Treatment of Comorbid Sleep Disorders Improves Seizure Control

It is a widely known fact that Fyodor Dostoevsky, the famous 19th-century Russian novelist, suffered from epilepsy for most of his life. However, not too many persons are aware that Dostoevsky also had a sleep disorder called delayed sleep phase syndrome, which may have contributed to his seizures.¹ Although no one knows for certain, it is quite conceivable that Dostoevsky's sleep disorder worsened his epilepsy, according to Carl Bazil, MD, PhD, director of Clinical Anticonvulsant Drug Trials and director of the Neurology Division, Columbia Comprehensive Sleep Center, Columbia University, New York.

"Delayed sleep phase syndrome is quite common, especially among adolescents, and in and of itself it is unlikely to exacerbate epilepsy," Bazil said in an interview with Applied Neurology. "But if it's causing sleep deprivation, it could have an influence," he added.

Common sleep disorders include insomnia, restless legs syndrome (RLS), and obstructive sleep apnea (OSA). Evidence suggests that all of these are more common in persons with epilepsy than in the general population, Bazil said. "Overall, probably at least a third of the patients with epilepsy have some sort of sleep disturbance."

Despite their high prevalence, however, sleep disorders often remain undiagnosed and untreated in patients with epilepsy, according to Bazil. "This is unfortunate," he said, "because there is evidence that treating sleep disorders can help reduce the frequency or intensity of seizures."

RECIPROCAL RELATIONSHIP

The relationship between epilepsy and sleep is a reciprocal one because epilepsy has an adverse effect on sleep quality and sleep disturbance can exacerbate seizures. Sleep disorders can affect anyone. The most common symptoms are daytime sleepiness, difficulty in concentrating, and memory problems. But in persons with epilepsy, sleep disorders also can increase the likelihood of seizures, Bazil explained.

There are several purported mechanisms through which sleep disorders might lower seizure threshold, Bazil continued. In OSA, for example, persons become somewhat hypoxic. This may increase the seizure frequency, especially during sleep.

Another possible reason why some sleep disorders may have an adverse effect on epilepsy is that they result in sleep deprivation, which, in turn, increases cortical excitability, according to 2 recent studies.^2,3 These studies involved measuring the excitability of the cortex with the help of transcranial magnetic stimulation (TMS). TMS is a safe, painless, noninvasive technique that is based on the principle that a changing magnetic field induces an electrical current in any material that conducts electricity-including human brain tissue. Both of these studies found that sleep deprivation increased cortical excitability, as indicated by faster or greater responses to magnetic stimulation.

Frequent arousals at night, or stage shift into and out of sleep, may also facilitate seizures in patients with epilepsy, according to Beth Malow, MD, MS, medical director of the Vanderbilt Sleep Disorders Center at Vanderbilt University Medical Center, Nashville, Tennessee. She told Applied Neurology that scientists have not yet identified the exact mechanisms through which sleep disorders, such as sleep apnea, increase the frequency of seizures. "So this requires further study," she said. "But what we've noticed is that daytime sleepiness caused by sleep disturbance can have an indirect [ie, negative] effect on seizure control by making patients less likely to take or tolerate their drugs."

An increase in the number and duration of awakenings caused by seizures, as well as increased sleep stage shifts, are among the reasons why patients with epilepsy are more likely than the general population to experience sleep disruption and sleep deprivation, Malow explained during a presentation at the 9th Annual Meeting of the American Society for Experimental Neurotherapeutics, held March 8 to 10 in Washington, DC.⁴ "Seizures themselves have profound effects on sleep architecture, even apart from the resulting arousals and awakenings," she said. "Furthermore, epilepsy disrupts sleep organization even in the absence of seizures, and some antiepileptic drugs [AEDs] can adversely affect sleep quality or duration," she added.

AEDs AND SLEEP DISTURBANCE

Diagnosis of sleep disorders in patients with epilepsy is important because the presence of a sleep disorder has bearings on the antiepileptic medication chosen, according to Bazil. "You want to pick an agent that will potentially improve both sleep and seizure control," he said.

For a patient with both epilepsy and RLS, for example, physicians might consider using gabapentin (Neurontin), Bazil suggested. "There are some good randomized trials in RLS in which the drug has been used with good results in persons who don't have epilepsy." Other agents that may be useful in patients with epilepsy and RLS are pregabalin (Lyrica) and carbamazepine, Bazil added.

"Then there are drugs that tend to cause weight gain, such as valproic acid [Depakote]," Bazil continued. "This is a drug that you might not want to use in someone with obstructive sleep apnea, for example, because weight gain tends to worsen OSA," he cautioned.

Insomnia also can influence the choice or timing of AEDs. "There are some drugs that tend to worsen insomnia," Bazil said. "One that's really problematic is felbamate [Felbatol], which is only used in very difficult cases of epilepsy. But among all of the drugs that are on the market, this is the most likely to cause insomnia. When using a drug like this, you might want [to instruct the patient to take] it very early in the day, so that he or she has less in the system when it comes time to go to sleep," suggested Bazil.

Conversely, drugs that tend to be sedating, such as barbiturates or benzodiazepines, as well as phenytoin (Dilantin) should be given in the evening, Bazil recommended. "Preferably the complete dose, or if that's not possible then the higher dose should be given at bedtime."

TREAT OSA TO IMPROVE SEIZURE CONTROL

OSA is highly prevalent among patients with epilepsy-especially those who do not respond to standard treatment. In a 2000 study, Malow and colleagues found that one third of 39 patients referred for epilepsy surgery had comorbid OSA.⁵ Possible reasons for the high prevalence of OSA in patients with epilepsy, according to Malow, are their sedentary lifestyles, weight gain from AEDs, and the effects of AEDs on the upper airway.

Since OSA appears to increase the frequency of seizures, it seems logical that successfully treating OSA would improve seizure control in patients with epilepsy. However, very little research has been done in this area to date, and there is a scarcity of empirical evidence in support of this notion.

One of the few studies to test the effects of OSA treatment in persons with epilepsy was done last year by Malow and colleagues.⁶ "We carried out a pilot clinical trial to work out critical design issues before embarking on a definitive phase 3 randomized clinical trial that will answer the following question: Does treatment of coexisting OSA in patients with epilepsy improve seizure frequency, daytime sleepiness, and health-related quality of life?" Malow said.

Forty-five adults with refractory epilepsy (ie, 2 or more seizures per month) were enrolled in the trial if they met study criteria that included a history suggestive of OSA. After polysomnography (PSG) confirmed OSA, study participants were randomly selected to receive treatment with either therapeutic continuous positive airway pressure (CPAP) or sham CPAP. Participants were maintained with stable doses of AEDs, and CPAP adherence was monitored with electronic cards.

Of the 45 participants undergoing PSG, 35 met the criteria for OSA, as defined by an apnea-hypopnea index of 5 or more events per hour. Twenty-two patients were randomly selected to receive therapeutic CPAP (with 19 completers) and 13 to receive sham CPAP (all of whom completed the trial).

An analysis of the outcome data showed that significantly more patients (32%) treated with therapeutic CPAP had a 50% or greater reduction in seizures than those receiving sham CPAP (15%). These results suggest that managing a sleep disorder improves seizure control.

References:

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