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Thinking About Sleep in Epilepsy Trials:
Interrelationships, Pitfalls, and Novel
Opportunities
Beth A. Malow, MD, MS
Associate Professor of Neurology and
Medical Director,
Vanderbilt Sleep Disorders Center
Director, Vanderbilt Sleep Research Core
No conflict of interest. Will be discussing unlabeled
use of commercial products.
Presentation Goals
• Identify the causes of disordered sleep in
patients with epilepsy (e.g., sleep apnea)
• Highlight the importance of these causes in
designing therapeutic trials
• Discuss indications and options for measuring
sleep and sleepiness in clinical studies
• Characterize the effects of antiepileptic
drugs on sleep, and their use in patients with
and without epilepsy
• Present preliminary data from an NINDS pilot
trial on the impact of treating obstructive
sleep apnea in epilepsy
Impact of Sleep on Epilepsy
• Sleep disruption/deprivation, either voluntary or
involuntary, contribute to impaired daytime
functioning and overall health in many individuals.
• Patients with epilepsy may be more likely to have
disturbed sleep.
• In addition, sleep disruption/deprivation may
affect seizure control, or a patient’s ability to
tolerate antiepileptic drugs. Daytime alertness
and vigilance may also be affected.
Epilepsy Affects Sleep Organization
• On seizure free nights, sleep organization was
affected in 80 epilepsy patients as compared to
17 normal controls
Decreased sleep efficiency
(time asleep/time in bed)
Increase in sleep stage shifts
Increase in number and duration of awakenings
• These parameters were most affected in
untreated, newly diagnosed patients
• Treatment with carbamazepine for 1 month
improved these parameters
Touchon J et al. Sleep organization and epilepsy. In Degen R and Rodin EA,
Epilepsy, Sleep, and Sleep Deprivation, 1991.
Epilepsy Affects Sleep Organization
• Temporal lobe epilepsy disrupts sleep organization
more than frontal lobe epilepsy and idiopathic
generalized epilepsy, even in the absence of
seizures
Touchon J et al. Sleep organization and epilepsy. In Degen R and Rodin EA,
Epilepsy, Sleep, and Sleep Deprivation, 1991. Crespel A et al., Epilepsia
1998;39:150-157. Montplaisir J et al., J Clin Neurophysiol 1987;4:383-388.
• Seizures themselves have profound effects on
sleep architecture, even apart from the resulting
arousals and awakenings
Adverse Effects of Antiepileptic Drugs
Somnolence
51/144 (35%)
Gingival Hyperplasia
34/144 (24%)
Nystagmus
23/144 (16%)
Ataxia
16/144 (11%)
Irritability
10/144 (7%)
Vertigo
10/144 (7%)
AEs were patient-reported and AEDs included PHT, PB, CBZ, VPA
Beghi E et al, Epilepsia 27(4):323-330, 1986.
Antiepileptic Drugs (AEDs) and Sleep
• Are AEDs that reduce sleep stage shifts, arousals,
and awakenings “better” than those that do not?
• Might these effects translate into improved daytime
alertness, health-related quality of life, or even
reduced seizure frequency?
• Does improving (or not suppressing) REM or slow
wave sleep affect cognition?
• Do these questions transcend the field of epilepsy
(e.g., individuals without epilepsy desiring sleep aids)?
Antiepileptic Drugs (AEDs) and Sleep
• Pregabalin received FDA approval for treating for neuropathic
pain (and as adjunctive treatment for partial seizures in adults)
• In one study presented in abstract form, with data drawn from
13 randomized controlled studies of chronic pain syndromes,
pregabalin significantly improved sleep components on the
Medical Outcomes Study (MOS) Sleep Scale
Freeman R et al, Abstract P04.010, AAN 2006 Meeting, San Diego
• Although not approved for this indication, sleep specialists
commonly use pregabalin or gabapentin off-label for treating
sleep in pain syndromes, including fibromyalgia
• We also commonly use pregabalin or gabapentin off-label as a
sleep aid, in patients with and without epilepsy
Antiepileptic Drugs (AEDs) and Sleep
• Topiramate has received FDA approval for the prophylaxis of
migraine headaches (and for treatment of seizures)
• Topiramate may also be effective in treating sleep-related
eating disorder or night eating syndrome
Winkelman JW et al, 2003, Sleep Med 4:243-6.
• How about considering topiramate for treating obese patients
with insomnia, who also have migraine?
• What about trying topiramate for insomnia in obese patients,
even if they don’t have migraine?
• What constitutes obesity? What constitutes insomnia?
Obstructive Sleep Apnea
 One of the most common sleep disorders, with as
many as 24% of men and 9% of women in the
general population affected (4% of men and 2% of
women with daytime sleepiness)1
 93% of women and 82% of men with moderate to
severe sleep apnea are undiagnosed2
 Sleep apnea is a risk factor for a myriad of
medical conditions, including hypertension, heart
disease, stroke, and impaired glucose tolerance
 Sleep apnea also contributes to daytime sleepiness
and impairs health-related quality of life
 Treated with continuous positive airway pressure
(CPAP), which splints airway open
1Young
T, et al, NEJM 1993; 328:1230-5. 2Young T et al, SLEEP 1997;20:705-706.
Epilepsy and OSA: Prior Studies
Sleep apnea may coexist with epilepsy; its treatment may improve
seizure control, daytime sleepiness, or both
 Tracheostomy diminished generalized seizures in 1 patient1
 CPAP or other therapy improved seizure control and daytime
alertness in 6 of 7 patients with partial seizures2
 CPAP or positional therapy improved seizure control in
7 of 10 patients with seizures and OSA; 3 had antiepileptic
medications optimized3
 CPAP improved seizure control or daytime sleepiness
in 7 of 9 adults.4 Prospective study showed 45% reduction in
seizure frequency in 3 adults and 1 child treated with CPAP.5
1. Wyler AR, Weymuller EA Jr. Ann Neurol. 1981;9(4):403-404. 2. Devinsky O, et al. Neurology.
1994;44(11):2060-2064. 3. Vaughn BV, et al. Seizure. 1996;5(1):73-78. 4. Malow BA, et al. Sleep.
1997;20(12):1105-1110. 5. Malow BA, et al. Sleep Medicine. 2003;4:209-215.
How Might OSA Facilitate Seizures?
Proposed mechanisms include:
 Sleep deprivation resulting from frequent arousals from
sleep, increasing neuronal excitability
 Frequent arousals or stage shifts into and out of sleep,
facilitating sleep-related seizures
 Cytokines? (increased by sleep apnea, facilitators of
seizures)
 Apneas and hypopneas causing seizures
 Episodes of hypoxemia
Less Likely
 Decreased cardiac output/arrhythmias
Is OSA More Common in Patients with
Epilepsy?
 One third of 39 epilepsy surgery candidates
had OSA (AHI >5) and 13% had AHIs >201
 60% of intractable epilepsy patients (>4 seizures/
month) had AHIs of 5 or greater, and 36% had AHIs
of 10 or greater2
 Possible reasons OSA may be more common:
 Sedentary lifestyles?
 Weight gain from antiepileptic drugs (AEDs)?
 Effects of AEDs on the upper airway?
1. Malow BA, et al. Neurology. 2000;55(7):1002-1007.
2. Vaughn BV, D'Cruz OF. Epilepsia. 2002;42(suppl 7):43.
Presentation Goals
• Identify the causes of disordered sleep in
patients with epilepsy (e.g., sleep apnea)
• Highlight the importance of these causes in
designing therapeutic trials
• Characterize the effects of antiepileptic drugs
on sleep, and their use in patients with and
without epilepsy
• Discuss indications and options for measuring
sleep and sleepiness in therapeutic trials
• Present preliminary data from an NINDS pilot
trial on the impact of treating obstructive sleep
apnea in epilepsy
Measuring Sleep and Related Variables in
Therapeutic Trials: Indications and Options
Indications include:
 Screening for sleep disorders in patients with
epilepsy being recruited for clinical trials to exclude
or at least take these disorders into account in
analyses
 Measuring the impact of AEDs and other therapies
on sleep and daytime alertness
Options range from questionnaires, to sleep
diaries, to actigraphy, to polysomnography and
daytime sleep studies.
Measuring Sleep and Related Variables in
Therapeutic Trials
• Screening for sleep disorders in patients with epilepsy
being recruited for clinical trials
• Is polysomnography necessary?
• Are questionnaires sufficient?
• What constitutes a sleep disorder?
• In the non-epilepsy population without medical illnesses,
loud snoring and daytime sleepiness are highly
predictive of OSA
• Screening for OSA in patients with epilepsy may be
more challenging. Patient may lack a bedpartner,
seizures may be paramount concern, and daytime
sleepiness may be due to seizures or AEDs
Can we effectively screen patients with
epilepsy for OSA (without PSGs)?
• We validated a 12-item scale developed for general
population, the Sleep Apnea scale of the Sleep
Disorders Questionnaire (SA-SDQ) in 125 patients with
epilepsy undergoing PSG.1
SA-SDQ asks questions about age, body mass index,
gender, presence of hypertension, loud snoring,
witnessed apnea, and other parameters.
• Positive predictive value: 0.75 in men and 0.8 in women
Negative predictive value: 0.65 in men and 0.67 in women
1Weatherwax,
KJ, et al. Sleep Medicine 2003;4: 517-521.
• Other screening questionnaires have shown similar
results. Adding a sleep evaluation may also help.
Measuring Daytime Alertness
• Several sleepiness scales exist, including the Epworth
Sleepiness Scale
• The Epworth Sleepiness Scale asks questions about how
likely the individual is to doze in a variety of situations (eg.,
watching TV; sitting and talking to someone)
• The Multiple Sleep Latency Test (MSLT) provides for
several naps, spaced out throughout the day, and measures
sleep latency and REM latency using sleep recordings.
• The Maintenance of Wakefulness Test (MWT) is similar to
the MSLT but instructs the individual to stay awake, rather
than fall asleep.
• A variety of psychomotor vigilance tasks exist as well
• Subjective and objective tests may not correlate and are
viewed by some as complementary
NINDS Pilot Clinical Trial
We carried out an NINDS-supported pilot
clinical trial to work out critical design issues
prior to embarking on a definitive Phase III
Randomized Clinical Trial that will answer the
question:
Does treatment of coexisting obstructive sleep
apnea in epilepsy patients improve seizure
frequency, daytime sleepiness, and healthrelated quality of life?
Sites: Vanderbilt, Michigan, Cleveland Clinic, UNC-Chapel Hill
Aim 1: Can we effectively identify patients
with epilepsy who have OSA prior to PSG?
 Of 43 patients with epilepsy meeting inclusion
criteria for likely OSA (by SA-SDQ score and
clinical impression), 35 had OSA on
polysomnography, defined by an apnea-hypopnea
index of 5 or greater.
 This translates into an 81% true positive rate or
only one in 5 screen failures
 As we only tested patients with suspected OSA,
the proportion of patients with epilepsy and OSA
who we missed in the screening is unknown
Aim 2: Is more than one night of PSG
needed to determine if an epilepsy patient
has OSA?
 Sleep research is affected by a first night effect, with
the first night of sleep in a laboratory affected by the
novelty of the laboratory, wires, etc.
 We compared night 1 and 2 of PSG in our cohort
 Other than decreased total sleep time and REM sleep on
night 1, sleep parameters, including sleep latency,
efficiency, stages, arousals, AHI and oxygen desaturation
were comparable.
 Using our AHI inclusion criterion of 5 or greater, the
first PSG identified all but one patient with OSA – night
1, AHI 3.0, night 2, 5.8.
 One night of PSG should be sufficient for diagnosing OSA
in patients with epilepsy
Aim 3: Will subjects use CPAP?
 Differences in CPAP adherence in the therapeutic and
sham CPAP groups were not statistically significant
 Percent of nights with CPAP device usage for our
sample as a whole was 71.8%, with the average number
of hours of CPAP usage per night on nights used being
4.4 hours.
 Older subjects (ages 45 or older) used their CPAP for a
greater number of hours/night than younger subjects
(5.4 hours vs. 3.4 hours; p=0.01).
 Subjects, Coordinators, and Principal Investigators
could not tell whether therapeutic or sham CPAP was
used (kappa values < 0.4)
What are important outcome measures
for patients with epilepsy and OSA?
 Is seizure frequency the most important outcome?
 Other outcome measures to consider are:
Daytime sleepiness
Insomnia
Health-related quality of life
Ability to tolerate AEDs if OSA treated
Improvement in obesity
Minimizing cardiovascular/cerebrovascular
consequences of OSA, especially in older adults
with epilepsy
What would a definitive trial of
treating OSA in epilepsy accomplish?
Heighten the awareness of identifying and treating OSA
in epilepsy among practitioners, in that the vast
majority of patients with OSA are still not diagnosed
and treated, even by neurologists
 Epilepsy patients may be more at risk for OSA, and
have more to gain from treatment
 Epilepsy patients tend to put seizures in the
forefront, and may not be attuned to possibility that
OSA may be contributing to daytime sleepiness, AED
intolerance, and impaired quality of life
 Patients with epilepsy may be more likely to use their
CPAP than those in the general population if they
perceive a benefit in seizures or daytime sleepiness
Conclusions
• Sleep is disturbed in patients with epilepsy due to a
variety of causes, including seizures, AEDs, and
sleep disorders
• Various options exist for measuring sleep and
related parameters in patients with epilepsy,
although further research will be needed to
determine optimal use of these measurement tools
• In designing therapeutic trials in epilepsy,
consideration of sleep disturbances presents
challenges, but also opportunities to improve
seizure control and other aspects of quality of life