LAS VEGAS—Several newer antiepileptic drugs (AEDs) are, along with new surgical options and nontraditional interventions such as medical marijuana, among a growing number of epilepsy treatments offering the potential for increased efficacy and improved patient care. However, subpopulations such as pregnant women pose special challenges for treatment selection, and the large number of patients who remain refractory to any epilepsy therapy represents perhaps the greatest challenge of all. Of the estimated three million people in the United States who have epilepsy, approximately one-third have uncontrolled seizures because no available treatment works for them, said Tracey A. Milligan, MD, at the American Academy of Neurology’s Fall 2016 Conference. Dr. Milligan is Vice Chair for Education in the Department of Neurology at Brigham and Women’s Hospital and Assistant Professor of Neurology at Harvard Medical School in Boston.

Illustrating the challenges of trying to achieve more widespread seizure control, Dr. Milligan cited a study of new-onset epilepsy by Brodie and colleagues, who found that 37% of patients had their seizures initially controlled, 22% had them eventually controlled, 16% had fluctuating control, and 25% had seizures that were refractory to treatment. This breakdown resonated with Dr. Milligan in terms of what she sees in her own practice—starting with the patients whose seizures are initially controlled. “They start a medication, they do well, they go on to live very full, active lives,” she said. “For the other 22%, we need to spend a little more time adjusting medications. Maybe they are adjusting lifestyle factors, but they do get to full control as well.”

Patients in the refractory group should be referred to epilepsy treatment centers, where surgical options can be considered. It is patients with fluctuating seizure control whom Dr. Milligan finds particularly interesting. “This is our sort of ‘relapsing-remitting’ epilepsy,” she said. “You start an agent, you think you have the seizures under control, and the drug works for a little while. Then the patient starts having seizures again…. These patients also need to be referred to an epilepsy treatment center to … be worked up and think about surgery if it is drug-resistant epilepsy.”

Questions for AED Selection

Clinical decisions such as the choice of an AED should be informed by the latest guidelines. Citing a 2015 report on unprovoked first seizures in adults, Dr. Milligan said that after one unprovoked seizure, there is a 21% to 45% risk of another seizure in two years. In her view, this new guideline raises more questions than it provides answers—like the new International League Against Epilepsy definition of epilepsy, in which one unprovoked seizure (rather than the previously required two) can be enough to support a diagnosis of epilepsy.

“How do we know which [patients] to diagnose with epilepsy after a single seizure?” she asked. “How do we know which patients are at highest risk of having a second seizure and we’re going to start with an AED?.... At this point we do not have an agreed-upon and reliable formula where we can plug in the demographics and the factors of the seizure and calculate the risk.”

In lieu of such information, clinicians need to ask several questions when selecting an AED, including which epilepsy syndrome the patient has, which medicines work best with it, and which patient factors apply. Dr. Milligan discussed four newer AEDS that are clinically available—clobazam, perampanel, eslicarbazepine, and brivaracetam. “These, for the most part, have been in trials involving patients with refractory seizures and all have a similar efficacy as add-on therapy.”

Onfi (Clobazam)

A benzodiazepine that offers fewer tolerance/sedation issues than others in its class, clobazam has been used since the 1970s as an anxiolytic/anticonvulsant. In 2011, Onfi (clobazam) was approved by the FDA for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients age 2 and older. Adverse effects include dizziness, somnolence, restlessness, and aggression. “It is a nice option when you are thinking about a benzodiazepine, because it does not have the same sort of tolerance/dependence [issues] as the other benzodiazepines do with epilepsy,” said Dr. Milligan.

Fycompa (Perampanel)

Fycompa (perampanel) is a noncompetitive AMPA-receptor inhibitor with a long half-life (70 to 100 hours). It is indicated for adjunctive treatment of focal epilepsy and primary generalized tonic-clonic seizures in patients age 12 and older. Side effects include dizziness, somnolence, and rash. The drug’s labeling includes a black-box warning for an occurrence Dr. Milligan described as unusual but important to be aware of: “Very interesting conversations you have with your patients when you prescribe this—where you have to say, ‘You may develop homicidal ideation on this medication. If you start to feel like killing somebody, please let me know right away.’”

Aptiom (Eslicarbazepine)

Approved by the FDA in 2013 for partial epilepsy (monotherapy or adjunctive treatment), Aptiom (eslicarbazepine) is a sodium-channel blocker whose longer half-life (20 hours) may help with peak effects and reduce hyponatremia and rash. It has few drug interactions and can be used with carbamazepine, though not with oxcarbazepine. Although the list of its most common side effects is long—dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor—it “probably has fewer adverse effects associated with it [overall] than other AEDs do.”

Briviact (Brivaracetam)

The newest agent, Briviact (brivaracetam), was approved in February 2016 as add-on therapy for refractory partial seizures in patients age 16 and older. Clinical trial results showed adverse effects such as somnolence, headache, dizziness, and fatigue to be mild and similar to what control patients experienced on placebo, but with a higher incidence of psychiatric/cognitive problems versus placebo. It is 20 times more potent at the SV2A receptor than levetiracetam, a related agent. “Unlike levetiracetam, it does [affect] oral contraceptives at a higher dose,” said Dr. Milligan, adding that she is inclined to use it after she has “tried tried agents that have been around longer”—at least until more data are in.

Marijuana, Pregnancy, and Depression

Dr. Milligan devoted the rest of her lecture to pregnancy, depression, and “the thing that everybody asks us about”—marijuana. She cited an open-label interventional trial by Devinsky and colleagues that found that cannabidiol might reduce seizure frequency and have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. “We do not have many randomized placebo-controlled trials at this point,” she said. “[Cannabidiol] probably works well for some syndromes but it does have adverse effects.”

Regarding pregnancy, a study by MacDonald and colleagues that examined complications in women giving birth showed a 10-times higher risk of death in women with epilepsy, along with a greater rate of every complication the investigators assessed. Other risks are associated with AED therapy. “We know that there are risks of seizures during pregnancy, and these are important to control,” said Dr. Milligan. “There are also risks that come along with taking certain AEDs—neural tube defects, small for gestational age, cleft lip and palate, and autism.”

One drug associated with cleft lip/palate and small size for gestational age is topiramate (FDA pregnancy category D). “Being a baby with small for gestational age carries an increased risk of obesity, cardiovascular disease, diabetes, and cognition [problems]—so it is important for us to be aware of [this fact] when we use topiramate,” said Dr. Milligan, who also cited findings from the North American Pregnancy Registry showing lamotrigine and levetiracetam to be the safest among AEDs assessed.

Depression is present in more than 33% of patients with epilepsy and entails a three- to four-times greater risk of suicide. Sudden death is 27 times more likely in patients with epilepsy than in the general population. “Seizures kill—this is something people are not aware of,” Dr. Milligan emphasized. “Depression is very prevalent, but there is also this high risk of death that goes along with epilepsy that is not just sudden unexplained death in epilepsy [SUDEP] but accidental death, assault….

“Mortality risk and years of potential life lost from epilepsy are second only to stroke. We need to think about education. For example, most patients who are found dead after a presumed seizure or from SUDEP are in a prone position. Maybe we should have for those refractory patients [something] like the sudden infant death syndrome campaign for babies to sleep on their backs, and not prone. It’s something to think about.”

—Fred Balzac

Suggested Reading

Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012;78(20):1548-1554.

Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270-278.

Devinsky O, Spruill T, Thurman D, Friedman D. Recognizing and preventing epilepsy-related mortality: a call for action. Neurology. 2016;86(8):779-786.

Hernandez-Diaz S. Evidence accumulates on the association between topiramate use early in pregnancy and the risk of oral clefts. Pharmacoepidemiol Drug Saf. 2014;23(10):1026-1028.

Krumholz A, Shinnar S, French J, et al. Evidence-based guideline: management of an unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2015;85(17):1526-1527.

Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-1077.

MacDonald SC, Bateman BT, McElrath TF, et al. Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States. JAMA Neurol. 2015;72(9):981-988.

Martin RC, Faught E, Richman J, et al. Psychiatric and neurologic risk factors for incident cases of new-onset epilepsy in older adults: data from U.S. Medicare beneficiaries. Epilepsia. 2014;55(7):1120-1127.

Pennell PB. Use of antiepileptic drugs during pregnancy: evolving concepts. Neurotherapeutics. 2016;13(4):811-820.

Vajda FJ, O’Brien TJ, Lander CM, et al. The teratogenicity of the newer antiepileptic drugs - an update. Acta Neurol Scand. 2014;130(4):234-238.

LAS VEGAS—Several newer antiepileptic drugs (AEDs) are, along with new surgical options and nontraditional interventions such as medical marijuana, among a growing number of epilepsy treatments offering the potential for increased efficacy and improved patient care. However, subpopulations such as pregnant women pose special challenges for treatment selection, and the large number of patients who remain refractory to any epilepsy therapy represents perhaps the greatest challenge of all. Of the estimated three million people in the United States who have epilepsy, approximately one-third have uncontrolled seizures because no available treatment works for them, said Tracey A. Milligan, MD, at the American Academy of Neurology’s Fall 2016 Conference. Dr. Milligan is Vice Chair for Education in the Department of Neurology at Brigham and Women’s Hospital and Assistant Professor of Neurology at Harvard Medical School in Boston.

Illustrating the challenges of trying to achieve more widespread seizure control, Dr. Milligan cited a study of new-onset epilepsy by Brodie and colleagues, who found that 37% of patients had their seizures initially controlled, 22% had them eventually controlled, 16% had fluctuating control, and 25% had seizures that were refractory to treatment. This breakdown resonated with Dr. Milligan in terms of what she sees in her own practice—starting with the patients whose seizures are initially controlled. “They start a medication, they do well, they go on to live very full, active lives,” she said. “For the other 22%, we need to spend a little more time adjusting medications. Maybe they are adjusting lifestyle factors, but they do get to full control as well.”

Patients in the refractory group should be referred to epilepsy treatment centers, where surgical options can be considered. It is patients with fluctuating seizure control whom Dr. Milligan finds particularly interesting. “This is our sort of ‘relapsing-remitting’ epilepsy,” she said. “You start an agent, you think you have the seizures under control, and the drug works for a little while. Then the patient starts having seizures again…. These patients also need to be referred to an epilepsy treatment center to … be worked up and think about surgery if it is drug-resistant epilepsy.”

Questions for AED Selection

Clinical decisions such as the choice of an AED should be informed by the latest guidelines. Citing a 2015 report on unprovoked first seizures in adults, Dr. Milligan said that after one unprovoked seizure, there is a 21% to 45% risk of another seizure in two years. In her view, this new guideline raises more questions than it provides answers—like the new International League Against Epilepsy definition of epilepsy, in which one unprovoked seizure (rather than the previously required two) can be enough to support a diagnosis of epilepsy.

“How do we know which [patients] to diagnose with epilepsy after a single seizure?” she asked. “How do we know which patients are at highest risk of having a second seizure and we’re going to start with an AED?.... At this point we do not have an agreed-upon and reliable formula where we can plug in the demographics and the factors of the seizure and calculate the risk.”

In lieu of such information, clinicians need to ask several questions when selecting an AED, including which epilepsy syndrome the patient has, which medicines work best with it, and which patient factors apply. Dr. Milligan discussed four newer AEDS that are clinically available—clobazam, perampanel, eslicarbazepine, and brivaracetam. “These, for the most part, have been in trials involving patients with refractory seizures and all have a similar efficacy as add-on therapy.”

Onfi (Clobazam)

A benzodiazepine that offers fewer tolerance/sedation issues than others in its class, clobazam has been used since the 1970s as an anxiolytic/anticonvulsant. In 2011, Onfi (clobazam) was approved by the FDA for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients age 2 and older. Adverse effects include dizziness, somnolence, restlessness, and aggression. “It is a nice option when you are thinking about a benzodiazepine, because it does not have the same sort of tolerance/dependence [issues] as the other benzodiazepines do with epilepsy,” said Dr. Milligan.

Fycompa (Perampanel)

Fycompa (perampanel) is a noncompetitive AMPA-receptor inhibitor with a long half-life (70 to 100 hours). It is indicated for adjunctive treatment of focal epilepsy and primary generalized tonic-clonic seizures in patients age 12 and older. Side effects include dizziness, somnolence, and rash. The drug’s labeling includes a black-box warning for an occurrence Dr. Milligan described as unusual but important to be aware of: “Very interesting conversations you have with your patients when you prescribe this—where you have to say, ‘You may develop homicidal ideation on this medication. If you start to feel like killing somebody, please let me know right away.’”

Aptiom (Eslicarbazepine)

Approved by the FDA in 2013 for partial epilepsy (monotherapy or adjunctive treatment), Aptiom (eslicarbazepine) is a sodium-channel blocker whose longer half-life (20 hours) may help with peak effects and reduce hyponatremia and rash. It has few drug interactions and can be used with carbamazepine, though not with oxcarbazepine. Although the list of its most common side effects is long—dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor—it “probably has fewer adverse effects associated with it [overall] than other AEDs do.”

Briviact (Brivaracetam)

The newest agent, Briviact (brivaracetam), was approved in February 2016 as add-on therapy for refractory partial seizures in patients age 16 and older. Clinical trial results showed adverse effects such as somnolence, headache, dizziness, and fatigue to be mild and similar to what control patients experienced on placebo, but with a higher incidence of psychiatric/cognitive problems versus placebo. It is 20 times more potent at the SV2A receptor than levetiracetam, a related agent. “Unlike levetiracetam, it does [affect] oral contraceptives at a higher dose,” said Dr. Milligan, adding that she is inclined to use it after she has “tried tried agents that have been around longer”—at least until more data are in.

Marijuana, Pregnancy, and Depression

Dr. Milligan devoted the rest of her lecture to pregnancy, depression, and “the thing that everybody asks us about”—marijuana. She cited an open-label interventional trial by Devinsky and colleagues that found that cannabidiol might reduce seizure frequency and have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. “We do not have many randomized placebo-controlled trials at this point,” she said. “[Cannabidiol] probably works well for some syndromes but it does have adverse effects.”

Regarding pregnancy, a study by MacDonald and colleagues that examined complications in women giving birth showed a 10-times higher risk of death in women with epilepsy, along with a greater rate of every complication the investigators assessed. Other risks are associated with AED therapy. “We know that there are risks of seizures during pregnancy, and these are important to control,” said Dr. Milligan. “There are also risks that come along with taking certain AEDs—neural tube defects, small for gestational age, cleft lip and palate, and autism.”

One drug associated with cleft lip/palate and small size for gestational age is topiramate (FDA pregnancy category D). “Being a baby with small for gestational age carries an increased risk of obesity, cardiovascular disease, diabetes, and cognition [problems]—so it is important for us to be aware of [this fact] when we use topiramate,” said Dr. Milligan, who also cited findings from the North American Pregnancy Registry showing lamotrigine and levetiracetam to be the safest among AEDs assessed.

Depression is present in more than 33% of patients with epilepsy and entails a three- to four-times greater risk of suicide. Sudden death is 27 times more likely in patients with epilepsy than in the general population. “Seizures kill—this is something people are not aware of,” Dr. Milligan emphasized. “Depression is very prevalent, but there is also this high risk of death that goes along with epilepsy that is not just sudden unexplained death in epilepsy [SUDEP] but accidental death, assault….

“Mortality risk and years of potential life lost from epilepsy are second only to stroke. We need to think about education. For example, most patients who are found dead after a presumed seizure or from SUDEP are in a prone position. Maybe we should have for those refractory patients [something] like the sudden infant death syndrome campaign for babies to sleep on their backs, and not prone. It’s something to think about.”

—Fred Balzac

Suggested Reading

Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012;78(20):1548-1554.

Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270-278.

Devinsky O, Spruill T, Thurman D, Friedman D. Recognizing and preventing epilepsy-related mortality: a call for action. Neurology. 2016;86(8):779-786.

Hernandez-Diaz S. Evidence accumulates on the association between topiramate use early in pregnancy and the risk of oral clefts. Pharmacoepidemiol Drug Saf. 2014;23(10):1026-1028.

Krumholz A, Shinnar S, French J, et al. Evidence-based guideline: management of an unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2015;85(17):1526-1527.

Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-1077.

MacDonald SC, Bateman BT, McElrath TF, et al. Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States. JAMA Neurol. 2015;72(9):981-988.

Martin RC, Faught E, Richman J, et al. Psychiatric and neurologic risk factors for incident cases of new-onset epilepsy in older adults: data from U.S. Medicare beneficiaries. Epilepsia. 2014;55(7):1120-1127.

Pennell PB. Use of antiepileptic drugs during pregnancy: evolving concepts. Neurotherapeutics. 2016;13(4):811-820.

Vajda FJ, O’Brien TJ, Lander CM, et al. The teratogenicity of the newer antiepileptic drugs - an update. Acta Neurol Scand. 2014;130(4):234-238.

LAS VEGAS—Several newer antiepileptic drugs (AEDs) are, along with new surgical options and nontraditional interventions such as medical marijuana, among a growing number of epilepsy treatments offering the potential for increased efficacy and improved patient care. However, subpopulations such as pregnant women pose special challenges for treatment selection, and the large number of patients who remain refractory to any epilepsy therapy represents perhaps the greatest challenge of all. Of the estimated three million people in the United States who have epilepsy, approximately one-third have uncontrolled seizures because no available treatment works for them, said Tracey A. Milligan, MD, at the American Academy of Neurology’s Fall 2016 Conference. Dr. Milligan is Vice Chair for Education in the Department of Neurology at Brigham and Women’s Hospital and Assistant Professor of Neurology at Harvard Medical School in Boston.

Illustrating the challenges of trying to achieve more widespread seizure control, Dr. Milligan cited a study of new-onset epilepsy by Brodie and colleagues, who found that 37% of patients had their seizures initially controlled, 22% had them eventually controlled, 16% had fluctuating control, and 25% had seizures that were refractory to treatment. This breakdown resonated with Dr. Milligan in terms of what she sees in her own practice—starting with the patients whose seizures are initially controlled. “They start a medication, they do well, they go on to live very full, active lives,” she said. “For the other 22%, we need to spend a little more time adjusting medications. Maybe they are adjusting lifestyle factors, but they do get to full control as well.”

Patients in the refractory group should be referred to epilepsy treatment centers, where surgical options can be considered. It is patients with fluctuating seizure control whom Dr. Milligan finds particularly interesting. “This is our sort of ‘relapsing-remitting’ epilepsy,” she said. “You start an agent, you think you have the seizures under control, and the drug works for a little while. Then the patient starts having seizures again…. These patients also need to be referred to an epilepsy treatment center to … be worked up and think about surgery if it is drug-resistant epilepsy.”

Questions for AED Selection

Clinical decisions such as the choice of an AED should be informed by the latest guidelines. Citing a 2015 report on unprovoked first seizures in adults, Dr. Milligan said that after one unprovoked seizure, there is a 21% to 45% risk of another seizure in two years. In her view, this new guideline raises more questions than it provides answers—like the new International League Against Epilepsy definition of epilepsy, in which one unprovoked seizure (rather than the previously required two) can be enough to support a diagnosis of epilepsy.

“How do we know which [patients] to diagnose with epilepsy after a single seizure?” she asked. “How do we know which patients are at highest risk of having a second seizure and we’re going to start with an AED?.... At this point we do not have an agreed-upon and reliable formula where we can plug in the demographics and the factors of the seizure and calculate the risk.”

In lieu of such information, clinicians need to ask several questions when selecting an AED, including which epilepsy syndrome the patient has, which medicines work best with it, and which patient factors apply. Dr. Milligan discussed four newer AEDS that are clinically available—clobazam, perampanel, eslicarbazepine, and brivaracetam. “These, for the most part, have been in trials involving patients with refractory seizures and all have a similar efficacy as add-on therapy.”

Onfi (Clobazam)

A benzodiazepine that offers fewer tolerance/sedation issues than others in its class, clobazam has been used since the 1970s as an anxiolytic/anticonvulsant. In 2011, Onfi (clobazam) was approved by the FDA for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients age 2 and older. Adverse effects include dizziness, somnolence, restlessness, and aggression. “It is a nice option when you are thinking about a benzodiazepine, because it does not have the same sort of tolerance/dependence [issues] as the other benzodiazepines do with epilepsy,” said Dr. Milligan.

Fycompa (Perampanel)

Fycompa (perampanel) is a noncompetitive AMPA-receptor inhibitor with a long half-life (70 to 100 hours). It is indicated for adjunctive treatment of focal epilepsy and primary generalized tonic-clonic seizures in patients age 12 and older. Side effects include dizziness, somnolence, and rash. The drug’s labeling includes a black-box warning for an occurrence Dr. Milligan described as unusual but important to be aware of: “Very interesting conversations you have with your patients when you prescribe this—where you have to say, ‘You may develop homicidal ideation on this medication. If you start to feel like killing somebody, please let me know right away.’”

Aptiom (Eslicarbazepine)

Approved by the FDA in 2013 for partial epilepsy (monotherapy or adjunctive treatment), Aptiom (eslicarbazepine) is a sodium-channel blocker whose longer half-life (20 hours) may help with peak effects and reduce hyponatremia and rash. It has few drug interactions and can be used with carbamazepine, though not with oxcarbazepine. Although the list of its most common side effects is long—dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor—it “probably has fewer adverse effects associated with it [overall] than other AEDs do.”

Briviact (Brivaracetam)

The newest agent, Briviact (brivaracetam), was approved in February 2016 as add-on therapy for refractory partial seizures in patients age 16 and older. Clinical trial results showed adverse effects such as somnolence, headache, dizziness, and fatigue to be mild and similar to what control patients experienced on placebo, but with a higher incidence of psychiatric/cognitive problems versus placebo. It is 20 times more potent at the SV2A receptor than levetiracetam, a related agent. “Unlike levetiracetam, it does [affect] oral contraceptives at a higher dose,” said Dr. Milligan, adding that she is inclined to use it after she has “tried tried agents that have been around longer”—at least until more data are in.

Marijuana, Pregnancy, and Depression

Dr. Milligan devoted the rest of her lecture to pregnancy, depression, and “the thing that everybody asks us about”—marijuana. She cited an open-label interventional trial by Devinsky and colleagues that found that cannabidiol might reduce seizure frequency and have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. “We do not have many randomized placebo-controlled trials at this point,” she said. “[Cannabidiol] probably works well for some syndromes but it does have adverse effects.”

Regarding pregnancy, a study by MacDonald and colleagues that examined complications in women giving birth showed a 10-times higher risk of death in women with epilepsy, along with a greater rate of every complication the investigators assessed. Other risks are associated with AED therapy. “We know that there are risks of seizures during pregnancy, and these are important to control,” said Dr. Milligan. “There are also risks that come along with taking certain AEDs—neural tube defects, small for gestational age, cleft lip and palate, and autism.”

One drug associated with cleft lip/palate and small size for gestational age is topiramate (FDA pregnancy category D). “Being a baby with small for gestational age carries an increased risk of obesity, cardiovascular disease, diabetes, and cognition [problems]—so it is important for us to be aware of [this fact] when we use topiramate,” said Dr. Milligan, who also cited findings from the North American Pregnancy Registry showing lamotrigine and levetiracetam to be the safest among AEDs assessed.

Depression is present in more than 33% of patients with epilepsy and entails a three- to four-times greater risk of suicide. Sudden death is 27 times more likely in patients with epilepsy than in the general population. “Seizures kill—this is something people are not aware of,” Dr. Milligan emphasized. “Depression is very prevalent, but there is also this high risk of death that goes along with epilepsy that is not just sudden unexplained death in epilepsy [SUDEP] but accidental death, assault….

“Mortality risk and years of potential life lost from epilepsy are second only to stroke. We need to think about education. For example, most patients who are found dead after a presumed seizure or from SUDEP are in a prone position. Maybe we should have for those refractory patients [something] like the sudden infant death syndrome campaign for babies to sleep on their backs, and not prone. It’s something to think about.”

—Fred Balzac

Suggested Reading

Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012;78(20):1548-1554.

Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270-278.

Devinsky O, Spruill T, Thurman D, Friedman D. Recognizing and preventing epilepsy-related mortality: a call for action. Neurology. 2016;86(8):779-786.

Hernandez-Diaz S. Evidence accumulates on the association between topiramate use early in pregnancy and the risk of oral clefts. Pharmacoepidemiol Drug Saf. 2014;23(10):1026-1028.

Krumholz A, Shinnar S, French J, et al. Evidence-based guideline: management of an unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2015;85(17):1526-1527.

Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-1077.

MacDonald SC, Bateman BT, McElrath TF, et al. Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States. JAMA Neurol. 2015;72(9):981-988.

Martin RC, Faught E, Richman J, et al. Psychiatric and neurologic risk factors for incident cases of new-onset epilepsy in older adults: data from U.S. Medicare beneficiaries. Epilepsia. 2014;55(7):1120-1127.

Pennell PB. Use of antiepileptic drugs during pregnancy: evolving concepts. Neurotherapeutics. 2016;13(4):811-820.

Vajda FJ, O’Brien TJ, Lander CM, et al. The teratogenicity of the newer antiepileptic drugs - an update. Acta Neurol Scand. 2014;130(4):234-238.

VANCOUVER—Erythropoietin (EPO) plus therapeutic hypothermia may reduce brain injury and improve one-year motor outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), according to phase II trial results presented at the 45th Annual Meeting of the Child Neurology Society.

A large number of in vitro and in vivo studies have shown that EPO has neuroprotective effects after neonatal HIE. “Acutely, it reduces inflammation and apoptosis and improves cell survival. In the long term, it enhances brain repair through a number of mechanisms,” said Yvonne Wu, MD, MPH, Professor of Neurology and Pediatrics at the University of California, San Francisco.

Hypothermia reduces the risk of death and moderate to severe disability, including cerebral palsy; however, about 40% of infants who are cooled still have adverse outcomes, said Dr. Wu. Studies suggest that multiple doses of EPO provide optimal neuro­protection. In addition, studies in animals have shown that EPO can be neuroprotective even when given up to seven days after the hypoxic-ischemic insult.

To study the effect of EPO and hypothermia combined in neonates with moderate to severe HIE, Dr. Wu and colleagues conducted a randomized, double-blind, placebo-controlled multicenter trial. They evaluated safety, feasibility, and biomarkers of brain injury.

Researchers randomized 50 patients at seven sites to receive either 1,000 U/kg of EPO plus hypothermia or placebo plus hypothermia. Twenty-four babies were randomized to receive EPO and 26 were randomized to receive placebo. Babies received the study drug on five days during the first week of age. Investigators performed MRI on days 4 through 7. They assessed patients’ outcomes at six months and 12 months.

Babies included in the study met standard cooling criteria, including evidence of perinatal distress (eg, Apgar score of less than 5 at 10 minutes). Investigators excluded babies with a genetic disorder, congenital malformation, birth weight less than 1,800 g, microcephaly, or no indwelling line, as well as babies for whom withdrawal of care was considered or who were unlikely to be followed up at 12 months.

To assess neurodevelopmental outcomes at 12 months, researchers administered the Warner Initial Developmental Evaluation (WIDEA), a parental questionnaire that assesses four domains of infant development. In addition, they rated motor function using the Alberta Infant Motor Scale (AIMS). At 12 months, the EPOgroup had a significantly higher AIMS score and a trend toward improvement on the WIDEA score, compared with the placebo group.

Out of 24 infants receiving EPO, 23 had MRI and received three or more doses of treatment. About half of the babies received four to five doses of EPO prior to the MRI.

Researchers scored eight regions of the brain based on the extent of abnormal signal intensity. They found that the babies in the EPO-treated group had a lower median global injury score than those in the placebo group (2 vs 11). In addition, the number of patients with moderate or severe brain MRI abnormalities was lower in the EPO group (one out of 24) versus the placebo group (11 out of 26).

Researchers also noted that EPO appeared to protect the subcortical region of the brain; fewer babies in the EPO-treated group had injury to the deep gray nuclei, compared with babies who received placebo. Two babies died before hospital discharge in the EPO plus hypothermia group, and five died in the hypothermia-alone group. One baby in each group was lost to follow-up at 12 months. No adverse events were considered related to EPO treatment.

“These are small numbers, but our findings raise the possibility that EPO is really doing what we see in animals, which is reducing injury and enhancing repair, so that outcomes are better than expected hypoxic-ischemic encephalopathy,” said Dr. Wu.

—Erica Tricarico

Suggested Reading

Rogers EE, Bonifacio Sl, Glass HC, et al. Erythropoieten and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol. 2014 Aug 24 [Epub ahead of print].

Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012 Sep 24 [Epub ahead of print].

Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6).

VANCOUVER—Erythropoietin (EPO) plus therapeutic hypothermia may reduce brain injury and improve one-year motor outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), according to phase II trial results presented at the 45th Annual Meeting of the Child Neurology Society.

A large number of in vitro and in vivo studies have shown that EPO has neuroprotective effects after neonatal HIE. “Acutely, it reduces inflammation and apoptosis and improves cell survival. In the long term, it enhances brain repair through a number of mechanisms,” said Yvonne Wu, MD, MPH, Professor of Neurology and Pediatrics at the University of California, San Francisco.

Hypothermia reduces the risk of death and moderate to severe disability, including cerebral palsy; however, about 40% of infants who are cooled still have adverse outcomes, said Dr. Wu. Studies suggest that multiple doses of EPO provide optimal neuro­protection. In addition, studies in animals have shown that EPO can be neuroprotective even when given up to seven days after the hypoxic-ischemic insult.

To study the effect of EPO and hypothermia combined in neonates with moderate to severe HIE, Dr. Wu and colleagues conducted a randomized, double-blind, placebo-controlled multicenter trial. They evaluated safety, feasibility, and biomarkers of brain injury.

Researchers randomized 50 patients at seven sites to receive either 1,000 U/kg of EPO plus hypothermia or placebo plus hypothermia. Twenty-four babies were randomized to receive EPO and 26 were randomized to receive placebo. Babies received the study drug on five days during the first week of age. Investigators performed MRI on days 4 through 7. They assessed patients’ outcomes at six months and 12 months.

Babies included in the study met standard cooling criteria, including evidence of perinatal distress (eg, Apgar score of less than 5 at 10 minutes). Investigators excluded babies with a genetic disorder, congenital malformation, birth weight less than 1,800 g, microcephaly, or no indwelling line, as well as babies for whom withdrawal of care was considered or who were unlikely to be followed up at 12 months.

To assess neurodevelopmental outcomes at 12 months, researchers administered the Warner Initial Developmental Evaluation (WIDEA), a parental questionnaire that assesses four domains of infant development. In addition, they rated motor function using the Alberta Infant Motor Scale (AIMS). At 12 months, the EPOgroup had a significantly higher AIMS score and a trend toward improvement on the WIDEA score, compared with the placebo group.

Out of 24 infants receiving EPO, 23 had MRI and received three or more doses of treatment. About half of the babies received four to five doses of EPO prior to the MRI.

Researchers scored eight regions of the brain based on the extent of abnormal signal intensity. They found that the babies in the EPO-treated group had a lower median global injury score than those in the placebo group (2 vs 11). In addition, the number of patients with moderate or severe brain MRI abnormalities was lower in the EPO group (one out of 24) versus the placebo group (11 out of 26).

Researchers also noted that EPO appeared to protect the subcortical region of the brain; fewer babies in the EPO-treated group had injury to the deep gray nuclei, compared with babies who received placebo. Two babies died before hospital discharge in the EPO plus hypothermia group, and five died in the hypothermia-alone group. One baby in each group was lost to follow-up at 12 months. No adverse events were considered related to EPO treatment.

“These are small numbers, but our findings raise the possibility that EPO is really doing what we see in animals, which is reducing injury and enhancing repair, so that outcomes are better than expected hypoxic-ischemic encephalopathy,” said Dr. Wu.

—Erica Tricarico

Suggested Reading

Rogers EE, Bonifacio Sl, Glass HC, et al. Erythropoieten and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol. 2014 Aug 24 [Epub ahead of print].

Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012 Sep 24 [Epub ahead of print].

Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6).

VANCOUVER—Erythropoietin (EPO) plus therapeutic hypothermia may reduce brain injury and improve one-year motor outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), according to phase II trial results presented at the 45th Annual Meeting of the Child Neurology Society.

A large number of in vitro and in vivo studies have shown that EPO has neuroprotective effects after neonatal HIE. “Acutely, it reduces inflammation and apoptosis and improves cell survival. In the long term, it enhances brain repair through a number of mechanisms,” said Yvonne Wu, MD, MPH, Professor of Neurology and Pediatrics at the University of California, San Francisco.

Hypothermia reduces the risk of death and moderate to severe disability, including cerebral palsy; however, about 40% of infants who are cooled still have adverse outcomes, said Dr. Wu. Studies suggest that multiple doses of EPO provide optimal neuro­protection. In addition, studies in animals have shown that EPO can be neuroprotective even when given up to seven days after the hypoxic-ischemic insult.

To study the effect of EPO and hypothermia combined in neonates with moderate to severe HIE, Dr. Wu and colleagues conducted a randomized, double-blind, placebo-controlled multicenter trial. They evaluated safety, feasibility, and biomarkers of brain injury.

Researchers randomized 50 patients at seven sites to receive either 1,000 U/kg of EPO plus hypothermia or placebo plus hypothermia. Twenty-four babies were randomized to receive EPO and 26 were randomized to receive placebo. Babies received the study drug on five days during the first week of age. Investigators performed MRI on days 4 through 7. They assessed patients’ outcomes at six months and 12 months.

Babies included in the study met standard cooling criteria, including evidence of perinatal distress (eg, Apgar score of less than 5 at 10 minutes). Investigators excluded babies with a genetic disorder, congenital malformation, birth weight less than 1,800 g, microcephaly, or no indwelling line, as well as babies for whom withdrawal of care was considered or who were unlikely to be followed up at 12 months.

To assess neurodevelopmental outcomes at 12 months, researchers administered the Warner Initial Developmental Evaluation (WIDEA), a parental questionnaire that assesses four domains of infant development. In addition, they rated motor function using the Alberta Infant Motor Scale (AIMS). At 12 months, the EPOgroup had a significantly higher AIMS score and a trend toward improvement on the WIDEA score, compared with the placebo group.

Out of 24 infants receiving EPO, 23 had MRI and received three or more doses of treatment. About half of the babies received four to five doses of EPO prior to the MRI.

Researchers scored eight regions of the brain based on the extent of abnormal signal intensity. They found that the babies in the EPO-treated group had a lower median global injury score than those in the placebo group (2 vs 11). In addition, the number of patients with moderate or severe brain MRI abnormalities was lower in the EPO group (one out of 24) versus the placebo group (11 out of 26).

Researchers also noted that EPO appeared to protect the subcortical region of the brain; fewer babies in the EPO-treated group had injury to the deep gray nuclei, compared with babies who received placebo. Two babies died before hospital discharge in the EPO plus hypothermia group, and five died in the hypothermia-alone group. One baby in each group was lost to follow-up at 12 months. No adverse events were considered related to EPO treatment.

“These are small numbers, but our findings raise the possibility that EPO is really doing what we see in animals, which is reducing injury and enhancing repair, so that outcomes are better than expected hypoxic-ischemic encephalopathy,” said Dr. Wu.

—Erica Tricarico

Suggested Reading

Rogers EE, Bonifacio Sl, Glass HC, et al. Erythropoieten and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol. 2014 Aug 24 [Epub ahead of print].

Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012 Sep 24 [Epub ahead of print].

Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6).

Diabetes, ischemic heart disease, and back and neck pain are the top three conditions accounting for the highest spending on personal health care in the United States, according to a report published online Dec. 27 in JAMA.

In addition, spending on pharmaceuticals – particularly diabetes therapies, antihypertensive drugs, and medications for hyperlipidemia – drove much of the massive increase in health care spending during the past 2 decades, said Joseph L. Dieleman, PhD, of the Institute for Health Metrics and Evaluation, University of Washington, Seattle, and his associates.

copyright Kativ/iStockphoto.com

• Twenty conditions accounted for approximately 58% of personal health care spending, which totaled an estimated $1.2 trillion in 2013.

• More resources were spent on diabetes than any other condition in 2013, at an estimated $101.4 billion. Prescribed medications accounted for nearly 60% of diabetes costs.

• The second-highest amount of health care spending was for ischemic heart disease, which accounted for $88.1 billion in 2013. Most such spending occurred in inpatient settings.

• Low-back and neck pain, comprising the third-highest level of spending, cost an estimated $87.6 billion. Approximately 60% of this spending occurred in ambulatory settings.

• Among all 155 conditions, spending for diabetes and low-back and neck pain increased the most during the 18-year study period.

• Among all six types of care, spending on pharmaceuticals and emergency care increased the most during the study period.

It is important to note that for the purposes of this study, cancer was disaggregated into 29 separate conditions, and none of them placed in the top 20 for health care spending, Dr. Dieleman and his associates noted (JAMA. 2016;316[24]:2627-46. doi: 10.1001/jama.2016.16885).

When spending was categorized by patient age groups, working-age adults accounted for the greatest amount spent in 2013, estimated at $1,070.1 billion. But that was followed closely by patients aged 65 and older, who accounted for an estimated $796.5 billion, much of which was spent on care in nursing facilities. The smallest amount of health care spending was in children over age 1 and adolescents, who accounted for an estimated $233.5 billion.

Among the other study findings:

• Spending on pharmaceutical treatment of two conditions, hypertension and hyperlipidemia, increased at more than double the rate of total health care spending. It totaled an estimated $135.7 billion in 2013.

• Other top-20 conditions included falls, depression, skin disorders such as acne and eczema, sense disorders such as vision correction and hearing loss, dental care, urinary disorders, and lower respiratory tract infection.

This work was supported by the National Institute on Aging and the Vitality Institute. Dr. Dieleman and his associates reported having no relevant financial disclosures.

Diabetes, ischemic heart disease, and back and neck pain are the top three conditions accounting for the highest spending on personal health care in the United States, according to a report published online Dec. 27 in JAMA.

In addition, spending on pharmaceuticals – particularly diabetes therapies, antihypertensive drugs, and medications for hyperlipidemia – drove much of the massive increase in health care spending during the past 2 decades, said Joseph L. Dieleman, PhD, of the Institute for Health Metrics and Evaluation, University of Washington, Seattle, and his associates.

copyright Kativ/iStockphoto.com

• Twenty conditions accounted for approximately 58% of personal health care spending, which totaled an estimated $1.2 trillion in 2013.

• More resources were spent on diabetes than any other condition in 2013, at an estimated $101.4 billion. Prescribed medications accounted for nearly 60% of diabetes costs.

• The second-highest amount of health care spending was for ischemic heart disease, which accounted for $88.1 billion in 2013. Most such spending occurred in inpatient settings.

• Low-back and neck pain, comprising the third-highest level of spending, cost an estimated $87.6 billion. Approximately 60% of this spending occurred in ambulatory settings.

• Among all 155 conditions, spending for diabetes and low-back and neck pain increased the most during the 18-year study period.

• Among all six types of care, spending on pharmaceuticals and emergency care increased the most during the study period.

It is important to note that for the purposes of this study, cancer was disaggregated into 29 separate conditions, and none of them placed in the top 20 for health care spending, Dr. Dieleman and his associates noted (JAMA. 2016;316[24]:2627-46. doi: 10.1001/jama.2016.16885).

When spending was categorized by patient age groups, working-age adults accounted for the greatest amount spent in 2013, estimated at $1,070.1 billion. But that was followed closely by patients aged 65 and older, who accounted for an estimated $796.5 billion, much of which was spent on care in nursing facilities. The smallest amount of health care spending was in children over age 1 and adolescents, who accounted for an estimated $233.5 billion.

Among the other study findings:

• Spending on pharmaceutical treatment of two conditions, hypertension and hyperlipidemia, increased at more than double the rate of total health care spending. It totaled an estimated $135.7 billion in 2013.

• Other top-20 conditions included falls, depression, skin disorders such as acne and eczema, sense disorders such as vision correction and hearing loss, dental care, urinary disorders, and lower respiratory tract infection.

This work was supported by the National Institute on Aging and the Vitality Institute. Dr. Dieleman and his associates reported having no relevant financial disclosures.

Diabetes, ischemic heart disease, and back and neck pain are the top three conditions accounting for the highest spending on personal health care in the United States, according to a report published online Dec. 27 in JAMA.

In addition, spending on pharmaceuticals – particularly diabetes therapies, antihypertensive drugs, and medications for hyperlipidemia – drove much of the massive increase in health care spending during the past 2 decades, said Joseph L. Dieleman, PhD, of the Institute for Health Metrics and Evaluation, University of Washington, Seattle, and his associates.

copyright Kativ/iStockphoto.com

• Twenty conditions accounted for approximately 58% of personal health care spending, which totaled an estimated $1.2 trillion in 2013.

• More resources were spent on diabetes than any other condition in 2013, at an estimated $101.4 billion. Prescribed medications accounted for nearly 60% of diabetes costs.

• The second-highest amount of health care spending was for ischemic heart disease, which accounted for $88.1 billion in 2013. Most such spending occurred in inpatient settings.

• Low-back and neck pain, comprising the third-highest level of spending, cost an estimated $87.6 billion. Approximately 60% of this spending occurred in ambulatory settings.

• Among all 155 conditions, spending for diabetes and low-back and neck pain increased the most during the 18-year study period.

• Among all six types of care, spending on pharmaceuticals and emergency care increased the most during the study period.

It is important to note that for the purposes of this study, cancer was disaggregated into 29 separate conditions, and none of them placed in the top 20 for health care spending, Dr. Dieleman and his associates noted (JAMA. 2016;316[24]:2627-46. doi: 10.1001/jama.2016.16885).

When spending was categorized by patient age groups, working-age adults accounted for the greatest amount spent in 2013, estimated at $1,070.1 billion. But that was followed closely by patients aged 65 and older, who accounted for an estimated $796.5 billion, much of which was spent on care in nursing facilities. The smallest amount of health care spending was in children over age 1 and adolescents, who accounted for an estimated $233.5 billion.

Among the other study findings:

• Spending on pharmaceutical treatment of two conditions, hypertension and hyperlipidemia, increased at more than double the rate of total health care spending. It totaled an estimated $135.7 billion in 2013.

• Other top-20 conditions included falls, depression, skin disorders such as acne and eczema, sense disorders such as vision correction and hearing loss, dental care, urinary disorders, and lower respiratory tract infection.

This work was supported by the National Institute on Aging and the Vitality Institute. Dr. Dieleman and his associates reported having no relevant financial disclosures.

LONDON—Many patients with multiple sclerosis (MS) suffer from bladder dysfunction, however, few of these patients have their symptoms managed, according to an overview presented at the 32nd Congress of the European Committee for Treatment and Research in MS.

If a patient reports bladder symptoms, most often those bladder symptoms will persist and increase, said Jalesh Panicker, MD, DM, Consultant Neurologist and Clinical Lead in Uroneurology at the University College London Institute of Neurology in Queen Square, London. Symptoms of urinary frequency, urgency, incontinence, and nocturia, which are collectively called overactive bladder syndrome, increase with increased duration of MS and tend to correlate with the neurologic disability, especially lower limb parameter weakness.

In a large survey of 3,000 patients with MS, 90% rated bladder complications as one of the top five common symptomatic problems. Seventy percent of the group reported that bladder issues had a moderate or high impact on them. Only one-third of patients surveyed reported improvement after starting disease-modifying therapies.

Bladder symptoms in MS occur, on average, six years into the illness. Lower urinary tract symptoms are present in 10% of patients at first diagnosis. To help address this issue, the Actionable eight-item questionnaire was developed to help make it easier for doctors to assess bladder problems, said Dr. Panicker.

Lesion location plays a significant role in urinary tract dysfunction. Patients with suprapontine lesions present predominantly with overactive bladder, whereas patients with spinal lesions tend to report voiding symptoms such as hesitancy and poor stream. Plaques in the cerebral cord can also alter the pattern of lower urinary tract dysfunction.

Measuring post-void residue is critical for bladder dysfunction management. Unlike in urgency and incontinence, patients tend to have difficulties expressing voiding and voiding dysfunction symptoms. A high post-void residue can cause urinary tract infections and lead to devastating effects on patients, Dr. Panicker said. Using a bladder scanner to detect high post-void residuals may help reduce urinary tract infections.

Oral Agents

The three most commonly used treatments for bladder dysfunction in patients with MS are oral agents, botulinum toxin, and neuromodulation. Oral antimuscarinics work through the muscarinic receptors of the bladder, reducing bladder sensation and intrusive pressures, inhibiting detrusor overactivity, and improving bladder capacity. Oxybutynin, for example, can cause dry mouth and dry eyes, whereas newer antimuscarinics such as tolteradine, solifenancin, or fesoteradine are less likely to cause dry eyes, dry mouth, or constipation, Dr. Panicker noted.

Anticholinergic burden refers to the cumulative effect of multiple medications with anticholinergic properties. The higher the anticholinergic burden, the greater the risk of cognitive impairment, impaired functional performance, mortality, and brain atrophy. The Anticholinergic Burden Scale (ACB) grades medications according to their anticholinergic burden—mild (ACB1), moderate (ACB2), and severe (ACB3). Total ACB score is the sum of each medication the patient is on; any ACB score over 3 is considered clinically relevant.

Beta 3 agonists are another class of oral agents used to control bladder symptoms. Beta 3 agonists inhibit intrusive muscle contractions and increase relaxation by acting on the beta 3 receptors present on the wall of the bladder. Unlike antimuscarinics, beta 3 agonists are devoid of side effects like dry mouth, dry eyes, and constipation; however, these oral agents are associated with cardiovascular side effects. Currently, there are pivotal phase III studies on the efficacy of mirabegron in the UK, however, there is limited evidence from neurologic patients and there is a need for more long-term data, Dr. Panicker said.

Botulinum Toxin

Botulinum toxin is effective for bladder management. Evidence shows that patients with MS experienced significant improvement in urinary incontinence, frequency, and urgency as early as four weeks after injections, and this beneficial effect is not lost with repeated injections. Three pivotal phase III studies have demonstrated the efficacy of onabotulinumtoxinA for improving incontinence. Studies suggest that onabotulinumtoxinA significantly improved incontinence at week 12. The median duration of retreatment was 42 weeks.

Neuromodulation

Stimulating the tibial nerve is beneficial in managing overactive bladder symptoms such as urinary frequency and incontinence. Percutaneous tibial nerve stimulation is one of the few treatments that does not tend to worsen voiding dysfunction. It is also potentially a treatment for patients who are retaining urine or experiencing incomplete bladder emptying.

“With several disease-modifying therapies over the last few years, it is clear that the number of MS relapses in patients is coming down. There is evidence to suggest that the neurologic disability that accumulates is also either halted or possibly even reversed. Whether the nonmotor symptoms of MS, such as urinary tract dysfunction, also would get halted or reversed with these treatments is an area for further research,” said Dr. Panicker.

—Erica Tricarico

Suggested Reading

Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol. 2012;187(6):2131-2139.

Jongen PJ, Blok BF, Heesakkers JP, et al. Simplified scoring of the Actionable 8-item screening questionnaire for neurogenic bladder overactivity in multiple sclerosis: a comparative analysis of test performance at different cut-off points. BMC Urol. 2015;15:106.

Wintner A, Kim MM, Bechis SK, Kreydin El. Voiding dysfunction in multiple sclerosis. Semin Neurol. 2016;36(1):34-40.

LONDON—Many patients with multiple sclerosis (MS) suffer from bladder dysfunction, however, few of these patients have their symptoms managed, according to an overview presented at the 32nd Congress of the European Committee for Treatment and Research in MS.

If a patient reports bladder symptoms, most often those bladder symptoms will persist and increase, said Jalesh Panicker, MD, DM, Consultant Neurologist and Clinical Lead in Uroneurology at the University College London Institute of Neurology in Queen Square, London. Symptoms of urinary frequency, urgency, incontinence, and nocturia, which are collectively called overactive bladder syndrome, increase with increased duration of MS and tend to correlate with the neurologic disability, especially lower limb parameter weakness.

In a large survey of 3,000 patients with MS, 90% rated bladder complications as one of the top five common symptomatic problems. Seventy percent of the group reported that bladder issues had a moderate or high impact on them. Only one-third of patients surveyed reported improvement after starting disease-modifying therapies.

Bladder symptoms in MS occur, on average, six years into the illness. Lower urinary tract symptoms are present in 10% of patients at first diagnosis. To help address this issue, the Actionable eight-item questionnaire was developed to help make it easier for doctors to assess bladder problems, said Dr. Panicker.

Lesion location plays a significant role in urinary tract dysfunction. Patients with suprapontine lesions present predominantly with overactive bladder, whereas patients with spinal lesions tend to report voiding symptoms such as hesitancy and poor stream. Plaques in the cerebral cord can also alter the pattern of lower urinary tract dysfunction.

Measuring post-void residue is critical for bladder dysfunction management. Unlike in urgency and incontinence, patients tend to have difficulties expressing voiding and voiding dysfunction symptoms. A high post-void residue can cause urinary tract infections and lead to devastating effects on patients, Dr. Panicker said. Using a bladder scanner to detect high post-void residuals may help reduce urinary tract infections.

Oral Agents

The three most commonly used treatments for bladder dysfunction in patients with MS are oral agents, botulinum toxin, and neuromodulation. Oral antimuscarinics work through the muscarinic receptors of the bladder, reducing bladder sensation and intrusive pressures, inhibiting detrusor overactivity, and improving bladder capacity. Oxybutynin, for example, can cause dry mouth and dry eyes, whereas newer antimuscarinics such as tolteradine, solifenancin, or fesoteradine are less likely to cause dry eyes, dry mouth, or constipation, Dr. Panicker noted.

Anticholinergic burden refers to the cumulative effect of multiple medications with anticholinergic properties. The higher the anticholinergic burden, the greater the risk of cognitive impairment, impaired functional performance, mortality, and brain atrophy. The Anticholinergic Burden Scale (ACB) grades medications according to their anticholinergic burden—mild (ACB1), moderate (ACB2), and severe (ACB3). Total ACB score is the sum of each medication the patient is on; any ACB score over 3 is considered clinically relevant.

Beta 3 agonists are another class of oral agents used to control bladder symptoms. Beta 3 agonists inhibit intrusive muscle contractions and increase relaxation by acting on the beta 3 receptors present on the wall of the bladder. Unlike antimuscarinics, beta 3 agonists are devoid of side effects like dry mouth, dry eyes, and constipation; however, these oral agents are associated with cardiovascular side effects. Currently, there are pivotal phase III studies on the efficacy of mirabegron in the UK, however, there is limited evidence from neurologic patients and there is a need for more long-term data, Dr. Panicker said.

Botulinum Toxin

Botulinum toxin is effective for bladder management. Evidence shows that patients with MS experienced significant improvement in urinary incontinence, frequency, and urgency as early as four weeks after injections, and this beneficial effect is not lost with repeated injections. Three pivotal phase III studies have demonstrated the efficacy of onabotulinumtoxinA for improving incontinence. Studies suggest that onabotulinumtoxinA significantly improved incontinence at week 12. The median duration of retreatment was 42 weeks.

Neuromodulation

Stimulating the tibial nerve is beneficial in managing overactive bladder symptoms such as urinary frequency and incontinence. Percutaneous tibial nerve stimulation is one of the few treatments that does not tend to worsen voiding dysfunction. It is also potentially a treatment for patients who are retaining urine or experiencing incomplete bladder emptying.

“With several disease-modifying therapies over the last few years, it is clear that the number of MS relapses in patients is coming down. There is evidence to suggest that the neurologic disability that accumulates is also either halted or possibly even reversed. Whether the nonmotor symptoms of MS, such as urinary tract dysfunction, also would get halted or reversed with these treatments is an area for further research,” said Dr. Panicker.

—Erica Tricarico

Suggested Reading

Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol. 2012;187(6):2131-2139.

Jongen PJ, Blok BF, Heesakkers JP, et al. Simplified scoring of the Actionable 8-item screening questionnaire for neurogenic bladder overactivity in multiple sclerosis: a comparative analysis of test performance at different cut-off points. BMC Urol. 2015;15:106.

Wintner A, Kim MM, Bechis SK, Kreydin El. Voiding dysfunction in multiple sclerosis. Semin Neurol. 2016;36(1):34-40.

LONDON—Many patients with multiple sclerosis (MS) suffer from bladder dysfunction, however, few of these patients have their symptoms managed, according to an overview presented at the 32nd Congress of the European Committee for Treatment and Research in MS.

If a patient reports bladder symptoms, most often those bladder symptoms will persist and increase, said Jalesh Panicker, MD, DM, Consultant Neurologist and Clinical Lead in Uroneurology at the University College London Institute of Neurology in Queen Square, London. Symptoms of urinary frequency, urgency, incontinence, and nocturia, which are collectively called overactive bladder syndrome, increase with increased duration of MS and tend to correlate with the neurologic disability, especially lower limb parameter weakness.

In a large survey of 3,000 patients with MS, 90% rated bladder complications as one of the top five common symptomatic problems. Seventy percent of the group reported that bladder issues had a moderate or high impact on them. Only one-third of patients surveyed reported improvement after starting disease-modifying therapies.

Bladder symptoms in MS occur, on average, six years into the illness. Lower urinary tract symptoms are present in 10% of patients at first diagnosis. To help address this issue, the Actionable eight-item questionnaire was developed to help make it easier for doctors to assess bladder problems, said Dr. Panicker.

Lesion location plays a significant role in urinary tract dysfunction. Patients with suprapontine lesions present predominantly with overactive bladder, whereas patients with spinal lesions tend to report voiding symptoms such as hesitancy and poor stream. Plaques in the cerebral cord can also alter the pattern of lower urinary tract dysfunction.

Measuring post-void residue is critical for bladder dysfunction management. Unlike in urgency and incontinence, patients tend to have difficulties expressing voiding and voiding dysfunction symptoms. A high post-void residue can cause urinary tract infections and lead to devastating effects on patients, Dr. Panicker said. Using a bladder scanner to detect high post-void residuals may help reduce urinary tract infections.

Oral Agents

The three most commonly used treatments for bladder dysfunction in patients with MS are oral agents, botulinum toxin, and neuromodulation. Oral antimuscarinics work through the muscarinic receptors of the bladder, reducing bladder sensation and intrusive pressures, inhibiting detrusor overactivity, and improving bladder capacity. Oxybutynin, for example, can cause dry mouth and dry eyes, whereas newer antimuscarinics such as tolteradine, solifenancin, or fesoteradine are less likely to cause dry eyes, dry mouth, or constipation, Dr. Panicker noted.

Anticholinergic burden refers to the cumulative effect of multiple medications with anticholinergic properties. The higher the anticholinergic burden, the greater the risk of cognitive impairment, impaired functional performance, mortality, and brain atrophy. The Anticholinergic Burden Scale (ACB) grades medications according to their anticholinergic burden—mild (ACB1), moderate (ACB2), and severe (ACB3). Total ACB score is the sum of each medication the patient is on; any ACB score over 3 is considered clinically relevant.

Beta 3 agonists are another class of oral agents used to control bladder symptoms. Beta 3 agonists inhibit intrusive muscle contractions and increase relaxation by acting on the beta 3 receptors present on the wall of the bladder. Unlike antimuscarinics, beta 3 agonists are devoid of side effects like dry mouth, dry eyes, and constipation; however, these oral agents are associated with cardiovascular side effects. Currently, there are pivotal phase III studies on the efficacy of mirabegron in the UK, however, there is limited evidence from neurologic patients and there is a need for more long-term data, Dr. Panicker said.

Botulinum Toxin

Botulinum toxin is effective for bladder management. Evidence shows that patients with MS experienced significant improvement in urinary incontinence, frequency, and urgency as early as four weeks after injections, and this beneficial effect is not lost with repeated injections. Three pivotal phase III studies have demonstrated the efficacy of onabotulinumtoxinA for improving incontinence. Studies suggest that onabotulinumtoxinA significantly improved incontinence at week 12. The median duration of retreatment was 42 weeks.

Neuromodulation

Stimulating the tibial nerve is beneficial in managing overactive bladder symptoms such as urinary frequency and incontinence. Percutaneous tibial nerve stimulation is one of the few treatments that does not tend to worsen voiding dysfunction. It is also potentially a treatment for patients who are retaining urine or experiencing incomplete bladder emptying.

“With several disease-modifying therapies over the last few years, it is clear that the number of MS relapses in patients is coming down. There is evidence to suggest that the neurologic disability that accumulates is also either halted or possibly even reversed. Whether the nonmotor symptoms of MS, such as urinary tract dysfunction, also would get halted or reversed with these treatments is an area for further research,” said Dr. Panicker.

—Erica Tricarico

Suggested Reading

Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol. 2012;187(6):2131-2139.

Jongen PJ, Blok BF, Heesakkers JP, et al. Simplified scoring of the Actionable 8-item screening questionnaire for neurogenic bladder overactivity in multiple sclerosis: a comparative analysis of test performance at different cut-off points. BMC Urol. 2015;15:106.

Wintner A, Kim MM, Bechis SK, Kreydin El. Voiding dysfunction in multiple sclerosis. Semin Neurol. 2016;36(1):34-40.

LAS VEGAS—Although continuous positive airway pressure (CPAP) failed to protect patients with obstructive sleep apnea from cardiovascular events in a recently completed large randomized trial, the results are not definitive, according to Alan Z. Segal, MD, Associate Professor of Clinical Neurology at Weill Cornell Medical College in New York City. In an update on sleep disorders at the American Academy of Neurology’s Fall 2016 Conference, Dr. Segal explained that the average adherence to CPAP in this trial, called SAVE, was less than that which has been widely accepted as adequate.

“Medicare has a requirement that CPAP be used for more than four hours on 70% of nights in a 30-day period for patients to keep their device,” observed Dr. Segal, providing one example of a way in which four hours or more of CPAP has been defined as a minimum duration. In the SAVE study by McEvoy et al, the mean duration of CPAP was 3.3 hours. Only 42% of patients met the four-hour definition of adherence, which was the duration the authors themselves had defined as good adherence.

“Our field was very much affected by this study,” Dr. Segal acknowledged. “It created quite a lot of controversy and criticisms over methodologic flaws. Like any study that does not produce the results we want, we start to pick at it to identify where it might have been inadequate, and the biggest inadequacy of this particular study is that patients in the CPAP arm may not have been adequately treated.”

Adherence Versus Effectiveness

In this study, 2,717 patients with moderate-to-severe obstructive sleep apnea and a history of coronary or cerebrovascular disease were randomized to CPAP plus usual care or usual care alone. The primary composite end point of the trial was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack.

After a mean follow-up of 3.7 years, an event had occurred in 17% of those in the CPAP group versus 15.4% of those in the usual-care group, producing a nonsignificantly increased hazard ratio (HR 1.10) for the primary end point in the CPAP arm. CPAP did reduce snoring and daytime sleepiness as well as improve quality of life and mood, all of which were secondary end points.

“The natural next step would be to look at the subgroup of patients who did have good adherence to CPAP, but the study was not powered to look at that,” Dr. Segal said. Although he reported that a post hoc analysis did show “a trend for benefit in those patients who actually adhered to the therapy,” these data are not sufficient to challenge the primary conclusion.

There was a reasonable expectation that CPAP, which has been an effective treatment in this and other trials for the symptoms of obstructive sleep apnea, would reduce cardiovascular events, according to the authors of the SAVE study. They cited strong evidence that obstructive sleep apnea increases the risk of stroke and other cardiovascular events, so control of the disorder had the potential to be protective. Moreover, CPAP has been specifically associated with improved endothelial function, improved insulin sensitivity, and reduced systolic blood pressure in patients with hypertension.

Study Flaw or Real-World Experience?

Yet judging CPAP on an intention-to-treat basis may be appropriate, because several other trials cited by the authors of SAVE, all of which were also negative for a cardiovascular benefit, have also found median adherence to be less than four hours. In SAVE, the mean adherence was 4.4 hours per night during the first 12 months of the trial, but it fell subsequently. As a reflection of what can be expected from a prescription of CPAP, the lack of protection from cardiovascular events in SAVE may not reflect a fundamental inability of CPAP to protect against vascular events, but the negative result is relevant if typical use means low adherence.

“CPAP adherence is a challenge,” Dr. Segal acknowledged. “In a dedicated sleep center such as ours, we work closely with patients to help them with adherence. One of the ways we do that is through mask fittings to find the style with which the patient is most comfortable.”

Mask styles range from minimalist devices that fit the nostrils to full “fighter-pilot” devices fitting over the entire face, according to Dr. Segal. He estimated that there are about 30 mask styles now available, and added that considerable time is devoted at his center to helping patients make the best choice.

Adherence may also be improved using modern devices, according to Dr. Segal. One example is software that ramps up pressure slowly so that the target pressure is not reached until the patient is already asleep, making use more acceptable. Another is technology that reduces pressure at each exhalation, facilitating a more natural breathing cycle and also increasing patient acceptance. Newer machines equipped with automated titration may also add convenience and ease of use.

Significant Benefit to Be Gained

The rewards of CPAP in patients who become comfortable with this therapy can be significant. The impairments in quality of sleep in patients with obstructive sleep apnea are often the impetus to seek care. “It is very important that patients get that subjective experience of feeling better the next day, and I would say about one-third of my patients get that next-day eureka feeling from initiating CPAP after sleeping so poorly for many years,” Dr. Segal reported.

These quality-of-life benefits were reflected in the SAVE study. For those in the CPAP arm, relative to those receiving usual care alone, there were highly significant improvements in objective anxiety and depression scales, as well as the physical and mental components of the 36-item Short Form (SF-36) quality of life tool. A reduction in daytime symptoms of sleep deprivation was also significant for CPAP on the Epworth Sleepiness Scale.

Relative to other tools to treat obstructive sleep apnea, CPAP is typically the most attractive option, according to Dr. Segal. For example, he is not an advocate of oral devices that advance the mandible, which he said have never been shown to be effective in moderate-to-severe apnea. He also suggested that surgery, which can be painful, does not uniformly provide benefit. However, he acknowledged that engaging patients in CPAP who do not experience a symptomatic benefit may now be more difficult after the results of the SAVE study. Although “the jury is still out” in regard to the ability of CPAP to reduce cardiovascular events in adherent patients, the evidence has now raised doubts for those already prescribed CPAP for the goal of reducing cardiovascular risk.“Those patients who are dedicated CPAP users will keep using this, but those who are perhaps looking for an excuse not to use CPAP may look at this data in a different way,” Dr. Segal said.

—Theodore Bosworth

Suggested Reading

McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med. 2016;375(10):919-931.

LAS VEGAS—Although continuous positive airway pressure (CPAP) failed to protect patients with obstructive sleep apnea from cardiovascular events in a recently completed large randomized trial, the results are not definitive, according to Alan Z. Segal, MD, Associate Professor of Clinical Neurology at Weill Cornell Medical College in New York City. In an update on sleep disorders at the American Academy of Neurology’s Fall 2016 Conference, Dr. Segal explained that the average adherence to CPAP in this trial, called SAVE, was less than that which has been widely accepted as adequate.

“Medicare has a requirement that CPAP be used for more than four hours on 70% of nights in a 30-day period for patients to keep their device,” observed Dr. Segal, providing one example of a way in which four hours or more of CPAP has been defined as a minimum duration. In the SAVE study by McEvoy et al, the mean duration of CPAP was 3.3 hours. Only 42% of patients met the four-hour definition of adherence, which was the duration the authors themselves had defined as good adherence.

“Our field was very much affected by this study,” Dr. Segal acknowledged. “It created quite a lot of controversy and criticisms over methodologic flaws. Like any study that does not produce the results we want, we start to pick at it to identify where it might have been inadequate, and the biggest inadequacy of this particular study is that patients in the CPAP arm may not have been adequately treated.”

Adherence Versus Effectiveness

In this study, 2,717 patients with moderate-to-severe obstructive sleep apnea and a history of coronary or cerebrovascular disease were randomized to CPAP plus usual care or usual care alone. The primary composite end point of the trial was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack.

After a mean follow-up of 3.7 years, an event had occurred in 17% of those in the CPAP group versus 15.4% of those in the usual-care group, producing a nonsignificantly increased hazard ratio (HR 1.10) for the primary end point in the CPAP arm. CPAP did reduce snoring and daytime sleepiness as well as improve quality of life and mood, all of which were secondary end points.

“The natural next step would be to look at the subgroup of patients who did have good adherence to CPAP, but the study was not powered to look at that,” Dr. Segal said. Although he reported that a post hoc analysis did show “a trend for benefit in those patients who actually adhered to the therapy,” these data are not sufficient to challenge the primary conclusion.

There was a reasonable expectation that CPAP, which has been an effective treatment in this and other trials for the symptoms of obstructive sleep apnea, would reduce cardiovascular events, according to the authors of the SAVE study. They cited strong evidence that obstructive sleep apnea increases the risk of stroke and other cardiovascular events, so control of the disorder had the potential to be protective. Moreover, CPAP has been specifically associated with improved endothelial function, improved insulin sensitivity, and reduced systolic blood pressure in patients with hypertension.

Study Flaw or Real-World Experience?

Yet judging CPAP on an intention-to-treat basis may be appropriate, because several other trials cited by the authors of SAVE, all of which were also negative for a cardiovascular benefit, have also found median adherence to be less than four hours. In SAVE, the mean adherence was 4.4 hours per night during the first 12 months of the trial, but it fell subsequently. As a reflection of what can be expected from a prescription of CPAP, the lack of protection from cardiovascular events in SAVE may not reflect a fundamental inability of CPAP to protect against vascular events, but the negative result is relevant if typical use means low adherence.

“CPAP adherence is a challenge,” Dr. Segal acknowledged. “In a dedicated sleep center such as ours, we work closely with patients to help them with adherence. One of the ways we do that is through mask fittings to find the style with which the patient is most comfortable.”

Mask styles range from minimalist devices that fit the nostrils to full “fighter-pilot” devices fitting over the entire face, according to Dr. Segal. He estimated that there are about 30 mask styles now available, and added that considerable time is devoted at his center to helping patients make the best choice.

Adherence may also be improved using modern devices, according to Dr. Segal. One example is software that ramps up pressure slowly so that the target pressure is not reached until the patient is already asleep, making use more acceptable. Another is technology that reduces pressure at each exhalation, facilitating a more natural breathing cycle and also increasing patient acceptance. Newer machines equipped with automated titration may also add convenience and ease of use.

Significant Benefit to Be Gained

The rewards of CPAP in patients who become comfortable with this therapy can be significant. The impairments in quality of sleep in patients with obstructive sleep apnea are often the impetus to seek care. “It is very important that patients get that subjective experience of feeling better the next day, and I would say about one-third of my patients get that next-day eureka feeling from initiating CPAP after sleeping so poorly for many years,” Dr. Segal reported.

These quality-of-life benefits were reflected in the SAVE study. For those in the CPAP arm, relative to those receiving usual care alone, there were highly significant improvements in objective anxiety and depression scales, as well as the physical and mental components of the 36-item Short Form (SF-36) quality of life tool. A reduction in daytime symptoms of sleep deprivation was also significant for CPAP on the Epworth Sleepiness Scale.

Relative to other tools to treat obstructive sleep apnea, CPAP is typically the most attractive option, according to Dr. Segal. For example, he is not an advocate of oral devices that advance the mandible, which he said have never been shown to be effective in moderate-to-severe apnea. He also suggested that surgery, which can be painful, does not uniformly provide benefit. However, he acknowledged that engaging patients in CPAP who do not experience a symptomatic benefit may now be more difficult after the results of the SAVE study. Although “the jury is still out” in regard to the ability of CPAP to reduce cardiovascular events in adherent patients, the evidence has now raised doubts for those already prescribed CPAP for the goal of reducing cardiovascular risk.“Those patients who are dedicated CPAP users will keep using this, but those who are perhaps looking for an excuse not to use CPAP may look at this data in a different way,” Dr. Segal said.

—Theodore Bosworth

Suggested Reading

McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med. 2016;375(10):919-931.

LAS VEGAS—Although continuous positive airway pressure (CPAP) failed to protect patients with obstructive sleep apnea from cardiovascular events in a recently completed large randomized trial, the results are not definitive, according to Alan Z. Segal, MD, Associate Professor of Clinical Neurology at Weill Cornell Medical College in New York City. In an update on sleep disorders at the American Academy of Neurology’s Fall 2016 Conference, Dr. Segal explained that the average adherence to CPAP in this trial, called SAVE, was less than that which has been widely accepted as adequate.

“Medicare has a requirement that CPAP be used for more than four hours on 70% of nights in a 30-day period for patients to keep their device,” observed Dr. Segal, providing one example of a way in which four hours or more of CPAP has been defined as a minimum duration. In the SAVE study by McEvoy et al, the mean duration of CPAP was 3.3 hours. Only 42% of patients met the four-hour definition of adherence, which was the duration the authors themselves had defined as good adherence.

“Our field was very much affected by this study,” Dr. Segal acknowledged. “It created quite a lot of controversy and criticisms over methodologic flaws. Like any study that does not produce the results we want, we start to pick at it to identify where it might have been inadequate, and the biggest inadequacy of this particular study is that patients in the CPAP arm may not have been adequately treated.”

Adherence Versus Effectiveness

In this study, 2,717 patients with moderate-to-severe obstructive sleep apnea and a history of coronary or cerebrovascular disease were randomized to CPAP plus usual care or usual care alone. The primary composite end point of the trial was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack.

After a mean follow-up of 3.7 years, an event had occurred in 17% of those in the CPAP group versus 15.4% of those in the usual-care group, producing a nonsignificantly increased hazard ratio (HR 1.10) for the primary end point in the CPAP arm. CPAP did reduce snoring and daytime sleepiness as well as improve quality of life and mood, all of which were secondary end points.

“The natural next step would be to look at the subgroup of patients who did have good adherence to CPAP, but the study was not powered to look at that,” Dr. Segal said. Although he reported that a post hoc analysis did show “a trend for benefit in those patients who actually adhered to the therapy,” these data are not sufficient to challenge the primary conclusion.

There was a reasonable expectation that CPAP, which has been an effective treatment in this and other trials for the symptoms of obstructive sleep apnea, would reduce cardiovascular events, according to the authors of the SAVE study. They cited strong evidence that obstructive sleep apnea increases the risk of stroke and other cardiovascular events, so control of the disorder had the potential to be protective. Moreover, CPAP has been specifically associated with improved endothelial function, improved insulin sensitivity, and reduced systolic blood pressure in patients with hypertension.

Study Flaw or Real-World Experience?

Yet judging CPAP on an intention-to-treat basis may be appropriate, because several other trials cited by the authors of SAVE, all of which were also negative for a cardiovascular benefit, have also found median adherence to be less than four hours. In SAVE, the mean adherence was 4.4 hours per night during the first 12 months of the trial, but it fell subsequently. As a reflection of what can be expected from a prescription of CPAP, the lack of protection from cardiovascular events in SAVE may not reflect a fundamental inability of CPAP to protect against vascular events, but the negative result is relevant if typical use means low adherence.

“CPAP adherence is a challenge,” Dr. Segal acknowledged. “In a dedicated sleep center such as ours, we work closely with patients to help them with adherence. One of the ways we do that is through mask fittings to find the style with which the patient is most comfortable.”

Mask styles range from minimalist devices that fit the nostrils to full “fighter-pilot” devices fitting over the entire face, according to Dr. Segal. He estimated that there are about 30 mask styles now available, and added that considerable time is devoted at his center to helping patients make the best choice.

Adherence may also be improved using modern devices, according to Dr. Segal. One example is software that ramps up pressure slowly so that the target pressure is not reached until the patient is already asleep, making use more acceptable. Another is technology that reduces pressure at each exhalation, facilitating a more natural breathing cycle and also increasing patient acceptance. Newer machines equipped with automated titration may also add convenience and ease of use.

Significant Benefit to Be Gained

The rewards of CPAP in patients who become comfortable with this therapy can be significant. The impairments in quality of sleep in patients with obstructive sleep apnea are often the impetus to seek care. “It is very important that patients get that subjective experience of feeling better the next day, and I would say about one-third of my patients get that next-day eureka feeling from initiating CPAP after sleeping so poorly for many years,” Dr. Segal reported.

These quality-of-life benefits were reflected in the SAVE study. For those in the CPAP arm, relative to those receiving usual care alone, there were highly significant improvements in objective anxiety and depression scales, as well as the physical and mental components of the 36-item Short Form (SF-36) quality of life tool. A reduction in daytime symptoms of sleep deprivation was also significant for CPAP on the Epworth Sleepiness Scale.

Relative to other tools to treat obstructive sleep apnea, CPAP is typically the most attractive option, according to Dr. Segal. For example, he is not an advocate of oral devices that advance the mandible, which he said have never been shown to be effective in moderate-to-severe apnea. He also suggested that surgery, which can be painful, does not uniformly provide benefit. However, he acknowledged that engaging patients in CPAP who do not experience a symptomatic benefit may now be more difficult after the results of the SAVE study. Although “the jury is still out” in regard to the ability of CPAP to reduce cardiovascular events in adherent patients, the evidence has now raised doubts for those already prescribed CPAP for the goal of reducing cardiovascular risk.“Those patients who are dedicated CPAP users will keep using this, but those who are perhaps looking for an excuse not to use CPAP may look at this data in a different way,” Dr. Segal said.

—Theodore Bosworth

Suggested Reading

McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med. 2016;375(10):919-931.

In our December 2016 issue, we reported the results of our first annual survey on nonmonetary compensation (ie, the “perks”) and overall employment satisfaction (Clinician Reviews. 2016;26[12]:23-26). But the feedback I found most interesting came from the narrative responses—particularly those referencing patient satisfaction and the stress it creates for NPs and PAs.

Safety, quality, and affordability have been touted as today’s health care priorities. But it is unclear whether the majority of health care consumers agree with them. Patients may express understanding or accord initially, but when the discussion turns to what is appropriate as opposed to what is desired, conflict may arise.

Judging by the verbatim responses to our survey, NPs and PAs are concerned that quality measures don’t reflect the demands of our practice or focus on what matters to our patients.

One participant analogized, “Medicine is now like McDonalds or Burger King—patients want it their way, regardless of whether it’s in their best interest. I was fee-for-service for more than 10 years. As reimbursements have decreased significantly over time, I’m now employed by a hospital. I have become a waitress, considering my patients’ wishes—not for the benefit of their health, but to meet their more trivial ‘needs.’ These requirements can be as absurd as a specific brand of sweetener! If patients’ preferred sugar substitutes aren’t offered at my hospital, their ‘satisfaction’ may drop and I won’t get reimbursed as much. It’s a miserable experience.”

Perhaps the disparate views of what matters—Is it the softness of the pillows, or is it measurable improvement in the patient’s condition?—is the origin of the stress expressed by clinicians. This dissonance, in my opinion, exists among all involved—providers, patients, and payers. Today, patients see themselves as buyers of health services, and health care corporations have begun to function as a service industry. It may also explain why the concept of patient satisfaction has seemingly morphed into customer service, frustrating many of our colleagues.

Because it can affect clinical outcomes, patient retention, and medical malpractice claims, patient satisfaction is commonly used as a proxy for the success of doctors and hospitals.¹ We know there is a correlation between higher patient satisfaction rates and improved outcomes—and conversely, research has demonstrated that unmet expectations significantly decrease satisfaction.²

However, there has been no explicit definition of patient satisfaction, nor systematic consideration of its determinants and consequences.³ As a result, measurement of “satisfaction” and its use as an indicator of quality of care remains controversial among health care providers. It can be a difficult concept to embrace.

Even setting aside the question of “amenities” and focusing on actual clinical care, satisfaction has different meanings for different people. For some, it is a positive, immediate improvement in the patient’s condition (recall my comments on pain management in my previous editorial).⁴ While that might be an unrealistic expectation, it is a factor in whether the patient and/or family express satisfaction with the care provided.

These high (if not unreasonable) expectations are fueled by the availability of information via the Internet. Patient attitudes and perceptions prior to receiving care also play a role. Instead of correlating with high-quality, appropriate, affordable care, a patient’s satisfaction might instead be based on the fulfillment of his or her predetermined ideas as to what treatment is needed!

The impetus for this change in perspective was the development of the patient-centered care model, which has patient satisfaction at its core.⁵ The model is intended to make patients partners in their health care; instead of depending solely on provider tools or standards, patients and providers discuss the options and preferences and develop a plan of care together. We all know that the relationship between patients and their providers greatly affects both treatment outcomes and patient satisfaction. But implementing a patient-centered care model means understanding and accepting from the start that patients will be asked to rate or judge their health care. It is therefore essential that there is agreement as to the standards that constitute “quality care” and congruence between these beliefs and the satisfaction ratings. You need to know what your patient expects to determine your likelihood of delivering it.

The patient-provider relationship has been a focus of the Consumer Assessment of Healthcare Providers and Systems (CAHPS®) Hospital Survey, which, since 2006, has measured patients’ perceptions of their hospital experiences.⁶ The CAHPS Clinician and Group Survey, initiated in 2011, is a standardized tool to measure patients’ perceptions of care in an office setting.⁷ Data from both surveys are used to improve performance and productivity in these settings. But while the information about quality of care has enabled consumers to make more informed decisions, the data are in many ways limited and subjective.

What cannot be measured by either survey alone is the health of patients, employees, and the community. This limitation is reflected in the feedback to our survey, which suggests a preponderance of NP and PA dissatisfaction with the current methods of evaluating the health care system. How much strain is incurred when evaluative measures fail to demonstrate that high-quality, safe, affordable care is being provided? That is difficult to ascertain, but it does give one pause. We know that providers who experience professional satisfaction have higher overall patient satisfaction scores.⁸ If we’re frustrated, are we able to provide the highest quality care? If not, our scores will suffer. If our scores drop … around we go again.

Currently, most data collection methods focus on physicians, making NPs and PAs “invisible” providers. That certainly won’t help our satisfaction! Only when the data gleaned from these measurement tools include all ambulatory settings, and all providers are recognized as valued contributors to patient health and satisfaction, will we have the information we need to improve satisfaction levels. That will benefit not only our patients, but also ourselves.

Please share your thoughts on patient satisfaction and “customer service” by emailing [email protected].

In our December 2016 issue, we reported the results of our first annual survey on nonmonetary compensation (ie, the “perks”) and overall employment satisfaction (Clinician Reviews. 2016;26[12]:23-26). But the feedback I found most interesting came from the narrative responses—particularly those referencing patient satisfaction and the stress it creates for NPs and PAs.

Safety, quality, and affordability have been touted as today’s health care priorities. But it is unclear whether the majority of health care consumers agree with them. Patients may express understanding or accord initially, but when the discussion turns to what is appropriate as opposed to what is desired, conflict may arise.

Judging by the verbatim responses to our survey, NPs and PAs are concerned that quality measures don’t reflect the demands of our practice or focus on what matters to our patients.

One participant analogized, “Medicine is now like McDonalds or Burger King—patients want it their way, regardless of whether it’s in their best interest. I was fee-for-service for more than 10 years. As reimbursements have decreased significantly over time, I’m now employed by a hospital. I have become a waitress, considering my patients’ wishes—not for the benefit of their health, but to meet their more trivial ‘needs.’ These requirements can be as absurd as a specific brand of sweetener! If patients’ preferred sugar substitutes aren’t offered at my hospital, their ‘satisfaction’ may drop and I won’t get reimbursed as much. It’s a miserable experience.”

Perhaps the disparate views of what matters—Is it the softness of the pillows, or is it measurable improvement in the patient’s condition?—is the origin of the stress expressed by clinicians. This dissonance, in my opinion, exists among all involved—providers, patients, and payers. Today, patients see themselves as buyers of health services, and health care corporations have begun to function as a service industry. It may also explain why the concept of patient satisfaction has seemingly morphed into customer service, frustrating many of our colleagues.

Because it can affect clinical outcomes, patient retention, and medical malpractice claims, patient satisfaction is commonly used as a proxy for the success of doctors and hospitals.¹ We know there is a correlation between higher patient satisfaction rates and improved outcomes—and conversely, research has demonstrated that unmet expectations significantly decrease satisfaction.²

However, there has been no explicit definition of patient satisfaction, nor systematic consideration of its determinants and consequences.³ As a result, measurement of “satisfaction” and its use as an indicator of quality of care remains controversial among health care providers. It can be a difficult concept to embrace.

Even setting aside the question of “amenities” and focusing on actual clinical care, satisfaction has different meanings for different people. For some, it is a positive, immediate improvement in the patient’s condition (recall my comments on pain management in my previous editorial).⁴ While that might be an unrealistic expectation, it is a factor in whether the patient and/or family express satisfaction with the care provided.

These high (if not unreasonable) expectations are fueled by the availability of information via the Internet. Patient attitudes and perceptions prior to receiving care also play a role. Instead of correlating with high-quality, appropriate, affordable care, a patient’s satisfaction might instead be based on the fulfillment of his or her predetermined ideas as to what treatment is needed!

The impetus for this change in perspective was the development of the patient-centered care model, which has patient satisfaction at its core.⁵ The model is intended to make patients partners in their health care; instead of depending solely on provider tools or standards, patients and providers discuss the options and preferences and develop a plan of care together. We all know that the relationship between patients and their providers greatly affects both treatment outcomes and patient satisfaction. But implementing a patient-centered care model means understanding and accepting from the start that patients will be asked to rate or judge their health care. It is therefore essential that there is agreement as to the standards that constitute “quality care” and congruence between these beliefs and the satisfaction ratings. You need to know what your patient expects to determine your likelihood of delivering it.

The patient-provider relationship has been a focus of the Consumer Assessment of Healthcare Providers and Systems (CAHPS®) Hospital Survey, which, since 2006, has measured patients’ perceptions of their hospital experiences.⁶ The CAHPS Clinician and Group Survey, initiated in 2011, is a standardized tool to measure patients’ perceptions of care in an office setting.⁷ Data from both surveys are used to improve performance and productivity in these settings. But while the information about quality of care has enabled consumers to make more informed decisions, the data are in many ways limited and subjective.

What cannot be measured by either survey alone is the health of patients, employees, and the community. This limitation is reflected in the feedback to our survey, which suggests a preponderance of NP and PA dissatisfaction with the current methods of evaluating the health care system. How much strain is incurred when evaluative measures fail to demonstrate that high-quality, safe, affordable care is being provided? That is difficult to ascertain, but it does give one pause. We know that providers who experience professional satisfaction have higher overall patient satisfaction scores.⁸ If we’re frustrated, are we able to provide the highest quality care? If not, our scores will suffer. If our scores drop … around we go again.

Currently, most data collection methods focus on physicians, making NPs and PAs “invisible” providers. That certainly won’t help our satisfaction! Only when the data gleaned from these measurement tools include all ambulatory settings, and all providers are recognized as valued contributors to patient health and satisfaction, will we have the information we need to improve satisfaction levels. That will benefit not only our patients, but also ourselves.

Please share your thoughts on patient satisfaction and “customer service” by emailing [email protected].

In our December 2016 issue, we reported the results of our first annual survey on nonmonetary compensation (ie, the “perks”) and overall employment satisfaction (Clinician Reviews. 2016;26[12]:23-26). But the feedback I found most interesting came from the narrative responses—particularly those referencing patient satisfaction and the stress it creates for NPs and PAs.

Safety, quality, and affordability have been touted as today’s health care priorities. But it is unclear whether the majority of health care consumers agree with them. Patients may express understanding or accord initially, but when the discussion turns to what is appropriate as opposed to what is desired, conflict may arise.

Judging by the verbatim responses to our survey, NPs and PAs are concerned that quality measures don’t reflect the demands of our practice or focus on what matters to our patients.

One participant analogized, “Medicine is now like McDonalds or Burger King—patients want it their way, regardless of whether it’s in their best interest. I was fee-for-service for more than 10 years. As reimbursements have decreased significantly over time, I’m now employed by a hospital. I have become a waitress, considering my patients’ wishes—not for the benefit of their health, but to meet their more trivial ‘needs.’ These requirements can be as absurd as a specific brand of sweetener! If patients’ preferred sugar substitutes aren’t offered at my hospital, their ‘satisfaction’ may drop and I won’t get reimbursed as much. It’s a miserable experience.”

Perhaps the disparate views of what matters—Is it the softness of the pillows, or is it measurable improvement in the patient’s condition?—is the origin of the stress expressed by clinicians. This dissonance, in my opinion, exists among all involved—providers, patients, and payers. Today, patients see themselves as buyers of health services, and health care corporations have begun to function as a service industry. It may also explain why the concept of patient satisfaction has seemingly morphed into customer service, frustrating many of our colleagues.

Because it can affect clinical outcomes, patient retention, and medical malpractice claims, patient satisfaction is commonly used as a proxy for the success of doctors and hospitals.¹ We know there is a correlation between higher patient satisfaction rates and improved outcomes—and conversely, research has demonstrated that unmet expectations significantly decrease satisfaction.²

However, there has been no explicit definition of patient satisfaction, nor systematic consideration of its determinants and consequences.³ As a result, measurement of “satisfaction” and its use as an indicator of quality of care remains controversial among health care providers. It can be a difficult concept to embrace.

Even setting aside the question of “amenities” and focusing on actual clinical care, satisfaction has different meanings for different people. For some, it is a positive, immediate improvement in the patient’s condition (recall my comments on pain management in my previous editorial).⁴ While that might be an unrealistic expectation, it is a factor in whether the patient and/or family express satisfaction with the care provided.

These high (if not unreasonable) expectations are fueled by the availability of information via the Internet. Patient attitudes and perceptions prior to receiving care also play a role. Instead of correlating with high-quality, appropriate, affordable care, a patient’s satisfaction might instead be based on the fulfillment of his or her predetermined ideas as to what treatment is needed!

The impetus for this change in perspective was the development of the patient-centered care model, which has patient satisfaction at its core.⁵ The model is intended to make patients partners in their health care; instead of depending solely on provider tools or standards, patients and providers discuss the options and preferences and develop a plan of care together. We all know that the relationship between patients and their providers greatly affects both treatment outcomes and patient satisfaction. But implementing a patient-centered care model means understanding and accepting from the start that patients will be asked to rate or judge their health care. It is therefore essential that there is agreement as to the standards that constitute “quality care” and congruence between these beliefs and the satisfaction ratings. You need to know what your patient expects to determine your likelihood of delivering it.

The patient-provider relationship has been a focus of the Consumer Assessment of Healthcare Providers and Systems (CAHPS®) Hospital Survey, which, since 2006, has measured patients’ perceptions of their hospital experiences.⁶ The CAHPS Clinician and Group Survey, initiated in 2011, is a standardized tool to measure patients’ perceptions of care in an office setting.⁷ Data from both surveys are used to improve performance and productivity in these settings. But while the information about quality of care has enabled consumers to make more informed decisions, the data are in many ways limited and subjective.

What cannot be measured by either survey alone is the health of patients, employees, and the community. This limitation is reflected in the feedback to our survey, which suggests a preponderance of NP and PA dissatisfaction with the current methods of evaluating the health care system. How much strain is incurred when evaluative measures fail to demonstrate that high-quality, safe, affordable care is being provided? That is difficult to ascertain, but it does give one pause. We know that providers who experience professional satisfaction have higher overall patient satisfaction scores.⁸ If we’re frustrated, are we able to provide the highest quality care? If not, our scores will suffer. If our scores drop … around we go again.

Currently, most data collection methods focus on physicians, making NPs and PAs “invisible” providers. That certainly won’t help our satisfaction! Only when the data gleaned from these measurement tools include all ambulatory settings, and all providers are recognized as valued contributors to patient health and satisfaction, will we have the information we need to improve satisfaction levels. That will benefit not only our patients, but also ourselves.

Please share your thoughts on patient satisfaction and “customer service” by emailing [email protected].

NEW ORLEANS – Prepregnancy overweight and obesity are associated with increased incidence and severity of depressive symptoms during pregnancy, independent of preeclampsia and other hypertensive pregnancy disorders or gestational diabetes, Satu Kumpulainen reported at Obesity Week 2016.

The implications of this novel finding are clear: “Prepregnancy interventions targeting overweight and obesity and mental health will not only benefit the pregnant mother’s health but will also provide optimal odds for healthy development of the fetus as well,” said Ms. Kumpulainen, a doctoral student at the University of Helsinki Institute of Behavioral Sciences.

Bruce Jancin/Frontline Medical News

kzenon/ThinkStock

[email protected]


 

NEW ORLEANS – Prepregnancy overweight and obesity are associated with increased incidence and severity of depressive symptoms during pregnancy, independent of preeclampsia and other hypertensive pregnancy disorders or gestational diabetes, Satu Kumpulainen reported at Obesity Week 2016.

The implications of this novel finding are clear: “Prepregnancy interventions targeting overweight and obesity and mental health will not only benefit the pregnant mother’s health but will also provide optimal odds for healthy development of the fetus as well,” said Ms. Kumpulainen, a doctoral student at the University of Helsinki Institute of Behavioral Sciences.

Bruce Jancin/Frontline Medical News

kzenon/ThinkStock

[email protected]


 

NEW ORLEANS – Prepregnancy overweight and obesity are associated with increased incidence and severity of depressive symptoms during pregnancy, independent of preeclampsia and other hypertensive pregnancy disorders or gestational diabetes, Satu Kumpulainen reported at Obesity Week 2016.

The implications of this novel finding are clear: “Prepregnancy interventions targeting overweight and obesity and mental health will not only benefit the pregnant mother’s health but will also provide optimal odds for healthy development of the fetus as well,” said Ms. Kumpulainen, a doctoral student at the University of Helsinki Institute of Behavioral Sciences.

Bruce Jancin/Frontline Medical News

kzenon/ThinkStock

[email protected]


 

Empagliflozin (Jardiance) and liraglutide (Victoza) should be considered in type 2 diabetes patients with documented cardiovascular disease to reduce the risk of CV death, according to the American Diabetes Association 2017 Standards of Medical Care.

ADA updates it standards annually based on new information and research; like its predecessors, the 2017 guidance is comprehensive, addressing mental, social, and other challenges faced by patients with diabetes, along with clinical care (Diabetes Care. 2017 Jan;40(Suppl 1):S4-S5).

The 2017 guidance contains a great deal of new information. At 135 pages, there are 22 more pages than in 2016. “They did a really nice job. This guide is useful for anyone helping patients with diabetes,” including diabetologists, dietitians, educators, psychologists, and social workers, Richard Hellman, MD, a clinical endocrinologist in North Kansas City, Mo., said in an interview.

[email protected]

Empagliflozin (Jardiance) and liraglutide (Victoza) should be considered in type 2 diabetes patients with documented cardiovascular disease to reduce the risk of CV death, according to the American Diabetes Association 2017 Standards of Medical Care.

ADA updates it standards annually based on new information and research; like its predecessors, the 2017 guidance is comprehensive, addressing mental, social, and other challenges faced by patients with diabetes, along with clinical care (Diabetes Care. 2017 Jan;40(Suppl 1):S4-S5).

The 2017 guidance contains a great deal of new information. At 135 pages, there are 22 more pages than in 2016. “They did a really nice job. This guide is useful for anyone helping patients with diabetes,” including diabetologists, dietitians, educators, psychologists, and social workers, Richard Hellman, MD, a clinical endocrinologist in North Kansas City, Mo., said in an interview.

[email protected]

Empagliflozin (Jardiance) and liraglutide (Victoza) should be considered in type 2 diabetes patients with documented cardiovascular disease to reduce the risk of CV death, according to the American Diabetes Association 2017 Standards of Medical Care.

ADA updates it standards annually based on new information and research; like its predecessors, the 2017 guidance is comprehensive, addressing mental, social, and other challenges faced by patients with diabetes, along with clinical care (Diabetes Care. 2017 Jan;40(Suppl 1):S4-S5).

The 2017 guidance contains a great deal of new information. At 135 pages, there are 22 more pages than in 2016. “They did a really nice job. This guide is useful for anyone helping patients with diabetes,” including diabetologists, dietitians, educators, psychologists, and social workers, Richard Hellman, MD, a clinical endocrinologist in North Kansas City, Mo., said in an interview.

[email protected]

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been a welcome addition to the armamentarium for treating depressive disorders, neuropathic pain, and anxiety disorders. Despite the more favorable side-effect profile compared with tricyclic antidepressants and monoamine oxidase inhibitors, these serotonergic agents have been associated with bleeding disorders, purpura, thrombocytopenia, and, in extreme cases, death.^1-4

We describe a case of purpura associated with different classes of antidepressants, including the non-serotonergic agent bupropion, as well as a family history of similar adverse effects to antidepressants.

CASE Purpura resolves when drug is stopped

Ms. R, age 70, presents with major depressive disorder and fibromyalgia and is receiving duloxetine, 20 mg/d, which is gradually increased to 60 mg. She also has a history of chronic obstructive pulmonary disease (COPD), for which she is taking albuterol and a steroid inhaler. Ms. R responds well to treatment; however, she develops blue–purple purpura on her arms each measuring 1 to 2 inches. Laboratory test results including platelet count and prothrombin time/international normalized ratio are within normal ranges. Duloxetine is stopped, and purpura resolves in 1 to 2 weeks. To avoid serotonergic antidepressants, Ms. R receives bupropion XL, 150 mg; however, similar purpura develops, then resolves when the medication is discontinued. She is lost to follow up for approximately 6 months, but returns requesting a rechallenge with duloxetine for her depression, which has worsened. Duloxetine is restarted with similar results and is then discontinued. Because she has developed neuropathy, Ms. R is started on nortriptyline, 25 mg/d, increased to 50 mg/d, but purpura develops again, which resolves when medication is discontinued. Ms. R’s daughter reports she also developed a similar reaction with several antidepressants, which resolved with medication discontinuation.

Bleeding risk with antidepressants

The role of serotonin reuptake inhibitors (SRIs) in inducing bleeding has emerged as a safety concern,^5,6 which have been documented in case reports.^7-11 Mechanisms of action that have been thought to affect platelet aggregation include:

• depletion of serotonin in platelets
• increase in capillary fragility
• modification of platelet plug formation
• responsiveness of peptide-induced activation of platelets through stimulation of the thrombin receptor.^7,8,12,13

The severity of bleeding varies with patient-related factors, such as a history of gastritis, peptic ulcer disease, and heavy bleeding during menses; use of gastrotoxic drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), also have been shown to increase this risk.^14,15 For patients taking SRIs and gastrotoxic drugs (eg, NSAIDs), use of acid-suppressing agents have been shown to limit the risk of bleeding.¹⁶

Studies evaluating relative bleeding risks among classes of antidepressants have not shown increased risk with tricyclic antidepressants compared with SSRIs.¹⁷ Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) are signaling molecules in the vascular system and are important in the thromboregulatory system. Studies in rats reported significant inhibition of ATP, ADP, and AMP hydrolysis with chronic treatment with fluoxetine and nortriptyline, and suggested that both medications changed the nucleotide catabolism, which means that homeostasis of the vascular system can be altered by antidepressant treatments.¹⁸ This is one possible pathway in the role these medications play in the etiology of dysregulation of the thromboregulatory system.

We did not anticipate that our patient would develop similar purpura with bupropion because the bleeding risk associated with antidepressants has been attributed to the effect of serotonin on platelets. Studies observing the effect of SSRIs, SNRIs, and bupropion on platelets and bleeding have not shown significant risk with bupropion.¹⁹ Bleeding associated with bupropion is atypical and needs to be further studied. Although this medication is centrally selective in its action on dopamine receptors, it might have possible peripheral effect on other neurotransmitters, including serotonin.

Ms. R had no personal or family history of purpura or a bleeding disorder. Significant improvement in her physical signs after discontinuing medications and recurrence of pupura with rechallenge indicate that this reaction was triggered by 3 different classes of antidepressants. Family history of similar reaction further suggests a genetic predisposition to platelet dysfunction to antidepressant treatment in a select group of patients.

Limitations include the possibility of senile purpura, which cannot be ruled out despite strong indications that antidepressants were the cause. The possibility of drug interactions needs be considered as well. Ms. R was taking albuterol and a steroid inhaler for her COPD at the time of the initial medication trials, which did not interact with duloxetine or bupropion. During the trials with duloxetine and then nortriptyline, she was taking acetaminophen/hydrocodone in addition to her inhalers, and no significant interactions with the antidepressants were identified. Interactions with unreported or over-the-counter medications or supplements are a possibility.

Before prescribing an antidepressant, we suggest taking a careful history including a family history of bleeding disorders and adverse effects of antidepressants, especially in patients who have risk factors (eg, concomitant use of gastrotoxic medications). Use of gastric acid-suppressing medications could be considered if antidepressants are used. Further investigations into the incidence, risk factors, mechanism of action, and treatment of this adverse effect are indicated.

Drug Brand Names
Acetaminophen/hydrocodone • Lorcet, Norco, Vicodin
Albuterol • Proventil
Bupropion • Wellbutrin
Duloxetine • Cymbalta
Nortriptyline • Pamelor, Aventyl

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been a welcome addition to the armamentarium for treating depressive disorders, neuropathic pain, and anxiety disorders. Despite the more favorable side-effect profile compared with tricyclic antidepressants and monoamine oxidase inhibitors, these serotonergic agents have been associated with bleeding disorders, purpura, thrombocytopenia, and, in extreme cases, death.^1-4

We describe a case of purpura associated with different classes of antidepressants, including the non-serotonergic agent bupropion, as well as a family history of similar adverse effects to antidepressants.

CASE Purpura resolves when drug is stopped

Ms. R, age 70, presents with major depressive disorder and fibromyalgia and is receiving duloxetine, 20 mg/d, which is gradually increased to 60 mg. She also has a history of chronic obstructive pulmonary disease (COPD), for which she is taking albuterol and a steroid inhaler. Ms. R responds well to treatment; however, she develops blue–purple purpura on her arms each measuring 1 to 2 inches. Laboratory test results including platelet count and prothrombin time/international normalized ratio are within normal ranges. Duloxetine is stopped, and purpura resolves in 1 to 2 weeks. To avoid serotonergic antidepressants, Ms. R receives bupropion XL, 150 mg; however, similar purpura develops, then resolves when the medication is discontinued. She is lost to follow up for approximately 6 months, but returns requesting a rechallenge with duloxetine for her depression, which has worsened. Duloxetine is restarted with similar results and is then discontinued. Because she has developed neuropathy, Ms. R is started on nortriptyline, 25 mg/d, increased to 50 mg/d, but purpura develops again, which resolves when medication is discontinued. Ms. R’s daughter reports she also developed a similar reaction with several antidepressants, which resolved with medication discontinuation.

Bleeding risk with antidepressants

The role of serotonin reuptake inhibitors (SRIs) in inducing bleeding has emerged as a safety concern,^5,6 which have been documented in case reports.^7-11 Mechanisms of action that have been thought to affect platelet aggregation include:

• depletion of serotonin in platelets
• increase in capillary fragility
• modification of platelet plug formation
• responsiveness of peptide-induced activation of platelets through stimulation of the thrombin receptor.^7,8,12,13

The severity of bleeding varies with patient-related factors, such as a history of gastritis, peptic ulcer disease, and heavy bleeding during menses; use of gastrotoxic drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), also have been shown to increase this risk.^14,15 For patients taking SRIs and gastrotoxic drugs (eg, NSAIDs), use of acid-suppressing agents have been shown to limit the risk of bleeding.¹⁶

Studies evaluating relative bleeding risks among classes of antidepressants have not shown increased risk with tricyclic antidepressants compared with SSRIs.¹⁷ Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) are signaling molecules in the vascular system and are important in the thromboregulatory system. Studies in rats reported significant inhibition of ATP, ADP, and AMP hydrolysis with chronic treatment with fluoxetine and nortriptyline, and suggested that both medications changed the nucleotide catabolism, which means that homeostasis of the vascular system can be altered by antidepressant treatments.¹⁸ This is one possible pathway in the role these medications play in the etiology of dysregulation of the thromboregulatory system.

We did not anticipate that our patient would develop similar purpura with bupropion because the bleeding risk associated with antidepressants has been attributed to the effect of serotonin on platelets. Studies observing the effect of SSRIs, SNRIs, and bupropion on platelets and bleeding have not shown significant risk with bupropion.¹⁹ Bleeding associated with bupropion is atypical and needs to be further studied. Although this medication is centrally selective in its action on dopamine receptors, it might have possible peripheral effect on other neurotransmitters, including serotonin.

Ms. R had no personal or family history of purpura or a bleeding disorder. Significant improvement in her physical signs after discontinuing medications and recurrence of pupura with rechallenge indicate that this reaction was triggered by 3 different classes of antidepressants. Family history of similar reaction further suggests a genetic predisposition to platelet dysfunction to antidepressant treatment in a select group of patients.

Limitations include the possibility of senile purpura, which cannot be ruled out despite strong indications that antidepressants were the cause. The possibility of drug interactions needs be considered as well. Ms. R was taking albuterol and a steroid inhaler for her COPD at the time of the initial medication trials, which did not interact with duloxetine or bupropion. During the trials with duloxetine and then nortriptyline, she was taking acetaminophen/hydrocodone in addition to her inhalers, and no significant interactions with the antidepressants were identified. Interactions with unreported or over-the-counter medications or supplements are a possibility.

Before prescribing an antidepressant, we suggest taking a careful history including a family history of bleeding disorders and adverse effects of antidepressants, especially in patients who have risk factors (eg, concomitant use of gastrotoxic medications). Use of gastric acid-suppressing medications could be considered if antidepressants are used. Further investigations into the incidence, risk factors, mechanism of action, and treatment of this adverse effect are indicated.

Drug Brand Names
Acetaminophen/hydrocodone • Lorcet, Norco, Vicodin
Albuterol • Proventil
Bupropion • Wellbutrin
Duloxetine • Cymbalta
Nortriptyline • Pamelor, Aventyl

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been a welcome addition to the armamentarium for treating depressive disorders, neuropathic pain, and anxiety disorders. Despite the more favorable side-effect profile compared with tricyclic antidepressants and monoamine oxidase inhibitors, these serotonergic agents have been associated with bleeding disorders, purpura, thrombocytopenia, and, in extreme cases, death.^1-4

We describe a case of purpura associated with different classes of antidepressants, including the non-serotonergic agent bupropion, as well as a family history of similar adverse effects to antidepressants.

CASE Purpura resolves when drug is stopped

Ms. R, age 70, presents with major depressive disorder and fibromyalgia and is receiving duloxetine, 20 mg/d, which is gradually increased to 60 mg. She also has a history of chronic obstructive pulmonary disease (COPD), for which she is taking albuterol and a steroid inhaler. Ms. R responds well to treatment; however, she develops blue–purple purpura on her arms each measuring 1 to 2 inches. Laboratory test results including platelet count and prothrombin time/international normalized ratio are within normal ranges. Duloxetine is stopped, and purpura resolves in 1 to 2 weeks. To avoid serotonergic antidepressants, Ms. R receives bupropion XL, 150 mg; however, similar purpura develops, then resolves when the medication is discontinued. She is lost to follow up for approximately 6 months, but returns requesting a rechallenge with duloxetine for her depression, which has worsened. Duloxetine is restarted with similar results and is then discontinued. Because she has developed neuropathy, Ms. R is started on nortriptyline, 25 mg/d, increased to 50 mg/d, but purpura develops again, which resolves when medication is discontinued. Ms. R’s daughter reports she also developed a similar reaction with several antidepressants, which resolved with medication discontinuation.

Bleeding risk with antidepressants

The role of serotonin reuptake inhibitors (SRIs) in inducing bleeding has emerged as a safety concern,^5,6 which have been documented in case reports.^7-11 Mechanisms of action that have been thought to affect platelet aggregation include:

• depletion of serotonin in platelets
• increase in capillary fragility
• modification of platelet plug formation
• responsiveness of peptide-induced activation of platelets through stimulation of the thrombin receptor.^7,8,12,13

The severity of bleeding varies with patient-related factors, such as a history of gastritis, peptic ulcer disease, and heavy bleeding during menses; use of gastrotoxic drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), also have been shown to increase this risk.^14,15 For patients taking SRIs and gastrotoxic drugs (eg, NSAIDs), use of acid-suppressing agents have been shown to limit the risk of bleeding.¹⁶

Studies evaluating relative bleeding risks among classes of antidepressants have not shown increased risk with tricyclic antidepressants compared with SSRIs.¹⁷ Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) are signaling molecules in the vascular system and are important in the thromboregulatory system. Studies in rats reported significant inhibition of ATP, ADP, and AMP hydrolysis with chronic treatment with fluoxetine and nortriptyline, and suggested that both medications changed the nucleotide catabolism, which means that homeostasis of the vascular system can be altered by antidepressant treatments.¹⁸ This is one possible pathway in the role these medications play in the etiology of dysregulation of the thromboregulatory system.

We did not anticipate that our patient would develop similar purpura with bupropion because the bleeding risk associated with antidepressants has been attributed to the effect of serotonin on platelets. Studies observing the effect of SSRIs, SNRIs, and bupropion on platelets and bleeding have not shown significant risk with bupropion.¹⁹ Bleeding associated with bupropion is atypical and needs to be further studied. Although this medication is centrally selective in its action on dopamine receptors, it might have possible peripheral effect on other neurotransmitters, including serotonin.

Ms. R had no personal or family history of purpura or a bleeding disorder. Significant improvement in her physical signs after discontinuing medications and recurrence of pupura with rechallenge indicate that this reaction was triggered by 3 different classes of antidepressants. Family history of similar reaction further suggests a genetic predisposition to platelet dysfunction to antidepressant treatment in a select group of patients.

Limitations include the possibility of senile purpura, which cannot be ruled out despite strong indications that antidepressants were the cause. The possibility of drug interactions needs be considered as well. Ms. R was taking albuterol and a steroid inhaler for her COPD at the time of the initial medication trials, which did not interact with duloxetine or bupropion. During the trials with duloxetine and then nortriptyline, she was taking acetaminophen/hydrocodone in addition to her inhalers, and no significant interactions with the antidepressants were identified. Interactions with unreported or over-the-counter medications or supplements are a possibility.

Before prescribing an antidepressant, we suggest taking a careful history including a family history of bleeding disorders and adverse effects of antidepressants, especially in patients who have risk factors (eg, concomitant use of gastrotoxic medications). Use of gastric acid-suppressing medications could be considered if antidepressants are used. Further investigations into the incidence, risk factors, mechanism of action, and treatment of this adverse effect are indicated.

Drug Brand Names
Acetaminophen/hydrocodone • Lorcet, Norco, Vicodin
Albuterol • Proventil
Bupropion • Wellbutrin
Duloxetine • Cymbalta
Nortriptyline • Pamelor, Aventyl

High doses of radiation are often followed by infection. HHS is preparing for emergencies by buying 2 colony-stimulating factor (CSF) products to reduce infection and risk of death in radiologic or nuclear incidents.
Related: Emergency Test for Absorbed Radiation

HHS is purchasing Neulasta (Amgen USA, Inc) and Leukine (Sanofi-Aventis US), under agreements totaling about $37.7 million and 37.6 million, respectively. Neulasta already is FDA approved to treat cancer patients exposed to high levels of radiation that damage bone marrow. Leukine is undergoing studies needed for approval.

The Biomedical Advanced Research and Development Authority had earlier sponsored advanced development and purchase of Neupogen, another leukocyte growth factor product approved for treating adults and children exposed to radiation that damages bone marrow.

Related: HHS Hails Big Ideas

The deal for Neulasta and Leukine thus increases the number of CSF factor doses available for use in an emergency. It also increases operational capability, HHS says, since treatments with Neulasta are given once weekly, whereas treatment with Neupogen is daily.

High doses of radiation are often followed by infection. HHS is preparing for emergencies by buying 2 colony-stimulating factor (CSF) products to reduce infection and risk of death in radiologic or nuclear incidents.
Related: Emergency Test for Absorbed Radiation

HHS is purchasing Neulasta (Amgen USA, Inc) and Leukine (Sanofi-Aventis US), under agreements totaling about $37.7 million and 37.6 million, respectively. Neulasta already is FDA approved to treat cancer patients exposed to high levels of radiation that damage bone marrow. Leukine is undergoing studies needed for approval.

The Biomedical Advanced Research and Development Authority had earlier sponsored advanced development and purchase of Neupogen, another leukocyte growth factor product approved for treating adults and children exposed to radiation that damages bone marrow.

Related: HHS Hails Big Ideas

The deal for Neulasta and Leukine thus increases the number of CSF factor doses available for use in an emergency. It also increases operational capability, HHS says, since treatments with Neulasta are given once weekly, whereas treatment with Neupogen is daily.

High doses of radiation are often followed by infection. HHS is preparing for emergencies by buying 2 colony-stimulating factor (CSF) products to reduce infection and risk of death in radiologic or nuclear incidents.
Related: Emergency Test for Absorbed Radiation

HHS is purchasing Neulasta (Amgen USA, Inc) and Leukine (Sanofi-Aventis US), under agreements totaling about $37.7 million and 37.6 million, respectively. Neulasta already is FDA approved to treat cancer patients exposed to high levels of radiation that damage bone marrow. Leukine is undergoing studies needed for approval.

The Biomedical Advanced Research and Development Authority had earlier sponsored advanced development and purchase of Neupogen, another leukocyte growth factor product approved for treating adults and children exposed to radiation that damages bone marrow.

Related: HHS Hails Big Ideas

The deal for Neulasta and Leukine thus increases the number of CSF factor doses available for use in an emergency. It also increases operational capability, HHS says, since treatments with Neulasta are given once weekly, whereas treatment with Neupogen is daily.