- Email: [email protected]
Epilepsy and Sleep-Related Breathing Disturbances
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Epilepsy and Sleep-Related Breathing Disturbances
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Thapanee Somboon, MD; Madeleine M. Grigg-Damberger, MD; and Nancy Foldvary-Schaefer, DO
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Epilepsy is the fourth most common neurologic disorder in the United States, affecting over 2.2
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million people. Epilepsy is associated with a number of medical and psychiatric comorbidities,
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higher health-care utilization and cost, and substantial economic burden. OSA is twofold more
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common in adults with epilepsy than in age-matched control subjects, and the incidence in-
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creases with age. Self-reported daytime sleepiness is not helpful in predicting OSA, possibly
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related to the ceiling effect of general sleepiness among people with epilepsy from diverse
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causes. Mostly small retrospective series found a significant reduction in seizures in people with
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epilepsy and OSA adherent with positive airway pressure therapy compared with untreated
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individuals. This finding illustrates the potential beneficial effects of sleep therapies on epilepsy.
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Central apnea, oxygen desaturations, and hypercapnia can occur during the ictal and imme-
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diate postictal period, especially with generalized tonic-clonic seizures. Central apneas have
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been produced by electrical stimulation of mesial temporal structures. These respiratory dis-
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turbances suggest activation of the central autonomic network and may contribute to sudden
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unexpected death in epilepsy (SUDEP), the leading cause of epilepsy-related death in people
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with drug-resistant epilepsy. SUDEP typically occurs during sleep, and patients are more often
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found in a prone position and have a history of nocturnal seizures. Whether OSA contributes to
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SUDEP is unknown. Vagus nerve stimulation is a form of neuromodulation for drug-resistant
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focal epilepsy. When the device activates during sleep it causes reduction in airflow and res-
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piratory effort, airflow obstruction, and oxygen desaturations, sometimes producing a clinical
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sleep apnea syndrome. The goal of this review is to discuss firmly established and recently
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recognized clinical, neurobiologic, electrophysiologic, and polysomnographic relationships be-
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tween sleep-disordered breathing and epilepsy.
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KEY WORDS:
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epilepsy; sleep-disordered breathing; sudden death
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Epilepsy is the fourth most common chronic neurologic disease, affecting more than 65 million people worldwide and accounting for 0.6% of the global burden of disease.1-3 Ten percent of people will experience a seizure
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(one-third of them febrile seizures), and one in 26 will develop epilepsy over their lifetime.2 Epilepsy is most common in adults over 75 years of age and children under 5 years of age.1,2 Seizures are resistant to
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ABBREVIATIONS:
AED = antiepileptic drug; AHI = apnea-hypopnea index; GTC = generalized tonic-clonic; ILAE = International League Against Epilepsy; PetCO2 = end-tidal partial pressure of carbon dioxide; PSG = polysomnography; PWE = people with epilepsy; SpO2 = oxygen saturation as determined by pulse oximetry; SSRI = selective serotonin reuptake inhibitor; SUDEP = sudden unexpected death in epilepsy; vEEG = video EEG; VNS = vagus nerve stimulation AFFILIATIONS: From the Cleveland Clinic Sleep Disorders Center (Drs Somboon and Foldvary-Schaefer), Cleveland, OH; the Epilepsy Unit (Dr Somboon), Neurological Department, Prasat Neurological
Institute, Bangkok, Thailand; and the Department of Neurology (Dr Grigg-Damberger), University of New Mexico, Albuquerque, NM. Q3 CORRESPONDENCE TO: Nancy Foldvary-Schaefer, DO, Cleveland Clinic Sleep Disorders Center, 9500 Euclid Ave, S73, Cleveland, OH 44195; e-mail: [email protected] Q4 Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.01.016
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antiepileptic drugs (AEDs) in one-third of people with epilepsy (PWE). Many PWE suffer from the stress of living with a chronic unpredictable disease made worse by social stigma, discrimination, and loss of autonomy.3
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An epileptic seizure is defined by the International League Against Epilepsy (ILAE) as a transient occurrence of signs and/or symptoms due to abnormal, excessive, and synchronous neuronal activity in the brain.4,5 Epilepsy is an enduring predisposition of the brain to generate epileptic seizures with neurobiologic, cognitive, psychological, and/or social consequences.4 Because conceptual definitions for seizures and epilepsy can be difficult to apply in clinical practice, the ILAE has published practical operational definitions and classifications for seizures and epilepsy types.4-8 The ILAE now defines epilepsy as: (1) $ two unprovoked seizures > 24 h apart; or (2) one unprovoked seizure and a $ 60% probability of further seizures over 10 years compared with the general population; or (3) diagnosis of a distinctive epilepsy syndrome.5 Figure 1 summarizes the framework of the 2017 ILAE classification.
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Active epilepsy is associated with higher health-care utilization and cost as well as substantial economic burden for health systems, individuals, and their families.9 Inpatient health-care costs are 2.4 and 2.6 times greater for prevalent and incident epilepsy, respectively, compared with age-matched control subjects.10 A 2009 study reported a mean of $4,523 higher annual health-care expenses for PWE, with a national impact of $9.6 billion.11
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Sleep-related breathing disorders are highly prevalent. According to the Wisconsin Sleep Cohort, approximately 13% of men and 6% of women have moderate-to-severe sleep apnea, and 14% of men and 5% of women have an apnea-hypopnea index (AHI) on polysomnography (PSG) of at least 5 with daytime sleepiness.12 These estimates have grown substantially over the last two decades, largely due to the rising obesity epidemic.13 Obesity and craniofacial and upper airway abnormalities are the most important risk factors.14 Intermittent hypoxia, sympathetic activity, cortical arousal, and sleep fragmentation caused by recurrent upper airway obstruction lead to a number of
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Seizure type
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Focal onset
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Generalized onset
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Unknown onset
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Aware
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Unaware
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Motor -Tonic-clonic -Other motor
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Non motor -Absence
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Etiology
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Focal to bilateral tonic-clonic
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Unclassified
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Infectious
Epilepsy type
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Metabolic
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Focal
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Generalized
Combined generalized & focal
Unknown
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comorbidities
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Structural
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Genetic
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Immune
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Unknown
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Epilepsy syndrome Figure 1 – Operational definitions for seizure types use key symptoms and signs of seizures (called seizure semiology) and first categorize seizures as focal, generalized, or unknown.6,7 Focal seizures engage neuronal networks within one hemisphere at onset. If awareness is retained throughout a focal seizure it is called a focal onset with retained awareness (formerly called a simple partial seizure). If awareness is impaired during any part of a focal seizure, it is called a focal impaired awareness seizure (former terms dyscognitive or complex partial seizure now discarded). Generalized onset seizures originate at some point within and rapidly engage bilaterally distributed networks. Seizures in which onset is uncertain are termed seizures of unknown onset until the nature of their onset is known. Epilepsies are first classified on the basis of seizure type(s), and then classified as to whether they have a focal, generalized, combined, or unknown epilepsy type.8 If sufficient data are available, an epilepsy syndrome diagnosis is made. An epilepsy syndrome is a cluster of clinical characteristics (such as typical age at onset, seizure types, EEG and neuroimaging findings, seizure triggers, diurnal variation, and sometimes prognosis).8 Identifying the epilepsy syndrome often provides information on etiology, parts of the brain involved, genetic predispositions, and risk for sudden unexpected death in epilepsy, and guides medical therapy.8 (Adapted with permission from Fisher et al.7)
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long-term consequences including cardiovascular events and metabolic disorders.15
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High Prevalence of Medical Comorbidities in Adults With Active Epilepsy Several large studies using population-based cohorts and administrative databases in the United States, United Kingdom, Canada, and Scotland have consistently shown a higher prevalence of certain medical disorders in PWE compared with those without epilepsy.16-19 A population-based, cross-sectional study involving 1.5 million people $ 14 years of age in Scotland found that 70% of PWE had $ one comorbid medical condition and 19% had $ four, compared with 47% and 9% of people without epilepsy, respectively.16 Two validated health surveys representing 98% of the Canadian population found prevalence rates two to four times higher for gastrointestinal ulcers, stroke, urinary incontinence, inflammatory bowel disorders, migraine, Alzheimer’s disease, and chronic fatigue in PWE compared with the general population.18 Chest specialists may be unaware that the prevalence of COPD, asthma, and emphysema was found to be 1.9- to 2.9-fold, 1.1- to 1.4-fold, and 1.3-fold higher, respectively, in PWE than in the general population in studies of large community-dwelling populations.16,18,20,21 Cardiovascular comorbidities are common in epilepsy, the subject of a comprehensive review.22 Arrhythmias are induced by seizures and also result from a shared genetic susceptibility. Sinus tachycardia is observed in 80% of all seizures and is usually asymptomatic.23 Ictal asystole was found in 0.3% of patients with drugresistant epilepsy undergoing video EEG (vEEG), typically in temporal lobe seizures.24 Seizure-induced arrhythmias are likely due to direct stimulation of the central autonomic network or an indirect effect of catecholamine release evoking a vasovagal reflex.24 Sodium channel-blocking AEDs are associated with arrhythmias or conduction abnormalities including atrioventricular conduction delays, ST changes, Brugada-like patterns, atrial fibrillation, and QTc prolongation.22 Several genetic ion channel mutations in epilepsy are associated with cardiac phenotypes. For instance, mutations of the sodium channel gene SCN5A and potassium channel gene KCNQ1/KCNQ2 cause long QT syndrome and epilepsy, affecting 1:2,000 in the general population.25 Epidemiologic studies have consistently demonstrated that PWE have a higher
prevalence of structural cardiac disease than nonepilepsy populations, contributing to increased mortality.22 Some comorbid relationships with epilepsy are likely to be causative (eg, cerebrovascular disease contributes to about 10% of incident epilepsies).26 Others could result from epilepsy (such as aspiration pneumonia and seizurerelated skeletal fractures).27 Still others relate to genetic predisposition (such as an increased risk for epilepsy after traumatic brain injury in carriers of apolipoprotein E [APOE] ε4).28 Some may be shared risk factors (such as Q7 the higher prevalence of migraine in PWE due to excessive cortical hyperexcitability or the presence of anti-glutamic acid decarboxylase antibodies in 80% of individuals with diabetes mellitus type 1 and 6% of PWE).29 Several longitudinal studies report bidirectional relationships between epilepsy and autism spectrum disorder, migraine, stroke, dementia, depression, anxiety, psychosis, and schizophrenia.27 Experimental studies are needed to better elucidate these relationships.
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Sleep-Related Breathing Disorders Are Common in Adults With Epilepsy
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OSA is twofold more common in adults with epilepsy than in age-matched control subjects, and the incidence increases with age.30-36 Table 1 summarizes studies examining the prevalence of sleep-related breathing disorders in epilepsy populations.30,32,37-40 The largest cross-sectional study exploring the prevalence and predictors of OSA in epilepsy, using PSG, found OSA (AHI $ 10) in 30% of 130 consecutive adult patients presenting for new evaluations and unselected for sleep disorder symptoms or epilepsy severity.32 Sixteen percent had moderate-to-severe disease (AHI $ 15), rates that exceed general population estimates. OSA predictors in multivariate modeling were age, dental problems, and standardized AED dose, a measure of drug burden, but not seizure frequency. Male sex, age > 50 years, obesity, hypertension, and dental problems were associated with higher AHI. A history of epilepsy surgery appeared protective as only 1 of 17 operated patients had an AHI $ 10. Self-reported excessive daytime sleepiness and Epworth Sleepiness Scale scores were not helpful in predicting OSA, possibly related to the ceiling effect of general sleepiness among PWE from diverse causes. A meta-analysis found the prevalence of OSA in PWE to be 33% (95% CI, 20.8%-46.1%), 2.4-fold greater than in control subjects (OR, 2.36; 95% CI, 1.334.18) and three times more likely in men with epilepsy than in women (OR, 3.00; 95% CI, 2.25-3.99).31
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TABLE 1
] Prevalence of OSA in Adults With Epilepsy
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Study/Year Malow et al /2000
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Retrospective uncontrolled
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Prospective uncontrolled
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RDI $ 5
Uncontrolled, 6 (40%)
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AHI $ 5a,b
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Focal, 97 (75%); generalized, 27 (21%); unknown, 6 (5%)
Seizure-free, 34 (26%)
AHI $ 10a,c
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Prospective uncontrolled
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NR
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AHI $ 5a,c
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Prospective uncontrolled
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AHI ¼ apnea-hypopnea index; NR ¼ not reported; RDI ¼ respiratory disturbance index. a Apnea defined by a decrease in airflow or effort to 20% or less of baseline for $ 10 s. b Hypopnea defined as any reduction in airflow from baseline accompanied with either a $ 4% reduction in oxygen or arousal. c Hypopnea defined as $ 50% reduction in airflow from baseline accompanied with either a $ 3% reduction in oxygen saturation or arousal.
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While a relationship between OSA and seizure control has not been firmly established, some studies found this to be the case. In a cross-sectional study of adults over 50 years of age presenting to a tertiary care epilepsy clinic, excluding those with prior OSA diagnosis, lateonset or worsening epilepsy was associated with higher AHI and Epworth Sleepiness Scale score (more severe daytime sleepiness) compared with those who were seizure free or with improved seizure control.34 In retrospective PSG review of adults (median age, 56 years) with OSA and epilepsy, the onset of OSA symptoms coincided with the first episode of status epilepticus or a clear increase in seizure frequency in 21 of 29 cases (72.4%).35 A population-based cohort study using the National Health Insurance Research Database of Taiwan found the adjusted hazard ratio for OSA to be 1.50 and increasing with age in 138,507 adults with epilepsy compared with an equal number of control subjects.36
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OSA
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Temporal lobe epilepsy, 39 (100%)
OSA Diagnostic Criteria
Focal, 12 (92%); generalized, 1 (8%)
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Impact of Treating Sleep-Related Breathing Disorders in Adults With Epilepsy Improved seizure control with continuous positive airway pressure (CPAP) therapy for OSA was found in several small studies. A randomized, controlled trial exploring the feasibility of CPAP therapy in 35 adults with drug-resistant epilepsy found that seizures were
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reduced by $ 50% in 28% of patients receiving therapeutic CPAP vs 15% of patients receiving sham CPAP (P ¼ .40).41 A case-control study found seizure frequency decreased $ 50% from a mean of 1.8 to 1 seizure per month in 28 patients treated with CPAP for at least 6 months.42 No decrease in seizure frequency was noted in those nonadherent with CPAP (2.1 to 1.8/ month). Sixteen of 28 adherent subjects were seizure free vs 3 of 13 nonadherent subjects (relative risk, 1.54). A retrospective chart review involving 132 adults with epilepsy referred to the Cleveland Clinic for PSG from 1997 to 2010 found significant improvements in seizure control with CPAP therapy.43 Seizure outcome at the time of diagnostic PSG and 1 year later was compared in PAP-treated OSA, untreated OSA, and no OSA (AHI < 5) groups. Seventy-six subjects (58%) had OSA; of these, 57% were receiving PAP therapy, and 43% were not (either PAP-intolerant or refused therapy). Eighty-four percent of the PAP-treated patients with OSA were adherent (use, $ 4 h/night $ 5 nights/week). The percentage of subjects with $ 50% seizure reduction and the mean percentage of seizure reduction were significantly greater in the PAP-treated OSA group (74% and 59%, respectively) than in the untreated OSA group (14% and 17%, respectively) and no-OSA group (41% and 18%, respectively). Successful outcomes ($ 50% seizure reduction or seizure free at both baseline
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and follow-up) were more common in the PAP-treated OSA group (84%) than in the no-OSA group (54%) and untreated OSA group (39%). After adjusting for age, sex, body mass index, AHI, and epilepsy duration, the odds of having a successful outcome were 9.9 times greater with PAP therapy than no treatment for the group with OSA and 3.9 times greater for the group without OSA. Further, the odds of achieving $ 50% seizure reduction were 32 times greater in PAP-treated OSA than untreated OSA and six times greater than in the group without OSA.43 The greater improvement of seizure control with CPAP in patients with OSA (AHI > 5) than in the no-OSA patients, in this population referred for OSA evaluation, suggests that milder degrees of sleepdisordered breathing not meeting the AHI threshold for OSA could also be relevant to seizure control. Importantly, this study did not address the potential impact of treating milder forms of sleep-disordered breathing, such as primary snoring and upper airway resistance syndrome. A meta-analysis confirmed improved seizure control with CPAP therapy compared with no treatment for OSA (OR, 5.26; 95% CI, 2.0413.5).31
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Apnea and Respiratory Dysfunction Are Common During Seizures Hughlings Jackson in 1899 was the first to report that respiratory arrest could occur in humans during temporal lobe seizures originating near the uncus, leading to patients “turning blue.”44 Recordings of respiration and oxygen saturation as determined by pulse oximetry (SpO2) during vEEG in 1996 found that 10 of 17 PWE (59%) during 47 seizures developed apnea (mean, 24 s; longest, 64 s) and six had seizures with oxygen desaturations in the range of 55% to 83%.45 Apnea was typically central; obstructive events were observed in only 30%. More recent work has extended these early observations. Among 56 patients with drug-resistant focal epilepsy, central apneas or hypopneas occurred in 53% of seizures with desaturations < 90% in 33% and < 70% in 4%.46 End-tidal partial pressure of carbon dioxide (PetCO2) data were available for seven patients during 19 seizures and demonstrated a mean rise of 19 18 mm Hg accompanying a fall in SpO2 < 85%, consistent with hypoventilation. In 187 seizures recorded in 33 patients with focal epilepsy, PetCO2 increased by a mean of 14 11 to $ 50 mm Hg in 37%; $ 60 mm Hg in 16%; and $ 70 mm Hg in 5%.47 The mean duration of apnea (mostly central) during seizures was 49 46 s (longest, 222 s).
Oxygen desaturation to # 60% occurred in 10 seizures, including five that did not evolve to generalized tonicclonic (GTC) seizures. Respiratory rate and amplitude increased postictally. A recent prospective multicenter study recorded SpO2, inductance plethysmography, and ECG during vEEG in 473 PWE.48 Ictal central apnea (1) occurred exclusively during focal seizures (47% of 109 patients in 37% of 312 seizures), (2) preceded EEG seizure onset by 8 5 s in 54% of 103 seizures, and (3) when it lasted $ 60 s was associated with SpO2 < 75%. Figure 2 shows a central apnea occurring after the onset of ictal discharges in a patient with epilepsy from our laboratory.
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Brainstem and Cortical Mechanisms for Seizure-Induced Apnea
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Seizure-induced inhibition of respiration leading to respiratory arrest and death has been demonstrated in several animal models including DBA/1, DBA/2, and Htr2C knockout mice.49 Supplemental oxygen use during seizures prevented sudden respiratory death in these models. Considerable experimental work has shown that lower brain serotonergic systems regulate cardiorespiratory changes during and after seizures.50 Using multiunit and single-unit recordings, firing of neurons in the medullary and midbrain raphe was significantly decreased during the ictal and postictal periods. The marked suppression of medullary serotonergic firing supports its role in simultaneously impaired cardiorespiratory function in seizures. Decreased arousal likely arises from depression of several neuronal pools in the upper brainstem and forebrain. Electrical stimulation of the amygdala; hippocampus; and orbitofrontal, temporal tip, and temporal neocortex in three patients undergoing stereotactic depth electrode Q10 evaluation found that stimulation of either the amygdala or hippocampal head consistently elicited central apnea during the expiratory phase (ie, inhibiting inspiration).51 When spontaneous amygdalohippocampal seizures occurred, apnea duration was prolonged but ended before the seizure did. Slight increases in PetCO2 were noted. Patients were unaware of the apnea. In another report of two patients with intracranial EEG electrodes, breathing was inhibited when seizures spread to the amygdala or on amygdala stimulation.52
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Most recently, electrical stimulation of the amygdala during intracranial EEG in seven adults with drugresistant temporal lobe epilepsy consistently induced
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Figure 2 – Seizure-induced apnea and desaturation. Illustrated is a generalized tonic-clonic seizure in a patient with generalized epilepsy. Solid arrows signify EEG onset and offset, and the arrowhead signifies clinical onset. Note the central apnea (dashed arrow) during the tonic-clonic phase followed by a desaturation and EEG suppression following EEG offset. Postictal generalized EEG suppression is a proposed biomarker of sudden unexpected death in epilepsy. ETCO2 ¼ end-tidal partial pressure of carbon dioxide; SaO2 ¼ arterial blood oxygen saturation.
apnea.53 Induced apnea could be prevented by asking the patient to breathe through the mouth for several minutes before delivering stimulation and interrupted by asking the patient to take a breath during the apnea. Apnea was induced only by stimulating the medial amygdala (central nucleus), a region with afferent connections to brainstem respiratory centers.53,54
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Sudden Unexpected Death in Epilepsy Most Often Occurs During Sleep Sudden unexpected death in epilepsy (SUDEP) is defined as sudden, unexpected, witnessed or unwitnessed, nontraumatic and nondrowning death occurring in benign circumstances in an individual with epilepsy with or without evidence for a seizure and excluding documented status epilepticus (seizure duration $ 30 min or seizures without recovery in between) in which postmortem examination does not reveal a cause of death.55 Among patients with drugresistant epilepsy SUDEP is the leading cause of epilepsy-related death, with a 35% lifetime risk.56 SUDEP has an annual incidence of 0.81 cases per 100,000 or 1.16 cases per 1,000 PWE.57 SUDEP most often occurs during sleep in a prone position.58-61 A large cohort study found the risk for SUDEP was 2.6 times higher in PWE if they had nocturnal seizures after controlling for other SUDEP risk factors.61 The multicenter MORTEMUS (Mortality in Epilepsy
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Monitoring Units Study) analyzed 16 cases of definite or probable SUDEP and nine cases of near SUDEP occurring during vEEG in patients with drug-resistant epilepsy.62 Key findings included the following: (1) all 16 SUDEP and seven of nine near-SUDEP events occurred after GTC seizures; (2) 14 of the 16 SUDEP events occurred at night, and patients died in the prone position; and (3) cardiopulmonary resuscitation was successful in seven patients when started within 3 min but unsuccessful when started after 10 min. The most consistent sequence of events leading to SUDEP was rapid breathing (18-50 breaths/min) following the seizure, then apnea, bradycardia, and postictal generalized EEG suppression with terminal apnea preceding the terminal asystole. Therefore, abnormal breathing patterns including apnea may be part of a cascade of events that culminate in SUDEP. In addition to central and obstructive apnea, laryngospasm has been associated with sudden death in a kainic acid model of SUDEP in rats.63,64 Lack of apnearelated heart rate variability has been demonstrated in both temporal lobe and juvenile myoclonic epilepsy and may contribute to SUDEP.65,66 Measures to prevent SUDEP are summarized in Table 2. Limited evidence shows that nocturnal supervision may reduce SUDEP risk. A case-control study of adults showed that the risk of SUDEP was reduced by a factor of 2.5 if another person older than 10 years was in the room, and by a factor of 10 if frequent nighttime checks or a sound-monitoring device was used.67
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TABLE. 2
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] Strategies to Reduce Risk for Sudden Unexpected Death in Epilepsy
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671
Educate patient and family about risks of SUDEP and importance of good compliance with AED medications and a healthy lifestyle Good sleep hygiene; identify and treat insomnia and sleep apnea Higher AED doses at night if seizures occur mostly then Optimize and simplify AED regimen and avoid frequent AED changes
672
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Epilepsy surgery evaluation for drug-resistant cases
673
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Close supervision when sleeping, particularly in the intellectually or neurologically challenged (audio or audiovisual nocturnal monitor, bed partner)
674 675 676
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Encourage patient to avoid sleeping prone
677
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Observe closely after a seizure; reposition supine or lateral; stimulate the patient; watch for apnea or severe hypoventilation (if observed, initiate cardiopulmonary resuscitation and call emergency services)
678 679 680 681 682 683
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Avoid drugs that lower seizure threshold (phenylephrine, bupropion, pseudoephedrine)
AED ¼ antiepileptic drug; SUDEP ¼ sudden unexpected death in epilepsy.
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Pharmacologic treatments to reduce SUDEP and periictal respiratory disturbances, using selective serotonin reuptake inhibitors (SSRIs) and supplemental oxygen, are promising.68,69 Mice with sudden fatal audiogenic seizures treated with supplemental oxygen before inducing fatal seizures survived, while the majority not given it died.49 A study recording vEEG and pulse oximetry in 496 seizures of 73 patients with focal epilepsy found that those taking SSRIs had less severe oxygen desaturations during focal seizures.69 SSRI use did not lessen the degree of desaturation (< 85%) when focal seizures evolved to GTC seizures.
Sleep-Disordered Breathing and Laryngeal Dysfunction Induced by Vagus Nerve Stimulation Vagus nerve stimulation (VNS) was approved by the US Food and Drug Administration as an adjunctive treatment for drug-resistant focal epilepsy in 1997. In 2005, it was approved for treatment-resistant moderateto-severe major depressive disorders.70 The VNS neurostimulator (Cyberonics, Inc) is a compact generator implanted subcutaneously in the left thorax or anterior axillary region with two platinum helical bipolar electrode wires and the anchor tether wrapped around the left vagus nerve distal to the superior laryngeal nerve and superior and inferior cervical cardiac branches.71 The left vagus has proportionally fewer cardiac efferent fibers than the right.
The VNS delivers electrical stimulation using programmed and adjustable settings (stimulation ontime, stimulation off-time, output current, frequency, and pulse width). The generator typically produces a 0.5-millisecond pulse repeated at 10 to 30 Hz for 30 s every 150 to 300 s. The current output is typically increased by 0.25 to 0.50 mA every 2 to 4 weeks to control seizures and minimize side effects. The patient can initiate stimulation when a seizure is felt; this can shorten or abort the seizure. The VNS can be “turned off” by taping a magnet over the generator. A 2015 Cochrane analysis showed that $ 50% reduction in seizures occurred in 40% of 439 patients enrolled in five prospective VNS trials.72 The most common adverse events were dyspnea (OR, 2.45), voice alteration and hoarseness (OR, 2.17), and cough (OR, 1.09), all of which occur during the ON phase. Most adverse events remitted after 1 year of continued treatment. VNS is well tolerated, and complications are relatively uncommon and minor.73 Stimulation activates brainstem nuclei (including the nucleus tractus solitarius) that have widespread projections to limbic, reticular, and autonomic regions of the brain, and may influence norepinephrine levels and desynchronize interconnected cortical regions responsible for seizure activity.74 VNS can cause an increase in respiratory rate and decrease in respiratory amplitude, tidal volume, and oxygen saturation during periods of device activation (Fig 3).71 Some patients have an increase in AHI (perhaps because of airflow obstruction induced by stimulation). Patients with VNS can have central apneas, obstructive hypopneas, and obstructive apneas. Laryngeal stridor has also been reported.75
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Respiratory events during VNS ON time can usually be reduced or eliminated by lengthening the duration of OFF time (increasing the cycling time to 300 s) and reducing the stimulation intensity from 30 to 20 Hz, and if needed 10 Hz. Some have observed that the VNS effect on sleep apnea is positional and that avoiding the supine position is effective. Sometimes, CPAP is tried for apneas and hypopneas, but it is rarely effective. As a last resort, the device can be turned off when sleeping by taping a magnet over it.
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Mechanisms underlying the emergence of sleep apnea with VNS therapy are uncertain. Experimental stimulation of the vagus nerve in humans produces partial or complete inhibition of inspiration, prolongation of expiratory time, and modest changes in
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Figure 3 – Vagus nerve stimulation-induced respiratory events. Illustrated is a 2-min PSG epoch demonstrating reduced flow and respiratory effort (dashed arrow) coinciding with device activation recorded by a surface electrode over the left lateral neck region (solid arrow). Note the stimulation artifact in the chin EMG channel lasting 10 s and recurring every 30 s. EMG ¼ electromyography; Pleth ¼ plethysmography; PSG ¼ polysomnography; VNS ¼ vagus nerve stimulation.
arterial pressure and bradycardia.76 A study recording home sleep apnea tests in 23 adults before and after VNS implantation found that the prevalence of OSA increased from 17% to 65%.17 Awake endoscopic laryngoscopy in 18 patient 4 years postimplantation showed left vocal cord adduction during the stimulation ON phase in 11 with new-onset or worsening OSA, suggesting that reduction of the glottal space or lack of coordination between inspiration and the glottal aperture may have a role in OSA after VNS therapy.74
epilepsy monitoring unit despite their potential contribution to SUDEP, the leading cause of epilepsyrelated death in drug-resistant epilepsy. Vagus nerve stimulation induces both central and obstructive apnea and desaturations that are often ignored in clinical practice. While epilepsy advocacy and funding organizations have made SUDEP a research priority, the mechanistic underpinnings of this devastating outcome remain incompletely understood and preventive strategies largely anecdotal.
Conclusions and Future Directions
Acknowledgments
Both firmly established and poorly elucidated relationships between sleep-related breathing disorders and epilepsy have been reviewed. OSA is highly prevalent, but recognizing it in people with epilepsy is more challenging since daytime sleepiness is not a reliable predictor. Validated screening instruments for OSA in epilepsy and long-term studies exploring the relationship between OSA and SUDEP are needed. The current data highlight the importance of respiratory monitoring in an epilepsy monitoring unit to identify seizure-related breathing issues. While the potential beneficial effects of PAP therapy on seizure control in PWE and OSA is becoming increasingly recognized, randomized trials are lacking and treatments other that PAP are unexplored. Further, the effect of mild degrees of sleep-disordered breathing on epilepsy outcomes is unknown. Periictal respiratory disturbances are common, particularly with GTC seizures; however, respiratory parameters are rarely recorded in the
Financial/nonfinancial disclosures: None declared.
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64. Stewart M, Kollmar R, Nakase K, et al. Obstructive apnea due to laryngospasm links ictal to postictal events in SUDEP cases and offers practical biomarkers for review of past cases and prevention of new ones. Epilepsia. 2017;58(6):e87-e90. 65. Nayak CS, Sinha S, Nagappa M, Thennarasu K, Taly AB. Lack of heart rate variability during sleep-related apnea in patients with temporal lobe epilepsy (TLE): an indirect marker of SUDEP? Sleep Breath. 2017;21(1):163-172. 66. Nayak C, Sinha S, Nagappa M, Thennarasu K, Taly AB. Lack of heart rate variability during apnea in patients with juvenile myoclonic epilepsy (JME). Sleep Breath. 2015;19(4):1175-1183.
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Epilepsy and Sleep-Related Breathing Disturbances
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Thapanee Somboon, MD; Madeleine M. Grigg-Damberger, MD; and Nancy Foldvary-Schaefer, DO
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Epilepsy is the fourth most common neurologic disorder in the United States, affecting over 2.2
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million people. Epilepsy is associated with a number of medical and psychiatric comorbidities,
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higher health-care utilization and cost, and substantial economic burden. OSA is twofold more
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common in adults with epilepsy than in age-matched control subjects, and the incidence in-
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creases with age. Self-reported daytime sleepiness is not helpful in predicting OSA, possibly
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causes. Mostly small retrospective series found a significant reduction in seizures in people with
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epilepsy and OSA adherent with positive airway pressure therapy compared with untreated
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individuals. This finding illustrates the potential beneficial effects of sleep therapies on epilepsy.
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Central apnea, oxygen desaturations, and hypercapnia can occur during the ictal and imme-
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diate postictal period, especially with generalized tonic-clonic seizures. Central apneas have
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been produced by electrical stimulation of mesial temporal structures. These respiratory dis-
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turbances suggest activation of the central autonomic network and may contribute to sudden
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unexpected death in epilepsy (SUDEP), the leading cause of epilepsy-related death in people
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with drug-resistant epilepsy. SUDEP typically occurs during sleep, and patients are more often
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found in a prone position and have a history of nocturnal seizures. Whether OSA contributes to
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SUDEP is unknown. Vagus nerve stimulation is a form of neuromodulation for drug-resistant
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focal epilepsy. When the device activates during sleep it causes reduction in airflow and res-
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piratory effort, airflow obstruction, and oxygen desaturations, sometimes producing a clinical
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sleep apnea syndrome. The goal of this review is to discuss firmly established and recently
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KEY WORDS:
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Epilepsy is the fourth most common chronic neurologic disease, affecting more than 65 million people worldwide and accounting for 0.6% of the global burden of disease.1-3 Ten percent of people will experience a seizure
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(one-third of them febrile seizures), and one in 26 will develop epilepsy over their lifetime.2 Epilepsy is most common in adults over 75 years of age and children under 5 years of age.1,2 Seizures are resistant to
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ABBREVIATIONS:
AED = antiepileptic drug; AHI = apnea-hypopnea index; GTC = generalized tonic-clonic; ILAE = International League Against Epilepsy; PetCO2 = end-tidal partial pressure of carbon dioxide; PSG = polysomnography; PWE = people with epilepsy; SpO2 = oxygen saturation as determined by pulse oximetry; SSRI = selective serotonin reuptake inhibitor; SUDEP = sudden unexpected death in epilepsy; vEEG = video EEG; VNS = vagus nerve stimulation AFFILIATIONS: From the Cleveland Clinic Sleep Disorders Center (Drs Somboon and Foldvary-Schaefer), Cleveland, OH; the Epilepsy Unit (Dr Somboon), Neurological Department, Prasat Neurological
Institute, Bangkok, Thailand; and the Department of Neurology (Dr Grigg-Damberger), University of New Mexico, Albuquerque, NM. Q3 CORRESPONDENCE TO: Nancy Foldvary-Schaefer, DO, Cleveland Clinic Sleep Disorders Center, 9500 Euclid Ave, S73, Cleveland, OH 44195; e-mail: [email protected] Q4 Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.01.016
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antiepileptic drugs (AEDs) in one-third of people with epilepsy (PWE). Many PWE suffer from the stress of living with a chronic unpredictable disease made worse by social stigma, discrimination, and loss of autonomy.3
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An epileptic seizure is defined by the International League Against Epilepsy (ILAE) as a transient occurrence of signs and/or symptoms due to abnormal, excessive, and synchronous neuronal activity in the brain.4,5 Epilepsy is an enduring predisposition of the brain to generate epileptic seizures with neurobiologic, cognitive, psychological, and/or social consequences.4 Because conceptual definitions for seizures and epilepsy can be difficult to apply in clinical practice, the ILAE has published practical operational definitions and classifications for seizures and epilepsy types.4-8 The ILAE now defines epilepsy as: (1) $ two unprovoked seizures > 24 h apart; or (2) one unprovoked seizure and a $ 60% probability of further seizures over 10 years compared with the general population; or (3) diagnosis of a distinctive epilepsy syndrome.5 Figure 1 summarizes the framework of the 2017 ILAE classification.
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Active epilepsy is associated with higher health-care utilization and cost as well as substantial economic burden for health systems, individuals, and their families.9 Inpatient health-care costs are 2.4 and 2.6 times greater for prevalent and incident epilepsy, respectively, compared with age-matched control subjects.10 A 2009 study reported a mean of $4,523 higher annual health-care expenses for PWE, with a national impact of $9.6 billion.11
167 168 169 170 171 Q6
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Sleep-related breathing disorders are highly prevalent. According to the Wisconsin Sleep Cohort, approximately 13% of men and 6% of women have moderate-to-severe sleep apnea, and 14% of men and 5% of women have an apnea-hypopnea index (AHI) on polysomnography (PSG) of at least 5 with daytime sleepiness.12 These estimates have grown substantially over the last two decades, largely due to the rising obesity epidemic.13 Obesity and craniofacial and upper airway abnormalities are the most important risk factors.14 Intermittent hypoxia, sympathetic activity, cortical arousal, and sleep fragmentation caused by recurrent upper airway obstruction lead to a number of
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136
191
137
192
Seizure type
138 139
Focal onset
140
Generalized onset
193 194
Unknown onset
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141
196
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Aware
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Unaware
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Motor -Tonic-clonic -Other motor
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Non motor -Absence
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Etiology
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200
Focal to bilateral tonic-clonic
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Unclassified
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Infectious
Epilepsy type
151
Metabolic
152
Focal
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Generalized
Combined generalized & focal
Unknown
203
comorbidities
149
155
201 202
Structural
148
154
Genetic
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Immune
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Unknown
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Epilepsy syndrome Figure 1 – Operational definitions for seizure types use key symptoms and signs of seizures (called seizure semiology) and first categorize seizures as focal, generalized, or unknown.6,7 Focal seizures engage neuronal networks within one hemisphere at onset. If awareness is retained throughout a focal seizure it is called a focal onset with retained awareness (formerly called a simple partial seizure). If awareness is impaired during any part of a focal seizure, it is called a focal impaired awareness seizure (former terms dyscognitive or complex partial seizure now discarded). Generalized onset seizures originate at some point within and rapidly engage bilaterally distributed networks. Seizures in which onset is uncertain are termed seizures of unknown onset until the nature of their onset is known. Epilepsies are first classified on the basis of seizure type(s), and then classified as to whether they have a focal, generalized, combined, or unknown epilepsy type.8 If sufficient data are available, an epilepsy syndrome diagnosis is made. An epilepsy syndrome is a cluster of clinical characteristics (such as typical age at onset, seizure types, EEG and neuroimaging findings, seizure triggers, diurnal variation, and sometimes prognosis).8 Identifying the epilepsy syndrome often provides information on etiology, parts of the brain involved, genetic predispositions, and risk for sudden unexpected death in epilepsy, and guides medical therapy.8 (Adapted with permission from Fisher et al.7)
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long-term consequences including cardiovascular events and metabolic disorders.15
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High Prevalence of Medical Comorbidities in Adults With Active Epilepsy Several large studies using population-based cohorts and administrative databases in the United States, United Kingdom, Canada, and Scotland have consistently shown a higher prevalence of certain medical disorders in PWE compared with those without epilepsy.16-19 A population-based, cross-sectional study involving 1.5 million people $ 14 years of age in Scotland found that 70% of PWE had $ one comorbid medical condition and 19% had $ four, compared with 47% and 9% of people without epilepsy, respectively.16 Two validated health surveys representing 98% of the Canadian population found prevalence rates two to four times higher for gastrointestinal ulcers, stroke, urinary incontinence, inflammatory bowel disorders, migraine, Alzheimer’s disease, and chronic fatigue in PWE compared with the general population.18 Chest specialists may be unaware that the prevalence of COPD, asthma, and emphysema was found to be 1.9- to 2.9-fold, 1.1- to 1.4-fold, and 1.3-fold higher, respectively, in PWE than in the general population in studies of large community-dwelling populations.16,18,20,21 Cardiovascular comorbidities are common in epilepsy, the subject of a comprehensive review.22 Arrhythmias are induced by seizures and also result from a shared genetic susceptibility. Sinus tachycardia is observed in 80% of all seizures and is usually asymptomatic.23 Ictal asystole was found in 0.3% of patients with drugresistant epilepsy undergoing video EEG (vEEG), typically in temporal lobe seizures.24 Seizure-induced arrhythmias are likely due to direct stimulation of the central autonomic network or an indirect effect of catecholamine release evoking a vasovagal reflex.24 Sodium channel-blocking AEDs are associated with arrhythmias or conduction abnormalities including atrioventricular conduction delays, ST changes, Brugada-like patterns, atrial fibrillation, and QTc prolongation.22 Several genetic ion channel mutations in epilepsy are associated with cardiac phenotypes. For instance, mutations of the sodium channel gene SCN5A and potassium channel gene KCNQ1/KCNQ2 cause long QT syndrome and epilepsy, affecting 1:2,000 in the general population.25 Epidemiologic studies have consistently demonstrated that PWE have a higher
prevalence of structural cardiac disease than nonepilepsy populations, contributing to increased mortality.22 Some comorbid relationships with epilepsy are likely to be causative (eg, cerebrovascular disease contributes to about 10% of incident epilepsies).26 Others could result from epilepsy (such as aspiration pneumonia and seizurerelated skeletal fractures).27 Still others relate to genetic predisposition (such as an increased risk for epilepsy after traumatic brain injury in carriers of apolipoprotein E [APOE] ε4).28 Some may be shared risk factors (such as Q7 the higher prevalence of migraine in PWE due to excessive cortical hyperexcitability or the presence of anti-glutamic acid decarboxylase antibodies in 80% of individuals with diabetes mellitus type 1 and 6% of PWE).29 Several longitudinal studies report bidirectional relationships between epilepsy and autism spectrum disorder, migraine, stroke, dementia, depression, anxiety, psychosis, and schizophrenia.27 Experimental studies are needed to better elucidate these relationships.
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Sleep-Related Breathing Disorders Are Common in Adults With Epilepsy
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OSA is twofold more common in adults with epilepsy than in age-matched control subjects, and the incidence increases with age.30-36 Table 1 summarizes studies examining the prevalence of sleep-related breathing disorders in epilepsy populations.30,32,37-40 The largest cross-sectional study exploring the prevalence and predictors of OSA in epilepsy, using PSG, found OSA (AHI $ 10) in 30% of 130 consecutive adult patients presenting for new evaluations and unselected for sleep disorder symptoms or epilepsy severity.32 Sixteen percent had moderate-to-severe disease (AHI $ 15), rates that exceed general population estimates. OSA predictors in multivariate modeling were age, dental problems, and standardized AED dose, a measure of drug burden, but not seizure frequency. Male sex, age > 50 years, obesity, hypertension, and dental problems were associated with higher AHI. A history of epilepsy surgery appeared protective as only 1 of 17 operated patients had an AHI $ 10. Self-reported excessive daytime sleepiness and Epworth Sleepiness Scale scores were not helpful in predicting OSA, possibly related to the ceiling effect of general sleepiness among PWE from diverse causes. A meta-analysis found the prevalence of OSA in PWE to be 33% (95% CI, 20.8%-46.1%), 2.4-fold greater than in control subjects (OR, 2.36; 95% CI, 1.334.18) and three times more likely in men with epilepsy than in women (OR, 3.00; 95% CI, 2.25-3.99).31
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TABLE 1
] Prevalence of OSA in Adults With Epilepsy
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Study/Year Malow et al /2000
Design 37
Retrospective uncontrolled
Age
Male
Epilepsy Type
Seizure Control
(y)
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[No. (%)]
[No. (%)]
18-65
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Prospective uncontrolled
> 18
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Prospective uncontrolled
37-79
FoldvarySchaefer et al32/2012
Retrospective uncontrolled
$ 18
18 (46) n ¼ 39 NR n ¼ 13
349 350 351 352 353 354
RDI $ 5
Uncontrolled, 6 (40%)
a,b
[No. (%)] 13 (33)
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379 380 381 382 383 384 385
389 391
RDI $ 10a,b
392
6 (46)
70 (56) n ¼ 125
NR
NR
AHI $ 5a,b
69 (55)
44 (34) n ¼ 130
Focal, 97 (75%); generalized, 27 (21%); unknown, 6 (5%)
Seizure-free, 34 (26%)
AHI $ 10a,c
39 (30)
393 394 395 396 397 398 399 400 401
Phillips et al40 /2013
Prospective uncontrolled
$ 18
22 (52) n ¼ 43
NR
NR
AHI $ 5a,c
21 (49)
402
Maurousset et al30/2017
Prospective uncontrolled
$ 50
16 (59) n ¼ 27
NR
NR
AHI $ 5a,c
24 (89)
404
403 405 406
AHI ¼ apnea-hypopnea index; NR ¼ not reported; RDI ¼ respiratory disturbance index. a Apnea defined by a decrease in airflow or effort to 20% or less of baseline for $ 10 s. b Hypopnea defined as any reduction in airflow from baseline accompanied with either a $ 4% reduction in oxygen or arousal. c Hypopnea defined as $ 50% reduction in airflow from baseline accompanied with either a $ 3% reduction in oxygen saturation or arousal.
407 408 409 410
While a relationship between OSA and seizure control has not been firmly established, some studies found this to be the case. In a cross-sectional study of adults over 50 years of age presenting to a tertiary care epilepsy clinic, excluding those with prior OSA diagnosis, lateonset or worsening epilepsy was associated with higher AHI and Epworth Sleepiness Scale score (more severe daytime sleepiness) compared with those who were seizure free or with improved seizure control.34 In retrospective PSG review of adults (median age, 56 years) with OSA and epilepsy, the onset of OSA symptoms coincided with the first episode of status epilepticus or a clear increase in seizure frequency in 21 of 29 cases (72.4%).35 A population-based cohort study using the National Health Insurance Research Database of Taiwan found the adjusted hazard ratio for OSA to be 1.50 and increasing with age in 138,507 adults with epilepsy compared with an equal number of control subjects.36
377 378
388 390
355 356
386 387
OSA
NR
346 348
Temporal lobe epilepsy, 39 (100%)
OSA Diagnostic Criteria
Focal, 12 (92%); generalized, 1 (8%)
345 347
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Impact of Treating Sleep-Related Breathing Disorders in Adults With Epilepsy Improved seizure control with continuous positive airway pressure (CPAP) therapy for OSA was found in several small studies. A randomized, controlled trial exploring the feasibility of CPAP therapy in 35 adults with drug-resistant epilepsy found that seizures were
4 Contemporary Reviews in Sleep Medicine
reduced by $ 50% in 28% of patients receiving therapeutic CPAP vs 15% of patients receiving sham CPAP (P ¼ .40).41 A case-control study found seizure frequency decreased $ 50% from a mean of 1.8 to 1 seizure per month in 28 patients treated with CPAP for at least 6 months.42 No decrease in seizure frequency was noted in those nonadherent with CPAP (2.1 to 1.8/ month). Sixteen of 28 adherent subjects were seizure free vs 3 of 13 nonadherent subjects (relative risk, 1.54). A retrospective chart review involving 132 adults with epilepsy referred to the Cleveland Clinic for PSG from 1997 to 2010 found significant improvements in seizure control with CPAP therapy.43 Seizure outcome at the time of diagnostic PSG and 1 year later was compared in PAP-treated OSA, untreated OSA, and no OSA (AHI < 5) groups. Seventy-six subjects (58%) had OSA; of these, 57% were receiving PAP therapy, and 43% were not (either PAP-intolerant or refused therapy). Eighty-four percent of the PAP-treated patients with OSA were adherent (use, $ 4 h/night $ 5 nights/week). The percentage of subjects with $ 50% seizure reduction and the mean percentage of seizure reduction were significantly greater in the PAP-treated OSA group (74% and 59%, respectively) than in the untreated OSA group (14% and 17%, respectively) and no-OSA group (41% and 18%, respectively). Successful outcomes ($ 50% seizure reduction or seizure free at both baseline
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and follow-up) were more common in the PAP-treated OSA group (84%) than in the no-OSA group (54%) and untreated OSA group (39%). After adjusting for age, sex, body mass index, AHI, and epilepsy duration, the odds of having a successful outcome were 9.9 times greater with PAP therapy than no treatment for the group with OSA and 3.9 times greater for the group without OSA. Further, the odds of achieving $ 50% seizure reduction were 32 times greater in PAP-treated OSA than untreated OSA and six times greater than in the group without OSA.43 The greater improvement of seizure control with CPAP in patients with OSA (AHI > 5) than in the no-OSA patients, in this population referred for OSA evaluation, suggests that milder degrees of sleepdisordered breathing not meeting the AHI threshold for OSA could also be relevant to seizure control. Importantly, this study did not address the potential impact of treating milder forms of sleep-disordered breathing, such as primary snoring and upper airway resistance syndrome. A meta-analysis confirmed improved seizure control with CPAP therapy compared with no treatment for OSA (OR, 5.26; 95% CI, 2.0413.5).31
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Apnea and Respiratory Dysfunction Are Common During Seizures Hughlings Jackson in 1899 was the first to report that respiratory arrest could occur in humans during temporal lobe seizures originating near the uncus, leading to patients “turning blue.”44 Recordings of respiration and oxygen saturation as determined by pulse oximetry (SpO2) during vEEG in 1996 found that 10 of 17 PWE (59%) during 47 seizures developed apnea (mean, 24 s; longest, 64 s) and six had seizures with oxygen desaturations in the range of 55% to 83%.45 Apnea was typically central; obstructive events were observed in only 30%. More recent work has extended these early observations. Among 56 patients with drug-resistant focal epilepsy, central apneas or hypopneas occurred in 53% of seizures with desaturations < 90% in 33% and < 70% in 4%.46 End-tidal partial pressure of carbon dioxide (PetCO2) data were available for seven patients during 19 seizures and demonstrated a mean rise of 19 18 mm Hg accompanying a fall in SpO2 < 85%, consistent with hypoventilation. In 187 seizures recorded in 33 patients with focal epilepsy, PetCO2 increased by a mean of 14 11 to $ 50 mm Hg in 37%; $ 60 mm Hg in 16%; and $ 70 mm Hg in 5%.47 The mean duration of apnea (mostly central) during seizures was 49 46 s (longest, 222 s).
Oxygen desaturation to # 60% occurred in 10 seizures, including five that did not evolve to generalized tonicclonic (GTC) seizures. Respiratory rate and amplitude increased postictally. A recent prospective multicenter study recorded SpO2, inductance plethysmography, and ECG during vEEG in 473 PWE.48 Ictal central apnea (1) occurred exclusively during focal seizures (47% of 109 patients in 37% of 312 seizures), (2) preceded EEG seizure onset by 8 5 s in 54% of 103 seizures, and (3) when it lasted $ 60 s was associated with SpO2 < 75%. Figure 2 shows a central apnea occurring after the onset of ictal discharges in a patient with epilepsy from our laboratory.
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Brainstem and Cortical Mechanisms for Seizure-Induced Apnea
513
Seizure-induced inhibition of respiration leading to respiratory arrest and death has been demonstrated in several animal models including DBA/1, DBA/2, and Htr2C knockout mice.49 Supplemental oxygen use during seizures prevented sudden respiratory death in these models. Considerable experimental work has shown that lower brain serotonergic systems regulate cardiorespiratory changes during and after seizures.50 Using multiunit and single-unit recordings, firing of neurons in the medullary and midbrain raphe was significantly decreased during the ictal and postictal periods. The marked suppression of medullary serotonergic firing supports its role in simultaneously impaired cardiorespiratory function in seizures. Decreased arousal likely arises from depression of several neuronal pools in the upper brainstem and forebrain. Electrical stimulation of the amygdala; hippocampus; and orbitofrontal, temporal tip, and temporal neocortex in three patients undergoing stereotactic depth electrode Q10 evaluation found that stimulation of either the amygdala or hippocampal head consistently elicited central apnea during the expiratory phase (ie, inhibiting inspiration).51 When spontaneous amygdalohippocampal seizures occurred, apnea duration was prolonged but ended before the seizure did. Slight increases in PetCO2 were noted. Patients were unaware of the apnea. In another report of two patients with intracranial EEG electrodes, breathing was inhibited when seizures spread to the amygdala or on amygdala stimulation.52
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Most recently, electrical stimulation of the amygdala during intracranial EEG in seven adults with drugresistant temporal lobe epilepsy consistently induced
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Figure 2 – Seizure-induced apnea and desaturation. Illustrated is a generalized tonic-clonic seizure in a patient with generalized epilepsy. Solid arrows signify EEG onset and offset, and the arrowhead signifies clinical onset. Note the central apnea (dashed arrow) during the tonic-clonic phase followed by a desaturation and EEG suppression following EEG offset. Postictal generalized EEG suppression is a proposed biomarker of sudden unexpected death in epilepsy. ETCO2 ¼ end-tidal partial pressure of carbon dioxide; SaO2 ¼ arterial blood oxygen saturation.
apnea.53 Induced apnea could be prevented by asking the patient to breathe through the mouth for several minutes before delivering stimulation and interrupted by asking the patient to take a breath during the apnea. Apnea was induced only by stimulating the medial amygdala (central nucleus), a region with afferent connections to brainstem respiratory centers.53,54
582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605
Sudden Unexpected Death in Epilepsy Most Often Occurs During Sleep Sudden unexpected death in epilepsy (SUDEP) is defined as sudden, unexpected, witnessed or unwitnessed, nontraumatic and nondrowning death occurring in benign circumstances in an individual with epilepsy with or without evidence for a seizure and excluding documented status epilepticus (seizure duration $ 30 min or seizures without recovery in between) in which postmortem examination does not reveal a cause of death.55 Among patients with drugresistant epilepsy SUDEP is the leading cause of epilepsy-related death, with a 35% lifetime risk.56 SUDEP has an annual incidence of 0.81 cases per 100,000 or 1.16 cases per 1,000 PWE.57 SUDEP most often occurs during sleep in a prone position.58-61 A large cohort study found the risk for SUDEP was 2.6 times higher in PWE if they had nocturnal seizures after controlling for other SUDEP risk factors.61 The multicenter MORTEMUS (Mortality in Epilepsy
6 Contemporary Reviews in Sleep Medicine
Monitoring Units Study) analyzed 16 cases of definite or probable SUDEP and nine cases of near SUDEP occurring during vEEG in patients with drug-resistant epilepsy.62 Key findings included the following: (1) all 16 SUDEP and seven of nine near-SUDEP events occurred after GTC seizures; (2) 14 of the 16 SUDEP events occurred at night, and patients died in the prone position; and (3) cardiopulmonary resuscitation was successful in seven patients when started within 3 min but unsuccessful when started after 10 min. The most consistent sequence of events leading to SUDEP was rapid breathing (18-50 breaths/min) following the seizure, then apnea, bradycardia, and postictal generalized EEG suppression with terminal apnea preceding the terminal asystole. Therefore, abnormal breathing patterns including apnea may be part of a cascade of events that culminate in SUDEP. In addition to central and obstructive apnea, laryngospasm has been associated with sudden death in a kainic acid model of SUDEP in rats.63,64 Lack of apnearelated heart rate variability has been demonstrated in both temporal lobe and juvenile myoclonic epilepsy and may contribute to SUDEP.65,66 Measures to prevent SUDEP are summarized in Table 2. Limited evidence shows that nocturnal supervision may reduce SUDEP risk. A case-control study of adults showed that the risk of SUDEP was reduced by a factor of 2.5 if another person older than 10 years was in the room, and by a factor of 10 if frequent nighttime checks or a sound-monitoring device was used.67
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661
TABLE. 2
663 664
-
665 666
-
667 668
-
669 670
] Strategies to Reduce Risk for Sudden Unexpected Death in Epilepsy
662
-
671
Educate patient and family about risks of SUDEP and importance of good compliance with AED medications and a healthy lifestyle Good sleep hygiene; identify and treat insomnia and sleep apnea Higher AED doses at night if seizures occur mostly then Optimize and simplify AED regimen and avoid frequent AED changes
672
-
Epilepsy surgery evaluation for drug-resistant cases
673
-
Close supervision when sleeping, particularly in the intellectually or neurologically challenged (audio or audiovisual nocturnal monitor, bed partner)
674 675 676
-
Encourage patient to avoid sleeping prone
677
-
Observe closely after a seizure; reposition supine or lateral; stimulate the patient; watch for apnea or severe hypoventilation (if observed, initiate cardiopulmonary resuscitation and call emergency services)
678 679 680 681 682 683
-
Avoid drugs that lower seizure threshold (phenylephrine, bupropion, pseudoephedrine)
AED ¼ antiepileptic drug; SUDEP ¼ sudden unexpected death in epilepsy.
684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715
Pharmacologic treatments to reduce SUDEP and periictal respiratory disturbances, using selective serotonin reuptake inhibitors (SSRIs) and supplemental oxygen, are promising.68,69 Mice with sudden fatal audiogenic seizures treated with supplemental oxygen before inducing fatal seizures survived, while the majority not given it died.49 A study recording vEEG and pulse oximetry in 496 seizures of 73 patients with focal epilepsy found that those taking SSRIs had less severe oxygen desaturations during focal seizures.69 SSRI use did not lessen the degree of desaturation (< 85%) when focal seizures evolved to GTC seizures.
Sleep-Disordered Breathing and Laryngeal Dysfunction Induced by Vagus Nerve Stimulation Vagus nerve stimulation (VNS) was approved by the US Food and Drug Administration as an adjunctive treatment for drug-resistant focal epilepsy in 1997. In 2005, it was approved for treatment-resistant moderateto-severe major depressive disorders.70 The VNS neurostimulator (Cyberonics, Inc) is a compact generator implanted subcutaneously in the left thorax or anterior axillary region with two platinum helical bipolar electrode wires and the anchor tether wrapped around the left vagus nerve distal to the superior laryngeal nerve and superior and inferior cervical cardiac branches.71 The left vagus has proportionally fewer cardiac efferent fibers than the right.
The VNS delivers electrical stimulation using programmed and adjustable settings (stimulation ontime, stimulation off-time, output current, frequency, and pulse width). The generator typically produces a 0.5-millisecond pulse repeated at 10 to 30 Hz for 30 s every 150 to 300 s. The current output is typically increased by 0.25 to 0.50 mA every 2 to 4 weeks to control seizures and minimize side effects. The patient can initiate stimulation when a seizure is felt; this can shorten or abort the seizure. The VNS can be “turned off” by taping a magnet over the generator. A 2015 Cochrane analysis showed that $ 50% reduction in seizures occurred in 40% of 439 patients enrolled in five prospective VNS trials.72 The most common adverse events were dyspnea (OR, 2.45), voice alteration and hoarseness (OR, 2.17), and cough (OR, 1.09), all of which occur during the ON phase. Most adverse events remitted after 1 year of continued treatment. VNS is well tolerated, and complications are relatively uncommon and minor.73 Stimulation activates brainstem nuclei (including the nucleus tractus solitarius) that have widespread projections to limbic, reticular, and autonomic regions of the brain, and may influence norepinephrine levels and desynchronize interconnected cortical regions responsible for seizure activity.74 VNS can cause an increase in respiratory rate and decrease in respiratory amplitude, tidal volume, and oxygen saturation during periods of device activation (Fig 3).71 Some patients have an increase in AHI (perhaps because of airflow obstruction induced by stimulation). Patients with VNS can have central apneas, obstructive hypopneas, and obstructive apneas. Laryngeal stridor has also been reported.75
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Respiratory events during VNS ON time can usually be reduced or eliminated by lengthening the duration of OFF time (increasing the cycling time to 300 s) and reducing the stimulation intensity from 30 to 20 Hz, and if needed 10 Hz. Some have observed that the VNS effect on sleep apnea is positional and that avoiding the supine position is effective. Sometimes, CPAP is tried for apneas and hypopneas, but it is rarely effective. As a last resort, the device can be turned off when sleeping by taping a magnet over it.
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Mechanisms underlying the emergence of sleep apnea with VNS therapy are uncertain. Experimental stimulation of the vagus nerve in humans produces partial or complete inhibition of inspiration, prolongation of expiratory time, and modest changes in
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Figure 3 – Vagus nerve stimulation-induced respiratory events. Illustrated is a 2-min PSG epoch demonstrating reduced flow and respiratory effort (dashed arrow) coinciding with device activation recorded by a surface electrode over the left lateral neck region (solid arrow). Note the stimulation artifact in the chin EMG channel lasting 10 s and recurring every 30 s. EMG ¼ electromyography; Pleth ¼ plethysmography; PSG ¼ polysomnography; VNS ¼ vagus nerve stimulation.
arterial pressure and bradycardia.76 A study recording home sleep apnea tests in 23 adults before and after VNS implantation found that the prevalence of OSA increased from 17% to 65%.17 Awake endoscopic laryngoscopy in 18 patient 4 years postimplantation showed left vocal cord adduction during the stimulation ON phase in 11 with new-onset or worsening OSA, suggesting that reduction of the glottal space or lack of coordination between inspiration and the glottal aperture may have a role in OSA after VNS therapy.74
epilepsy monitoring unit despite their potential contribution to SUDEP, the leading cause of epilepsyrelated death in drug-resistant epilepsy. Vagus nerve stimulation induces both central and obstructive apnea and desaturations that are often ignored in clinical practice. While epilepsy advocacy and funding organizations have made SUDEP a research priority, the mechanistic underpinnings of this devastating outcome remain incompletely understood and preventive strategies largely anecdotal.
Conclusions and Future Directions
Acknowledgments
Both firmly established and poorly elucidated relationships between sleep-related breathing disorders and epilepsy have been reviewed. OSA is highly prevalent, but recognizing it in people with epilepsy is more challenging since daytime sleepiness is not a reliable predictor. Validated screening instruments for OSA in epilepsy and long-term studies exploring the relationship between OSA and SUDEP are needed. The current data highlight the importance of respiratory monitoring in an epilepsy monitoring unit to identify seizure-related breathing issues. While the potential beneficial effects of PAP therapy on seizure control in PWE and OSA is becoming increasingly recognized, randomized trials are lacking and treatments other that PAP are unexplored. Further, the effect of mild degrees of sleep-disordered breathing on epilepsy outcomes is unknown. Periictal respiratory disturbances are common, particularly with GTC seizures; however, respiratory parameters are rarely recorded in the
Financial/nonfinancial disclosures: None declared.
8 Contemporary Reviews in Sleep Medicine
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2. Theodore WH, Spencer SS, Wiebe S, et al. Epilepsy in North America: a report prepared under the auspices of the global campaign against epilepsy, the International Bureau for Epilepsy, the International League Against Epilepsy, and the World Health Organization. Epilepsia. 2006;47(10):1700-1722. 3. Moshe SL, Perucca E, Ryvlin P, Tomson T. Epilepsy: new advances. Lancet. 2015;385(9971):884-898. 4. Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46(4):470-472.
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10 Contemporary Reviews in Sleep Medicine
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