1994; Richerson, 1995, 2004; Wang et al., 1998;
Severson et al., 2003). It is likely that 5-HT neurons in the
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