Curr Treat Options Neurol 32:81)602(

DOI 10.1007/s11940-016-0402-9

Sleep Disorders (A Iranzo, Section Editor)

Sleep-Related Epilepsy
Mar Carreño, MD, PhD1,*
Santiago Fernández, MD2
Address
*,1
Epilepsy Unit, Hospital Clínic, C/Villarroel, 170. 08036, Barcelona, Spain
Email: mcarreno@clinic.ub.es
2
Department of Neurology, Hospital Platón, Barcelona, Spain

* Springer Science+Business Media New York 2016

This article is part of the Topical Collection on Sleep Disorders

Keywords Epilepsy I Sleep I Obstructive sleep apnea I Nocturnal I Awakening I Treatment

Opinion statement
Sleep has a strong influence on interictal epileptiform discharges and on epileptic
seizures. Interictal epileptiform discharges are activated by sleep deprivation and
sleep, and some epilepsies occur almost exclusively during sleep. Treatment of
sleep-related epilepsy should take in account the type of epileptic syndrome, the
type of seizures, the patient characteristics, and also the pharmacokinetics of the
drug. Proper characterization of the epilepsy is essential to choose appropriate
antiepileptic drugs. Drugs effective in focal epilepsy may be used to treat benign
genetic focal epilepsies such as rolandic epilepsy and other focal (frontal or not)
sleep epilepsies. These include both classical (such as carbamazepine) and new
(such as levetiracetam and lacosamide) antiepileptic drugs. Drug-resistant cases
should be evaluated for epilepsy surgery, which may be efficacious in this setting.
Valproate, lamotrigine, topiramate, levetiracetam, and perampanel are effective
against generalized tonic-clonic seizures in genetic generalized epilepsies, which
frequently happen on awakening. Risks of valproate should be considered before
prescribing it to women of childbearing age. Specific syndromes such as ESES require
specific treatment such as a combination of high dose steroids, benzodiazepines,
levetiracetam, and even surgery when an epileptogenic lesion is present. Sleep
disorders that may worsen epilepsy such as obstructive sleep apnea or insomnia
should be adequately treated to improve seizure frequency. Adequate control of
seizures during sleep (especially generalized tonic-clonic seizures) decreases risk of
sudden unexpected death in epilepsy (SUDEP).

Introduction
The fact that sleep has effects on epilepsy has been this observation has been confirmed to the present
observed since the nineteenth century (1). Early day. Thus, there are some epilepsies in which sei-
studies observed that a significant number of sei- zures appear mainly or exclusively in this state (pure
zures occur during sleep or during awakening, and sleep epilepsy). Epilepsies whose seizures occur
23 Page 2 of 17 Curr Treat Options Neurol (2016)8:3

d ur i n g a w a k e n i n g ha v e b e e n c a l l e d Ba w ak e In this article, we will review the effects of sleep

epilepsy^. Sleep has also a strong influence on sei- on epilepsy in general and on specific epileptic syn-
zure frequency and types and electroencephalogram dromes. We will also discuss the most appropriate
abnormalities. treatment strategies for sleep-related seizures.

Effect of sleep on epilepsy

Effects of sleep on seizures and interictal epileptiform discharges (IEDs)
Sleep has an influence on seizures. It is accepted that non-REM sleep
(NREM) is a facilitator of seizure activity, while REM sleep is a sup-
pressor (2, 3). In NREM stage, epileptiform discharges increase in fre-
quency and spreading. This phenomenon occurs as we move towards a
deeper state of sleep, and presents in both generalized and focal epi-
lepsies (4, 5), but seizures usually appears in stage 2 sleep (2, 3). One
possible explanation of the increase of interictal discharges during
NREM sleep is the progressive neuronal synchronizations that occur in
deep sleep stages.
In REM sleep, both the frequency and the spread of interictal epilepti-
form discharges (IEDs) decrease. The extent and lateralization of IEDS is
useful to localize the epileptogenic foci in refractory temporal lobe epilepsy
(4, 6). In a recent study in children with generalized discharges in scalp EEG
and normal/subtle changes in the MRI evaluated for epilepsy surgery, IEDs
during REM helped to lateralize the epileptogenic hemisphere and proceed
to surgery (7•). There is also a very low rate of seizures arising from REM
sleep (3).
Sleep deprivation has long been recognized as a seizure precipitant,
especially in patients with awakening epilepsies. This influence is not un-
derstood, but there is some evidence that sleep deprivation increases neu-
ronal excitability (8). In a recent prospective study of a cohort of 104
patients, this was the second most frequent (71 % of cases) triggering factor
for seizures, with the patients with generalized epilepsy being specially
sensitive (9). Many other studies have also reported that sleep deprivation
can precipitate EEG epileptiform discharges (10, 11), even in the absence of
sleep during recordings (12). Comparative studies show that it activates
epileptiform discharges in 23 to 93 % of patients with definite or suspected
seizures (13).
Sleep deprivation has been used as a procedure for EEG activation.
There is only one prospective study to show a specific effect on EEG. The
authors reported 85 patients with suspected epilepsy to routine EEG, sleep-
deprived EEG, and EEG during drug-induced sleep in a random order, and
reported that sleep-deprived EEG was significantly more likely to show
IEDs (14). In another recent study (15•), sleep-deprived EEG was more
able to induce IEDs than routine EEG both in focal and generalized
epilepsies. Using a sleep-deprived EEG as the first protocol in young
patients with suspected epilepsy could reduce the number of EEGs re-
quested in this population. Most authors advocate that the activating effect
of IEDs of sleep-deprived EEG is a specific effect of deprivation, and not
only sleep (16•, 17••).
Curr Treat Options Neurol (2016)8:3 Page 3 of 17 23

Effect of sleep on epilepsy syndromes

There are a variety of epilepsies that are clearly related with sleep. These
epilepsies are mainly the following:

West syndrome
This syndrome is characterized by infantile spasms and hypsarrhythmia on
EEG, and usually starts between 3 and 12 months of age. The spasms are brief
and usually occur in clusters. Seizures most commonly occur shortly after
awakening. The characteristic high amplitude hypsarrhythmic EEG pattern is
seen prominently in early NREM sleep (18) and, even more, can appear only in
sleep (19). Recently, it has been shown that hypsarrhythmia impairs the phys-
iological overnight decrease of slow waves in NREM sleep (20).

Lennox-Gastaut syndrome
This syndrome is characterized by the presence of tonic seizures, atypical
absences, and tonic-clonic seizures. Typically, tonic seizures predominate dur-
ing NREM sleep.

Benign epilepsy with centrotemporal spikes (BECTS)

This is the most frequent epilepsy in children (21). The onset is between 3 and
13 years, with remission before the age of 16 years (22). Seizures are charac-
terized by hemifacial clonic and lateral clonic deviation of mouth and tongue
with salivary flow. Approximately 70 % of seizures occur during sleep, early
after falling asleep, or shortly before awakening. The syndrome, also known as
benign rolandic epilepsy, is generally self-remitting, and prognosis is excellent.
Interictal EEG is characterized by high-voltage centrotemporal spikes.
Amplitude and frequency of IEDs increases during sleep.

Panayiotopoulos syndrome
It is another benign age-related genetic focal epilepsy. Almost two thirds of
seizures occur while the patient is asleep. Seizures are characterized by nausea,
emesis, other autonomic features, loss of consciousness, and eye and head
deviation. Half of the seizures end up as a hemiconvulsion or generalized
convulsion. Interictal EEG shows focal or multifocal spikes that appear or
increase in frequency during sleep. Most frequent spikes are recorded from the
occipital regions but also from other locations such as the centrotemporal area
or the midline. Even irregular generalized spike and wave discharges may be
seen. A few cases display no interictal epileptiform activity (23).
Prognosis is excellent and more than 75 % of patients achieve complete
remission without treatment, within 1–2 years from onset (24).

Electrical status epilepticus during slow sleep (ESES)

It is an epileptic encephalopathy defined by the following features: (a) a
continuous EEG activity consistent in spike-wave discharges during slow sleep;
(b) frequent seizures; and (c) global cognitive regression (25••). The associa-
tion with seizures and cognitive impairment has been made since early reports
(26). Another term that has been used is Bcontinuous spike-wave discharges
during sleep^ (CSWS). ESES results from the association of various seizures
23 Page 4 of 17 Curr Treat Options Neurol (2016)8:3

types, partial or generalized, occurring during sleep, and atypical absences

during the awake state. The EEG pattern consists of continuous or almost
continuous diffuse spike waves during non-REM sleep. It is an age-related
syndrome with seizure onset between 2 months and 12 years, and a peak at 2–
4 years (27). This could be due to the fact that childhood is the period in which
slow waves are most prominent and synaptic density higher (28, 29). The
absence of tonic seizures differentiates it from Lennox-Gastaut Syndrome. ESES
is associated with cognitive and behavioral impairment, producing regression
that can be acute or subacute (30).
About half of patients with ESES have malformations or cortical lesions
(31). Pre or perinatal thalamic lesions have been associated with the ESES.
Mutations have also been described in gene GRIN2A (32•, 33•). The patho-
physiologic mechanism that triggers ESES is unknown. Cognitive impairment
has attributed to the influence of continuous epileptiform activity during sleep,
which does not allow adequate consolidation of memory during sleep (34).
Processing of cortical information is disrupted by epileptiform activity (35).
Similarly, some studies have established a correlation between neurocognitive
deficits and the brain regions where EEG abnormalities are more frequent and
dense (30, 36, 37). Two similar syndromes to ESES are also characterized by a
specific increase in spike-wave during sleep: Landau-Kleffner syndrome, also
known as acquired epileptic aphasia. Aphasia is due to hearing agnosia. Age of
onset is between 3 and 9 years. Typically, there is an acute or gradual language
regression, often with seizures. Sleep EEG may show continuous spikes and
waves in NREM sleep (38). Spike and waves can be unilateral, lateralized, or
diffuse (39, 40). There are no associated lesions on MRI and aphasia improves if
the EEG normalizes, but language and cognitive deficits can persist.
The second variant is atypical benign partial epilepsy. These patients meet
the criteria for benign partial epilepsy, but they have the continuous spike and
wave EEG pattern during sleep. Besides focal motor seizures, atypical absences,
myoclonic, and tonic seizures may occur (41). Cognition is preserved, but if
mental retardation is present, the term Bpseudo-Lennox-Gastaut^ is used. EEG
patterns and outcomes are similar to ESES.
Some authors consider these genetic or idiopathic focal epilepsies as a
continuum, in which the rolandic epilepsy represents the mildest form, and
ESES with this variants the most serious form (17••). To emphasize this
hypothesis, mutations of the GRIN2A gene in BECTS, ESES, and Landau-
Kleffner syndrome have been described (32•, 42, 43•). GRIN2A encodes the
GLuN2A subunit of the NMDA receptor, that has important roles in synapto-
genesis and synaptic plasticity (43•). According to some studies, these epilep-
sies may be associated with these mutations up to 10–20 % of cases (44, 45).

Genetic generalized epilepsies

Juvenile myoclonus epilepsy (JME)

It is also an age-related epilepsy and is clearly associated to sleep. Seizures

occur after awakening from sleep or in the evening relaxation period and
are facilitated by sleep deprivation and sudden arousal. JME is characterized
by the presence of short myoclonic jerks, generally in the morning after
awakening, without altered level of consciousness. The upper extremities
Curr Treat Options Neurol (2016)8:3 Page 5 of 17 23

are especially affected. The myoclonus may evolve to a generalized tonic-

clonic seizure. Recently it was established that the presence of myoclonus is
a requisite for the diagnosis of JME (46•). Absences and praxis-induced
seizures can occur (47). The EEG shows spikes and widespread polyspikes
and diffuse spike and wave at 2.5–3.5 Hz, increased at sleep onset and on
awakening, but less frequent in NREM and REM sleep and during the awake
state (48). Because sometimes the routine EEG is normal, it is recom-
mended to perform a prolonged EEG with sleep deprivation. Epileptiform
discharges on awakening are considered a marker of JME and other genetic
or idiopathic generalized epilepsies (49).

Epilepsy with tonic-clonic seizures on awakening

This syndrome may occur independently or as a part of other idiopathic

generalized epilepsy syndromes, as JME. Seizures occur after awakening or
during evening relaxation (50).

Nocturnal frontal lobe epilepsy (NFLE)

This is a frontal lobe epilepsy in which more than 90 % of attacks occur during
sleep (51). NFLE is an heterogeneous disease as idiopathic, sporadic, familial,
or symptomatic forms exist (51–53).
The genetic form of NFLE is heterogeneous with autosomal dominant inher-
itance (ADNFLE). Most frequent mutations involve genes coding for subunits of
the heteromeric neuronal nicotinic receptors (nAChRs). However, these mutations
account for around 12 % of cases (54•). ADNLFE is very similar to sporadic NFLE,
but some mutations are frequently associated with specific psychiatric symptoms.
ADNLFE was the first epilepsy in which genetic basis was detected (52). Recently, a
recessive form due to mutation in PRIMA1 gene has been described. PRIMA1 is a
transmembrane protein which anchors acetylcholinesterase to neuron mem-
branes, and the mutation causes increase in cholinergic responses (55•).
The most frequent etiology of symptomatic forms is type II focal cortical
dysplasia (56).
NFLE usually begins before 20 years of age, with different types of
seizures: (1) short-lasting stereotyped movements involving the limbs,
axial musculature, or head (57, 58); (2) paroxysmal arousals that are
sudden and brief (5–10 s), sometimes accompanied by stereotyped
movements, vocalizations, frightened expression, or fear (51); and (3)
major attacks, (20–30 s in duration), with tonic or dystonic posturing, or
complex movements such as pelvic thrusting, pedaling, or more violent
movements of limbs (51, 52, 57). Almost all seizures occur during NREM
sleep. NFLE has been studied with special interest for its resemblance to
NREM parasomnias (sleepwalking and night terrors). Nocturnal PSG with
synchronized audiovisual recording is often normal in NFLE. If the diag-
nosis is unclear, the use of sphenoidal electrodes to record epileptiform
activity can be helpful (59).

Other focal nocturnal epilepsies

Sleep-related complex motor seizures are not necessarily frontal in all occasions.
They may also originate from the temporal lobe (60, 61), the insula (62), and
23 Page 6 of 17 Curr Treat Options Neurol (2016)8:3

the posterior regions (63). In these cases, auras can help to differentiate them
from NFLE (64).
A nocturnal temporal lobe epilepsy has been described, but is uncommon (65).
Primary sleep disturbances and epilepsy
Excessive daytime sleepiness is the most common sleep complaint in patients
with epilepsy (66•). The origin is multifactorial, the most common being an
adverse effect of antiepileptic drugs (AED) and sleep disorders that frequently
coexist with epilepsy, such as insufficient nighttime sleep and obstructive sleep
apnea (OSA) (67). Excessive daytime sleepiness affects negatively the quality of
life of patients with epilepsy.
Obstructive sleep apnea is a primary sleep disorder, and is one of the most
frequent in patients with epilepsy. The prevalence of OSA in patients with
epilepsy exceeds that of the general population and is even more frequent in
patients with drug-resistant epilepsy (68). Risk factors are the same than in
general population: older age, male sex, and increased body mass index (69). A
recent study found that, in a regression model, only age, dental problems, and
standardized AED dose are predictors of OSA (66•). The pathophysiology of
OSA in patients with epilepsy however still remains unknown. Total load of
AEDs (especially of some such as benzodiazepines) may decrease upper airway
tone; in addition, the epileptic discharges and/or seizures could alter upper
airway control during sleep. However, this hypothesis remains untested (66•).
The Sleep Apnea Scale of the Sleep Disorders Questionnaire has shown validity
as a screening instrument for the diagnosis of OSA in adults with epilepsy (70).
OSA causes sleep deprivation because it results in fragmented sleep. OSA has
been associated with poor control of seizures (69, 71).
Association between NREM sleep parasomnias (sleepwalking and night
terrors) and NFLE is unclear, because both conditions are often difficult to
distinguish on clinical grounds and PSG findings may be unclear.
REM sleep behavior disorder (RBD) is a parasomnia characterized by ab-
normal and often violent motor behaviors and complex vocalizations in which
patients seem to enact their dreams while in REM sleep (72••). RBD can be
misdiagnosed as sleep-related epilepsy. In addition, elderly patients with epi-
lepsy may have RBD (73).

Sudden unexpected death in epilepsy (SUDEP)

Premature death among patients with epilepsy is higher than in the general
population, and SUDEP is the most common cause of this mortality. This is
defined as the sudden, unexpected, witnessed or unwitnessed, non-traumatic,
and non-drowning death in an individual with epilepsy, with or without
evidence of a seizure, and excluding documented status epilepticus, in which
the autopsy does not reveal a toxicological or anatomic cause of death (74).
Recent studies estimate 7000 deaths per year in Europe and USA (75) due to
SUDEP. The risk of sudden unexpected death is considered to be 24–40 times
higher than general population (76, 77). The cause of SUDEP is unknown, but
several risk factors have been reported: poor seizure control, frequent tonic-
clonic seizures, and long-standing epilepsy (78, 79). Deaths are typically
Curr Treat Options Neurol (2016)8:3 Page 7 of 17 23

unwitnessed, and associated with prone position (80), especially in individuals

40 or younger (81). Nocturnal seizures seem to be an independent risk factor
for SUDEP: in a study of 154 patients who died of SUDEP, it was primarily a
sleep-related (in 58 % of patients) and unwitnessed (86 %) event (82•). Several
studies point out that SUDEP usually happens during sleep (83–87).
Postmortem, half of the patients are found to have subtherapeutic levels of
AEDs and most display evidence of a recent seizure (tongue injury, petechial
hemorrhages in the skin, superior vena cava distribution, or conjunctiva) (74).
One study aimed to assess if NFLE could be a risk factor for SUDEP that
included 103 patients showed that the incidence of SUDEP was not higher than
the rates previously reported in prevalent epilepsy populations (88•), perhaps
because of the low incidence of GTC seizures in this type of epilepsy. Some
hypotheses that could explain the relationship between SUDEP and sleep are the
autonomic changes that occur during sleep, both physiologically and those
produced by seizures and the presence of other sleep disorders such as OSA (89).
SUDEPs reported in epilepsy monitoring units show combined cardiac and
respiratory failure after a generalized tonic-clonic seizure (90••). Prolonged
postictal generalized EEG suppression has been described in all observed cases of
SUDEP in monitoring units (90••). This pattern correlates with respiratory
depression and autonomic dysfunction (91, 92). To improve the knowledge
about SUDEP in order to establish preventing strategies and diminish SUDEP
incidence, a new multicenter collaborative research consortium is ongoing (75).
Night supervision, use of monitoring devices, treatment of sleep comorbid-
ities (89, 90••), or avoiding prone position (81) could reduce the occurrence of
this dreadful complication of epilepsy.

Treatment of sleep-related epilepsies and sleep-related seizures

(Table 1)

Specific literature on treatment of sleep-related epilepsy is scarce. Possible

reasons include the fact that pure sleep epilepsies are relatively uncommon and
for the rest, which combine diurnal and nocturnal seizures in variable propor-
tions, differential responses of diurnal and nocturnal seizures are often not
studied or reported. Efficacy of antiepileptic drugs is assumed to be similar in
sleep or a wake seizures, when that may not be necessarily the case.
In addition, objective measurement of nocturnal seizures is difficult due to
the need to perform PSG to exclude subtle seizures which may not be noticed by
the patient or the caregiver. This fact limits the possibility to perform random-
ized controlled studies. We will review the current treatment strategies in the
types of epilepsies presenting mainly during sleep.

Genetic focal epilepsies

In general, no antiepileptic treatment is recommended in patients with benign
epilepsy with centrotemporal spikes (rolandic epilepsy) and infrequent noc-
turnal seizures without secondary generalization, and the same may be applied
to Panayotopoulos syndrome or idiopathic occipital lobe epilepsy. The extent
of EEG abnormalities does not correlate with seizure frequency or prognosis,
23 Page 8 of 17 Curr Treat Options Neurol (2016)8:3

Table 1. Treatment of epileptic syndromes related with sleep

Epileptic syndrome Treatment and observations

All syndromes Avoid precipitating factors, such as sleep deprivation and alcohol intake.
Stress importance of being compliant with medications. Use chronopharmacology
to guide dose and timing of antiepileptic drugs
Benign epilepsy with Centrotemporal No treatment if few seizures and well tolerated
Spikes (BECTS) If frequent seizures, secondary generalization, high family anxiety: LEV,
sulthiame, VPA, CBZ, and OXC (atypical evolutions in some patients?)
Panayiotopoulos Syndrome No treatment if few seizures and well tolerated
If treatment needed: same than BECTs
Rectal diazepam for prolonged seizures
Electrical status epilepticus during Steroids, high dose BZDs (CLB), LEV, VPA, ETX, LTG, sulthiame, ketogenic diet,
slow sleep (ESES) and surgery
Genetic generalized epilepsies VPA, LEV, LTG, TPM, ZNS, and PER
Women of childbearing age: LEV, LTG (may aggravate myoclonic seizures)
Nocturnal frontal and other focal CBZ, OXC, TPM, ZNS, LCM, nicotinic patches (ADFLE)
epilepsies If drug resistant, consider presurgical evaluation
VGB vigabatrine, VPA valproate, LEV levetiracetam, CBZ carbamacepine, OXC oxcarbamacepine, LTG lamotrigine, TPM topiramate, ZNS zonisamide,
PER perampanel, BZD benzodiacepines, ETX ethosuximide, CLB clobazam, LCM lacosamide, GTCS generalized tonic-clonic seizures, ADFLE
autosomal dominant frontal lobe epilepsy

and so it should not be used to take treatment decisions. Antiepileptic drugs

may be considered in case of frequent seizures, occasional generalization, or
extreme family anxiety. During many years, carbamazepine has been the drug
of choice in rolandic epilepsy. Another option is oxcarbazepine (93). Valproate
may be used in the minority of patients (around 10–20 %) who fail carba-
mazepine (94). There have been some reports associating carbamazepine to
atypical negative evolutions, increasing the frequency of epileptiform dis-
charges and producing temporary cognitive symptoms, although evidence is
inconclusive (95–97). Sulthiame has been reported to be effective (98), even
more than carbamazepine (99), decreasing epileptiform activity and improving
cognition (100).
Levetiracetam monotherapy is also effective and well tolerated in patients
with rolandic epilepsy who need treatment, (101). It seems to be as efficacious
as valproic acid to control seizures (102•).

Continuous spike and wave during sleep (ESES)

In this pediatric syndrome with epileptic discharges highly activated by sleep,
treatment is directed to reduce epileptiform discharges during sleep, as this may
translate into cognitive improvement. However, there is no standard regimen
and different combinations are used in different centers, as no controlled
clinical trials have been conducted to establish the efficacy of various AEDs. For
this reason, evidence to guide therapeutic decisions is only class III (open-label
uncontrolled trials) or class IV (case reports or expert opinion).
High dose benzodiazepines (usually clobazam) and corticosteroids have
been used to diminish EEG abnormalities and improve cognition and behavior,
which has been shown to be associated with the duration of ESES (103).
Drowsiness associated to benzodiazepines may limit their usefulness in this
Curr Treat Options Neurol (2016)8:3 Page 9 of 17 23

particular syndrome. Corticosteroids are reserved for drug-resistant cases asso-

ciated to cognitive regression because of the side effect profile. In a series of 44
patients with ESES treated with oral hydrocortisone (initial dose 5 mg/kg/day in
the first month) with a progressive weaning and a total duration of corticoste-
roid treatment of 21 months, 75 % of patients responded in the first 3 months
but only 45 % were long-term responders (104). High dose valproate (associ-
ated to ethosuximide in those patients initially not responding) has been
reported to improve EEG pattern in more than 50 % of patients (105). Other
possible alternative treatments are sulthiame and lamotrigine.
Of the new drugs, add on therapy with levetiracetam has been shown to
improve EEG or cognition in more than 50 % of the patients, although some of
the initial responders may later relapse. A better response has been described in
those patients with ESES and underlying structural lesions (106, 107). Another
options for patients who are resistant to conventional AEDs and corticosteroids
is the ketogenic diet, which may cause some improvement in the EEG in a
minority of patients (108).
Multiple subpial transections, a surgical procedure which is sometimes
performed to treat language regression in Landau-Kleffner syndrome, may have
some positive effect over cognition and behavior in patients with ESES.
(109••). If the patient displays a clear-cut lesion in the MRI and the presurgical
evaluation is concordant, other surgical procedures such as hemispherectomy
or focal resections may be considered.
A recent study performed a pooled analysis of 112 articles including 950
treatments in 575 patients (110). Antiepileptic drugs were associated with
improvement (i.e., cognition or decrease of EEG discharges) in 49 % of
patients, benzodiazepines in 68 %, and steroids (n = 166) in 81 %. Surgery
resulted in improvement in 90 % of patients. In a subgroup analysis of
patients who were consecutively reported, the authors found improvement
in a smaller proportion treated with AEDs (34 %), benzodiazepines (59 %),
and steroids (75 %), whereas the improvement percentage after surgery was
preserved (93 %). Possible predictors of improved outcome were treatment
category, normal development before ESES onset, and the absence of
structural abnormalities (110).

Lennox-Gastaut syndrome
Tonic seizures during sleep which are a hallmark of Lennox-Gastaut syndrome
and occur in over 90 % of patients. Tonic status during sleep is a very difficult to
treat severe complication of this syndrome, and sometimes it is the result of
treating other seizure types with high doses of intravenous benzodiazepines
(111, 112).

Genetic generalized epilepsies

In general, seizures in idiopathic or genetic generalized epilepsies occur on
awakening. In particular, the syndromes of juvenile myoclonic epilepsy and
epilepsy with generalized tonic-clonic seizures (GTC) on awakening. Seizures
occur more frequently after nights of sleep deprivation and alcohol intake. As
these types of syndromes are seen preferentially in young patients, it is man-
datory to stress the importance of therapeutic compliance, to recommend
lifestyle with regular wake-sleep rhythm and to avoid sudden awakenings.
23 Page 10 of 17 Curr Treat Options Neurol (2016)8:3

Valproic acid is still the most effective drug against the different types of
seizures seen in idiopathic generalized epilepsies. However, careful assessment
of risk-benefit ratio is required when valproate is prescribed to women of
childbearing age, given its teratogenic potential and the negative impact on
the psychosocial development of children exposed in utero to this drug
(113••).
Other drugs that may be used in this population are lamotrigine (may
exacerbate myoclonus in some patients) (114), topiramate (effective in GTC
seizures) (115), levetiracetam (effective in myoclonic and GTC seizures) (116,
117), zonisamide (evidence in absences, myoclonus, and GTC shown in small
open series only) (118), and perampanel (efficacy in GTC) (119, 120•).
Some antiepileptic drugs should not be used in these types of epilepsy
because they either do not work or exacerbate seizure types other than GTC
seizures, that is, absence and myoclonic seizures. These include carbamazepine,
oxcarbazepine, phenytoin, gabapentin, and tiagabine (119).
Pharmacokinetics of the drug may be used to adjust the time of maximum
expected concentration to the habitual time of seizure occurrence. Extended-
release formulations may be used to delay time of maximum serum concen-
tration of the drug. An occasional extra dose of a benzodiazepine can be used at
bedtime if the patient has been sleep-deprived.
Only a minority of patients with idiopathic or genetic generalized epilepsy
will present with generalized tonic-clonic seizures restricted exclusively to sleep.
In these cases a frontal origin of the seizures should be ruled out.

Frontal and other focal sleep epilepsies

Antiepileptic drugs
The majority of pure sleep epilepsies are focal epilepsies (121), frequently non-
lesional and often with a relatively benign outcome and good response to
antiepileptic drugs. Focal seizures occurring mainly during sleep are usually
frontal in origin, although other seizure onset zones may be possible. Nocturnal
temporal lobe epilepsy is uncommon.
Treatment should be done with drugs which are effective in focal epilepsies.
Carbamazepine, oxcarbazepine, and topiramate are useful drugs in patients
with frontal and other focal sleep epilepsies (51, 122–125).
Specific treatments such as acetazolamide can be used in the 30 % of patients
with the genetic autosomal dominant frontal lobe epilepsy who do not respond
to carbamazepine (52).
Some studies have shown potential usefulness of nicotine patches in some
patients (126). Among new antiepileptic drugs, lacosamide seems to be also
efficacious in patients with focal epilepsy and nocturnal seizures, with up to 65 %
of patients with nocturnal drug-resistant seizures experiencing more than 50 % of
seizure reduction in a retrospective study (127).

Surgical treatment of focal sleep-related epilepsy

Focal sleep epilepsy may be drug resistant. When the patient has failed two trials
of appropriately given AEDs, he is considered to have drug-resistant epilepsy
and surgical options should be considered taking into account the individual
features of the epilepsy and the patient.
Curr Treat Options Neurol (2016)8:3 Page 11 of 17 23

In a recent study (128•), the outcome of 95 patients with refractory sleep

epilepsy who underwent presurgical evaluation and focal resection was
analyzed. Most patients (61 %) had frontal lobe epilepsy, as expected, but
up to 39 % underwent extrafrontal resection because of presumed seizure
onset outside the frontal lobes. Most patients (almost 80 %) had a lesion in
the MRI and the majority required invasive studies. 76 % of the patients,
after a mean follow up of 82 months, were seizure free. Positive MRI
findings, no need for invasive monitoring, complete removal of the epi-
leptogenic zone, and cortical dysplasia type II in the pathology were asso-
ciated with a good outcome. Cortical dysplasia type I was associated with
seizure recurrence. The authors concluded that drug-resistant focal sleep
epilepsy is cured with surgery in up to two thirds of cases including those
not arising from the frontal lobe (128•).
Chronopharmacology in sleep epilepsies
Basic principles of chronopharmacology can be applied to treatment of
sleep-related epilepsy. In a pilot trial (129), 18 patients with nocturnal or
early-morning seizures refractory to conventional AED therapy were pro-
spectively enrolled in a differential dosing trial. Patients were treated with
a schedule in which the evening dose was twice the morning dose,
keeping the total dose of medication constant. Of the 18 patients treated
by this dosing strategy, 11 patients became seizure free following a mean
follow up time of 5.3 months, and 4 patients had a 75–90 % reduction
of seizures. This study suggested that chronotherapy can provide im-
proved seizure control compared with conventional therapy in selected
patients.
If seizures tend to occur during the transition from wakefulness to
sleep, immediate release formulations can be more effective than
extended-release ones, who would be more efficacious in seizures hap-
pening later at night or during sleep-wakefulness transition.

Treatment of factors that may worsen sleep-related epilepsy

Several studies have shown that OSA treatment with CPAP decreases
interictal epileptiform activity and improves seizure control (130–132).
Surgical treatment of OSA in children is also associated with decrease in
seizure frequency, especially in those with elevated body mass index
scores and younger age at time of surgery (133•). Based on these
findings, some authors propose the implementation of OSA screening in
adult epilepsy clinics, especially in patients with poor seizure control
(66•, 134).
Insomnia is frequent in adults with epilepsy, being present in up to
40–55 % of patients (135, 136). It is correlated with number of AEDs
and higher scores on depression scales. In patients with epilepsy and
insomnia, melatonin can be used. However, its effect on seizure fre-
quency is unclear. One study reported improvement in seizure frequency
(137•), while other randomized placebo-controlled studies reported
better sleep but no change in interictal epileptiform discharges or seizure
23 Page 12 of 17 Curr Treat Options Neurol (2016)8:3

frequency (138•). More research will be needed to evaluate the efficacy

of melatonin for epilepsy.

Effect of epilepsy treatments on sleep

A different range of effects of antiepileptic drugs on sleep architecture have been
described, including reduced sleep onset latency (phenobarbital, phenytoin,
gabapentin), reduced arousals from sleep (phenobarbital, gabapentin), in-
crease in slow-wave sleep (pregabalin, carbamazepine, and gabapentin), de-
crease in slow-wave sleep (levetiracetam, ethosuximide), and increase
(ethosuximide, gabapentin) or decrease (phenobarbital, phenytoin) in REM
sleep (139, 140). Several non-pharmacological epilepsy treatments for drug-
resistant epilepsy (ketogenic diet, successful epilepsy surgery, and vagal nerve
stimulator) have been reported to improve sleep quality. However it is unclear
how much of this effect is due to improvement in seizure frequency.
Some epilepsy treatments, however, may have a negative impact on sleep
disorders. In some patients, vagal nerve stimulator may worsen OSA (141). This
complication can be treated with changes in the operational parameters of the
device or with the use of CPAP.

Compliance with Ethical Standards

Conflict of Interest
Santiago Fernández declares no conflict of interest.
Mar Carreño reports grants and personal fees from UCB Pharma and Eisai and personal fees from Esteve and Bial
Pharmaceutical.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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