Beth A. Malow

Obstructive sleep apnea is common in medically refractory epilepsy patients

Background: Previous reports have documented the coexistence of obstructive sleep apnea (OSA) and epilepsy and the therapeutic effects of treatment on seizure frequency and daytime sleepiness. The authors’ objective was to determine the prevalence of OSA and its association with survey items in a group of patients with medically refractory epilepsy undergoing polysomnography (PSG). Methods: Thirty-nine candidates for epilepsy surgery without a history of OSA underwent PSG as part of a research protocol examining the relationship of interictal epileptiform discharges to sleep state. Subjects also completed questionnaires about their sleep, including validated measures of sleep-related breathing disorders (Sleep Apnea Scale of the Sleep Disorders Questionnaire [SA/SDQ]) and subjective daytime sleepiness (Epworth Sleepiness Scale [ESS]). Results: One-third of subjects had OSA, defined by a respiratory disturbance index (RDI) ≥ 5. Five subjects (13%) had moderate to severe OSA (RDI > 20). Subjects with OSA were more likely to be older, male, have a higher SA/SDQ score, and more likely to have seizures during sleep than those without OSA (p < 0.05). Seizure frequency per month, the number or type of antiepileptic drugs (AED) prescribed, the localization of seizures (temporal versus extratemporal), and the ESS were not statistically different between the two groups. Conclusions: In our sample, previously undiagnosed obstructive sleep apnea was common, especially among men, older subjects, and those with seizures during sleep. The impact of treating OSA on seizure frequency and daytime sleepiness in medically refractory epilepsy patients warrants further controlled study.

Interictal spiking increases with sleep depth in temporal lobe epilepsy

Summary: Purpose: To test the hypothesis that deepening sleep activates focal interictal epileptiform discharges (IEDs), we performed EEG‐polysomnography in 21 subjects with medically refractory temporal lobe epilepsy.

Obstructive Sleep Apnea Is Common in Idiopathic Pulmonary Fibrosis

BACKGROUND From 1984 to 2006, studies of sleep in patients with interstitial lung disease revealed disturbed sleep, frequent nocturnal desaturations, nocturnal cough, and obstructive sleep apnea (OSA). Our goal was to analyze OSA in an outpatient population of stable patients with idiopathic pulmonary fibrosis (IPF). METHODS Patients with IPF who had been followed up in the Vanderbilt Pulmonary Clinic were asked to participate. All patients were given a diagnosis of IPF by the 2000 American Thoracic Society consensus statement criteria. Subjects completed an Epworth sleepiness scale (ESS) questionnaire and a sleep apnea scale of sleep disorders questionnaire (SA-SDQ) before undergoing nocturnal polysomnography (NPSG). OSA was defined as an apnea-hypopnea index (AHI) of > 5 events per hour. RESULTS Fifty subjects enrolled and completed a NPSG. The mean age was 64.9 years, and the mean BMI was 32.3. OSA was diagnosed in 88% of subjects. Ten subjects (20%) had mild OSA (AHI, 5 to 15 events per hour), and 34 subjects (68%) had moderate-to-severe OSA (AHI, > 15 events per hour). Only 6 subjects (12%) had a normal AHI. One patient was asymptomatic as determined by ESS and SA-SDQ, but had an AHI of 24 events per hour. The sensitivity of the ESS was 75% with a specificity of 15%, whereas the SA-SDQ had a sensitivity of 88% with a specificity of 50%. BMI did not correlate strongly with AHI (r = 0.30; p = 0.05). CONCLUSIONS OSA is prevalent in patients with IPF and may be underrecognized by primary care providers and specialists. Neither ESS nor SA-SDQ alone or in combination was a strong screening tool. Given the high prevalence found in our sample, formal sleep evaluation and polysomnography should be considered in patients with IPF.

Effects of vagus nerve stimulation on respiration during sleep: a pilot study.

Background: Vagus nerve stimulation (VNS) is associated with respiratory effects such as hoarseness, dyspnea, and laryngeal irritation. The effects of VNS on sleep-related breathing in humans have not been reported previously. Methods: Four epilepsy patients underwent polysomnography (PSG) before and after 3 months of treatment with VNS. Two of the four patients also underwent follow-up PSG to assess the effects of changing stimulus parameters on sleep-related breathing. Results: All patients showed consistent sleep-related decreases in airflow and effort coinciding with VNS activation, although most events did not meet laboratory criteria for apneas or hypopneas. Apneas and hypopneas were more frequent during VNS activation than during nonactivation. Apnea–hypopnea index (AHI) for three subjects during VNS treatment PSG was <5 apneas and hypopneas/hour. In one patient with obstructive sleep apnea (OSA) before VNS treatment, AHI rose from 4 (pretreatment) to 11.3 (treatment). In this patient and in another patient without clinically significant OSA, lowering stimulus frequency, but not stimulus intensity, pulse width, or on-time, ameliorated VNS-related apneas and hypopneas. Conclusions: VNS is associated with adverse changes in respiration during sleep. In patients without preexisting OSA, this VNS effect is probably not clinically significant. In patients with preexisting OSA, VNS should be administered with care. Lowering VNS stimulus frequency or prolonging off-time may prevent exacerbation of OSA.

Melatonin for Insomnia in Children With Autism Spectrum Disorders

We describe our experience in using melatonin to treat insomnia, a common sleep concern, in children with autism spectrum disorders. One hundred seven children (2—18 years of age) with a confirmed diagnosis of autism spectrum disorders who received melatonin were identified by reviewing the electronic medical records of a single pediatrician. All parents were counseled on sleep hygiene techniques. Clinical response to melatonin, based on parental report, was categorized as (1) sleep no longer a concern, (2) improved sleep but continued parental concerns, (3) sleep continues to be a major concern, and (4) worsened sleep. The melatonin dose varied from 0.75 to 6 mg. After initiation of melatonin, parents of 27 children (25%) no longer reported sleep concerns at follow-up visits. Parents of 64 children (60%) reported improved sleep, although continued to have concerns regarding sleep. Parents of 14 children (13%) continued to report sleep problems as a major concern, with only 1 child having worse sleep after starting melatonin (1%), and 1 child having undetermined response (1%). Only 3 children had mild side-effects after starting melatonin, which included morning sleepiness and increased enuresis. There was no reported increase in seizures after starting melatonin in children with pre-existing epilepsy and no new-onset seizures. The majority of children were taking psychotropic medications. Melatonin appears to be a safe and well-tolerated treatment for insomnia in children with autism spectrum disorders. Controlled trials to determine efficacy appear warranted.

Usefulness of polysomnography in epilepsy patients

we reviewed the records of 63 adult epilepsy patients who underwent polysomnograms in our laboratory since 1985 to determine the indications for polysomnography and the results of testing. Reasons for referral included excessive daytime sleepiness, suspected obstructive sleep apnea (OSA), and characterization of nocturnal spells. The most common polysomnographic diagnosis was OSA, although we also found narcolepsy, insufficient sleep syndrome with possible idiopathic hypersomnolence, and previously unrecognized nocturnal seizures. We treated OSA with continuous positive airway pressure in 28 patients, 15 of whom were using the device at follow-up appointments. The majority of patients treated for OSA or other disorders reported an improvement in sleepiness or seizure control. Polysomnography, when indicated, is beneficial in epilepsy patients.

Vagus nerve stimulation reduces daytime sleepiness in epilepsy patients

Background: Given that vagal afferents project to brainstem regions that promote alertness, the authors tested the hypothesis that vagus nerve stimulation (VNS) would improve daytime sleepiness in patients with epilepsy. Methods: Sixteen subjects with medically refractory seizures underwent polysomnography and multiple sleep latency tests (MSLT) and completed the Epworth Sleepiness Scale (ESS), a measure of subjective daytime sleepiness, before and after 3 months of VNS. Most subjects (>80%) were maintained on constant doses of antiepileptic medications. Results: In the 15 subjects who completed baseline and treatment MSLT, the mean sleep latency (MSL) improved from 6.4 ± 4.1 minutes to 9.8 ± 5.8 minutes (± SD; p = 0.033), indicating reduced daytime sleepiness. All subjects with stimulus intensities of ≤1.5 mA showed improved MSL. In the 16 subjects who completed baseline and treatment ESS, the mean ESS score decreased from 7.2 ± 4.4 to 5.6 ± 4.5 points (p = 0.049). Improvements in MSLT and ESS were not correlated with reduction in seizure frequency. Sleep-onset REM periods occurred more frequently in treatment naps as compared to baseline naps (p < 0.008; Cochran-Mantel-Haenszel test). The amount of REM sleep or other sleep stages recorded on overnight polysomnography did not change with VNS treatment. Conclusions: Treatment with VNS at low stimulus intensities improves daytime sleepiness, even in subjects without reductions in seizure frequency. Daytime REM sleep is enhanced with VNS. These findings support the role of VNS in activating cholinergic and other brain regions that promote alertness.

Cost-utility of three approaches to the diagnosis of sleep apnea: Polysomnography, home testing, and empirical therapy

Obstructive sleep apnea syndrome (OSAS) results from repeated obstruction of breathing during sleep and is associated with excessive daytime sleepiness, significant cardiovascular morbidity, and increased mortality (1-4). Recent data suggest that 2% to 4% of adults have this disorder (5). Nasal continuous positive airway pressure (CPAP) administered at home prevents collapse of the airway, is the most commonly used treatment, and has a favorable costutility ratio (6, 7). However, OSAS remains undiagnosed in at least 82% of men and 93% of women with the condition (8). The gold standard for diagnosis of OSAS is nocturnal polysomnography, a recording of brain waves, eye movements, muscle activity, chest movements, air movements, and blood oxygen saturation that must be performed by trained technologists using expensive equipment. The cost of polysomnographyabout

Effects of Vagus Nerve Stimulation on Sleep-related Breathing in Epilepsy Patients

1000 to

Treating obstructive sleep apnea in adults with epilepsy : A randomized pilot trial

1400has generated considerable interest in many different portable devices that can record nocturnal breathing and oxygenation at home, at a much lower cost and somewhat lower efficacy (9). In addition, some researchers have argued that the pretest suspicion of OSAS, based on symptoms and physical findings alone, is sometimes sufficient to make any test superfluous (10, 11). Whether decreased costs of home studies or bedside diagnosis adequately compensate for loss of diagnostic accuracy has not yet been evaluated. To model diagnosis of OSAS by polysomnography, home study, and no sleep testing, we applied decision analytical techniques to published data and to a range of reasonable estimates for unknown quantities. We then calculated costutility ratios that reflect the incremental costs of the preferred approach per quality-adjusted life-year (QALY) gained. Methods Model We constructed a decision tree (Figure 1) in which a hypothetical adult patient in whom OSAS is suspected enters at left and proceeds on a path to the right through a square node that represents the decision among three alternative approaches to diagnosis, circular nodes that represent the chances of a positive or negative test result (and treatment or no treatment with CPAP, respectively), circular nodes that represent the probability that OSAS is actually present, and terminal triangular nodes that reflect the utility of the resulting health state. The values for utilities and probabilities shown in Figure 1 and discussed below are calculated for a baseline case. Few assumptions were made about baseline patient age, comorbid conditions, or severity of sleep apnea. The published data used in the tree (for example, utility and survival data) were derived from consecutive, sleep-center-referred, adult case series in which inclusion criteria beyond a diagnosis of OSAS were avoided and stratified results for subcategories of patients were not given. The only exception is that health state utilities were derived from a series that did not include mild OSAS that might be treated at some other sleep centers (7). On average, the patients that we modeled were in the sixth decade of life, most were male, and many had cardiovascular comorbid conditions (3, 7). Figure 1. Decision tree with quality-adjusted life-years, calculated for the 5 years after initial evaluation ( QALY ), as the outcome measure. CPAP Outcome Measures Outcome utility can be calculated in QALYs (utility expected life span) when the utility of a health state is assumed to remain constant over time. To avoid such an assumption for patients with OSAS, we calculated QALYs for the first 5 years after evaluation for OSAS [QALY5 s] rather than for total life expectancy. The QALY5 s represent the product of 1) the utility of the health state and 2) the average number of years, within the 5-year period that follows diagnostic evaluation, that a patient in that health state can be expected to survive. We used QALY5 s because currently available data on compliance, quality of life, survival with and without CPAP, and costs for patients with OSAS are limited to approximately 5 years rather than remaining life spans. Data are limited in part because widespread diagnosis and treatment of OSAS represent relatively recent accomplishments. We used decision analysis software (TreePlan version 1.57, Decision Support Services, San Francisco, California) to help determine the magnitude of the advantage afforded by the best diagnostic approachpolysomnography, home study, or no testingmeasured in QALY5 s. We then calculated the 5-year cost in U.S. dollars of obtaining that advantage. In costutility ratios that compared polysomnography with either home study or no testing, the numerator was the 5-year difference in total costs and the denominator was the difference in QALY5 s for the same period. All costutility ratios discussed in this report are therefore incremental (they compare two diagnostic options) rather than absolute (referring to one option). The QALY5 s in this report cannot be compared directly with QALYs in other research, which are usually calculated with life expectancies rather than average survival during 5-year study periods. However, the final resultsincremental costutility ratios, measured in dollars per single QALY5 gainedare comparable to other incremental costutility ratios calculated in dollars per QALY gained; the subscript 5 is retained only as a reminder that current data are not derived from longer follow-up periods. Comparisons of costutility ratios among studies are important in assessment of the value of different tests or procedures in disparate medical fields. After we derived results for a base-case, we performed univariate sensitivity analyses to test the effects on the model of different but plausible utilities, survival rates, pretest probabilities of OSAS, test characteristics, and costs. We performed a two-variable sensitivity analysis to model the performance of a particularly inexpensive home study as a screening tool. To further explore the overall level of uncertainty in our model, we performed a 1000-iteration Monte Carlo simulation (DATA version 3.0, TreeAge Software, Inc., Williamstown, Massachusetts) in which all model variables were allowed to vary simultaneously, between trials, within plausible logit-normal distributions (12). Logit-normal distributions were used to normalize the distributions of variables with delimited ranges (for example, from 0 to 1 for probabilities). From these data, we calculated 2000 costutility ratios1000 for polysomnography compared with home study and 1000 for polysomnography compared with no testand estimated the frequency with which given levels of marginal costutility would be obtained. Utilities, Survival, Test Characteristics, Predictive Values, and Other Probabilities Baseline utility and survival values and their derivations are shown in Table 1. One-night laboratory polysomnography with standard equipment and scoring procedures is a gold standard considered sufficient to make or rule out the diagnosis of OSAS in most persons (16). A baseline assumption in our model (Figure 1) was that polysomnograms are positive in all patients with OSAS and negative in all patients without OSAS. However, results can vary night to night, and a small percentage of polysomnograms may meet criteria for OSAS on a second study after failing to do so on an initial night (17). Our model therefore included outcomes to represent false-positive and false-negative diagnoses based on polysomnography, and we performed narrow sensitivity analyses to determine whether results of our model would change on the basis of sensitivities and specificities between 0.95 and 1.0. Because biological night-to-night variability would affect the home studies in equal measure, their test characteristics were simultaneously reduced by equivalent amounts in these sensitivity analyses. Table 1. Baseline Utilities of Four Possible Health States (Outcomes), Mean Survival during 5-Year Periods after Diagnostic Evaluation, and Resulting Quality-Adjusted Life-Years The pretest probability of OSAS is high when most tested patients are referred by a sleep specialist: About 85% of polysomnograms obtained for suspected sleep apnea in the University of Michigan Sleep Laboratory confirm the diagnosis. However, this estimate is not easily generalized because of variation in sources of referrals and interpretation of test results. Some sleep specialists report that as few as 54% of their patients tested for OSAS have a positive polysomnogram (18). We therefore subjected our model to a wide range of pretest probabilities of OSAS. Like portable devices made by other companies, the EdenTrace Model 2700 (EdenTec, Eden Prairie, Minnesota) provides an unattended recording of several cardiorespiratory variables during sleep. The sensitivity of the EdenTrace Model 2700 for polysomnographically confirmed OSAS is 0.95 and the specificity is 0.96 (19). With a pretest probability of OSAS of 0.85, the positive predictive value of the EdenTrace Model 2700 is 0.99 and the negative predictive value is 0.77 (Figure 1). The proportion of all home studies expected to yield positive results is (0.95 0.85) + (0.04 0.15)=0.81. Home study devices other than the EdenTrace Model 2700 have sensitivities as low as 0.80 and specificities as low as 0.70 (9); thus, these ranges were also tested in our model. In the no-test branch of the model, all patients suspected of having OSAS receive treatment. The decision of whether to treat all or none of these patients with CPAP yields the highest QALY5 s when all patients are treated (as long as the pretest probability of OSAS is at least 0.31). Costs Because of a dearth of published data on costs, we used charges as a proxy for costs. Baseline values, shown in Table 2, were subjected to broad sensitivity analyses. We assumed that each patient who received a diagnosis of OSAS (by polysomnography, home study, or no testing) subsequently had polysomnography (at a charge of