Neurology

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

[email protected]

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

[email protected]

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

[email protected]

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

Age, symptom severity, and serum glucose do not influence the benefit of endovascular thrombectomy for patients with stroke, according to research published online ahead of print Jan. 28 in JAMA Neurology. The location of the arterial occlusive lesion and the imaging technique used to select patients for the procedure also do not influence the therapy’s benefits, the researchers said. Although the proportional benefit of thrombectomy plus medical management is uniform across subgroups, compared with medical management alone, patients may have different amounts of absolute benefit.

The results of the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trial, which were published in 2018, indicated that endovascular thrombectomy provided clinical benefits for patients with acute ischemic stroke if administered at 6-16 hours after stroke onset. As part of the trial’s prespecified analyses, Maarten G. Lansberg, MD, PhD, associate professor of neurology and neurological sciences at Stanford (Calif.) University Medical Center in California, and his colleagues sought to determine whether thrombectomy had uniform benefit among various patient subgroups (e.g., elderly people, patients with mild symptoms, and those who present late after onset).

A total of 296 patients were enrolled in the randomized, open-label, blinded-endpoint DEFUSE 3 trial at 38 sites in the United States. Eligible participants had acute ischemic stroke resulting from an occlusion of the internal carotid artery or middle cerebral artery and evidence of salvageable tissue on perfusion CT or MRI. In all, 182 patients met these criteria and were randomized and included in the intention-to-treat analysis. The researchers stopped DEFUSE 3 early because of efficacy.

The study’s primary endpoint was functional outcome at day 90, as measured with the modified Rankin Scale. Dr. Lansberg and his colleagues performed multivariate ordinal logistic regression to calculate the adjusted proportional association between endovascular treatment and clinical outcome among participants of various ages, baseline stroke severities, periods between onset and treatment, locations of the arterial occlusion, and imaging modalities, such as CT or MRI, used to identify salvageable tissue.

The population’s median age was 70 years, and 51% of participants were women. The median National Institutes of Health Stroke Scale score was 16. When the researchers considered the whole sample, they found that younger age, lower baseline NIHSS score, and lower serum glucose level independently predicted better functional outcome. The common odds ratio for improved functional outcome with endovascular therapy, adjusted for these variables, was 3.1. Age, NIHSS score, time to randomization, imaging modality, and location of the arterial occlusion did not interact significantly with treatment effect.

“Our results indicate that advanced age, up to 90 years, should not be considered a contraindication to thrombectomy, provided that the patient is fully independent prior to stroke onset,” said the researchers. “Although age did not modify the treatment effect, it was a strong independent predictor of 90-day disability, which is consistent with prior studies of both tissue plasminogen activator and endovascular therapy.”

The trial’s small sample size may have allowed small differences between groups to pass unnoticed, said the reseachers. Other trials of late-window thrombectomy will be required to validate these results, they concluded.

The National Institute for Neurological Disorders and Stroke supported the study through grants. Several investigators received consulting fees from and hold shares in iSchemaView, which manufactures the software that the investigators used for postprocessing of CT and MRI perfusion studies. Other authors received consulting fees from various pharmaceutical and medical device companies, including Genentech, Medtronic, Pfizer, and Stryker Neurovascular.

[email protected]

SOURCE: Lansberg MG et al. JAMA Neurol. 2019 Jan 28. doi: 10.1001/jamaneurol.2018.4587.

Age, symptom severity, and serum glucose do not influence the benefit of endovascular thrombectomy for patients with stroke, according to research published online ahead of print Jan. 28 in JAMA Neurology. The location of the arterial occlusive lesion and the imaging technique used to select patients for the procedure also do not influence the therapy’s benefits, the researchers said. Although the proportional benefit of thrombectomy plus medical management is uniform across subgroups, compared with medical management alone, patients may have different amounts of absolute benefit.

The results of the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trial, which were published in 2018, indicated that endovascular thrombectomy provided clinical benefits for patients with acute ischemic stroke if administered at 6-16 hours after stroke onset. As part of the trial’s prespecified analyses, Maarten G. Lansberg, MD, PhD, associate professor of neurology and neurological sciences at Stanford (Calif.) University Medical Center in California, and his colleagues sought to determine whether thrombectomy had uniform benefit among various patient subgroups (e.g., elderly people, patients with mild symptoms, and those who present late after onset).

A total of 296 patients were enrolled in the randomized, open-label, blinded-endpoint DEFUSE 3 trial at 38 sites in the United States. Eligible participants had acute ischemic stroke resulting from an occlusion of the internal carotid artery or middle cerebral artery and evidence of salvageable tissue on perfusion CT or MRI. In all, 182 patients met these criteria and were randomized and included in the intention-to-treat analysis. The researchers stopped DEFUSE 3 early because of efficacy.

The study’s primary endpoint was functional outcome at day 90, as measured with the modified Rankin Scale. Dr. Lansberg and his colleagues performed multivariate ordinal logistic regression to calculate the adjusted proportional association between endovascular treatment and clinical outcome among participants of various ages, baseline stroke severities, periods between onset and treatment, locations of the arterial occlusion, and imaging modalities, such as CT or MRI, used to identify salvageable tissue.

The population’s median age was 70 years, and 51% of participants were women. The median National Institutes of Health Stroke Scale score was 16. When the researchers considered the whole sample, they found that younger age, lower baseline NIHSS score, and lower serum glucose level independently predicted better functional outcome. The common odds ratio for improved functional outcome with endovascular therapy, adjusted for these variables, was 3.1. Age, NIHSS score, time to randomization, imaging modality, and location of the arterial occlusion did not interact significantly with treatment effect.

“Our results indicate that advanced age, up to 90 years, should not be considered a contraindication to thrombectomy, provided that the patient is fully independent prior to stroke onset,” said the researchers. “Although age did not modify the treatment effect, it was a strong independent predictor of 90-day disability, which is consistent with prior studies of both tissue plasminogen activator and endovascular therapy.”

The trial’s small sample size may have allowed small differences between groups to pass unnoticed, said the reseachers. Other trials of late-window thrombectomy will be required to validate these results, they concluded.

The National Institute for Neurological Disorders and Stroke supported the study through grants. Several investigators received consulting fees from and hold shares in iSchemaView, which manufactures the software that the investigators used for postprocessing of CT and MRI perfusion studies. Other authors received consulting fees from various pharmaceutical and medical device companies, including Genentech, Medtronic, Pfizer, and Stryker Neurovascular.

[email protected]

SOURCE: Lansberg MG et al. JAMA Neurol. 2019 Jan 28. doi: 10.1001/jamaneurol.2018.4587.

Age, symptom severity, and serum glucose do not influence the benefit of endovascular thrombectomy for patients with stroke, according to research published online ahead of print Jan. 28 in JAMA Neurology. The location of the arterial occlusive lesion and the imaging technique used to select patients for the procedure also do not influence the therapy’s benefits, the researchers said. Although the proportional benefit of thrombectomy plus medical management is uniform across subgroups, compared with medical management alone, patients may have different amounts of absolute benefit.

The results of the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trial, which were published in 2018, indicated that endovascular thrombectomy provided clinical benefits for patients with acute ischemic stroke if administered at 6-16 hours after stroke onset. As part of the trial’s prespecified analyses, Maarten G. Lansberg, MD, PhD, associate professor of neurology and neurological sciences at Stanford (Calif.) University Medical Center in California, and his colleagues sought to determine whether thrombectomy had uniform benefit among various patient subgroups (e.g., elderly people, patients with mild symptoms, and those who present late after onset).

A total of 296 patients were enrolled in the randomized, open-label, blinded-endpoint DEFUSE 3 trial at 38 sites in the United States. Eligible participants had acute ischemic stroke resulting from an occlusion of the internal carotid artery or middle cerebral artery and evidence of salvageable tissue on perfusion CT or MRI. In all, 182 patients met these criteria and were randomized and included in the intention-to-treat analysis. The researchers stopped DEFUSE 3 early because of efficacy.

The study’s primary endpoint was functional outcome at day 90, as measured with the modified Rankin Scale. Dr. Lansberg and his colleagues performed multivariate ordinal logistic regression to calculate the adjusted proportional association between endovascular treatment and clinical outcome among participants of various ages, baseline stroke severities, periods between onset and treatment, locations of the arterial occlusion, and imaging modalities, such as CT or MRI, used to identify salvageable tissue.

The population’s median age was 70 years, and 51% of participants were women. The median National Institutes of Health Stroke Scale score was 16. When the researchers considered the whole sample, they found that younger age, lower baseline NIHSS score, and lower serum glucose level independently predicted better functional outcome. The common odds ratio for improved functional outcome with endovascular therapy, adjusted for these variables, was 3.1. Age, NIHSS score, time to randomization, imaging modality, and location of the arterial occlusion did not interact significantly with treatment effect.

“Our results indicate that advanced age, up to 90 years, should not be considered a contraindication to thrombectomy, provided that the patient is fully independent prior to stroke onset,” said the researchers. “Although age did not modify the treatment effect, it was a strong independent predictor of 90-day disability, which is consistent with prior studies of both tissue plasminogen activator and endovascular therapy.”

The trial’s small sample size may have allowed small differences between groups to pass unnoticed, said the reseachers. Other trials of late-window thrombectomy will be required to validate these results, they concluded.

The National Institute for Neurological Disorders and Stroke supported the study through grants. Several investigators received consulting fees from and hold shares in iSchemaView, which manufactures the software that the investigators used for postprocessing of CT and MRI perfusion studies. Other authors received consulting fees from various pharmaceutical and medical device companies, including Genentech, Medtronic, Pfizer, and Stryker Neurovascular.

[email protected]

SOURCE: Lansberg MG et al. JAMA Neurol. 2019 Jan 28. doi: 10.1001/jamaneurol.2018.4587.

Among patients with epilepsy, a simple model that incorporates factors such as a patient’s sex and history of depression, anxiety, and recreational drug use may help predict the risk of a psychiatric adverse effect from levetiracetam, according to a study published in JAMA Neurology.

“This study derived 2 simple models that predict the risk of a psychiatric adverse effect from levetiracetam” and can “guide prescription in clinical practice,” said Colin B. Josephson, MD, of the department of clinical neurosciences at the University of Calgary (Canada) and his research colleagues.

Levetiracetam is a commonly used first-line treatment for epilepsy because of its ease of use, broad spectrum of action, and safety profile, the researchers said. Still, psychiatric adverse reactions occur in as many as 16% of patients and frequently require treatment discontinuation.

To evaluate whether routine clinical data can predict which patients with epilepsy will experience a psychiatric adverse event from levetiracetam, the investigators analyzed data from The Health Improvement Network (THIN) database, which includes anonymized patient records from general practices in the United Kingdom. They assessed 21 variables for possible inclusion in prediction models. They identified these variables by searching the literature and weighing input from a panel of experts.

Their analysis included data from Jan. 1, 2000–May 31, 2012. Among the more than 11 million patients in THIN, the researchers identified 7,300 incident cases of epilepsy. The researchers examined when patients received a first prescription for levetiracetam and whether patients experienced a psychiatric symptom or disorder within 2 years of the prescription.

Among 1,173 patients with epilepsy receiving levetiracetam, the median age was 39 years; about half were women. In all, 14.1% experienced a psychiatric symptom or disorder within 2 years of prescription. Women were more likely to report a psychiatric symptom (odds ratio, 1.41), as were patients with a history of social deprivation (OR, 1.15), anxiety (OR, 1.74), recreational drug use (OR, 2.02), or depression (OR, 2.20).

The final model included female sex, history of depression, history of anxiety, and history of recreational drug use. Low socioeconomic status was not included because “it would be challenging to assign this score in clinic,” the authors said.

“There was a gradient in risk probabilities increasing from 8% for 0 risk factors to 11%-17% for 1, 17% to 31% for 2, 30%-42% for 3, and 49% when all risk factors were present,” Dr. Josephson and his colleagues indicated. “The discovered incremental probability of reporting a psychiatric sign can help generate an index of suspicion to counsel patients.”

Using the example of a woman patient with depression, the model “suggests she would be at risk,” with a 22% chance of a psychiatric adverse event in the 2 years after receiving a levetiracetam prescription.

The researchers created a second prediction algorithm based on data from patients without documentation of a mental health sign, symptom, or disorder prior to their levetiracetam prescription. This model incorporated age, sex, recreational drug use, and levetiracetam daily dose; it performed comparably well and might be used to determine safety of prescription, according to Dr. Josephson and his colleagues.

The authors noted that the study was limited by an inability to evaluate medication adherence and seizure type and frequency. One advantage of the study’s design is that it may have circumvented expectation bias because general practitioners were not prone to anticipating psychiatric adverse events or to have a lower threshold for diagnosing them.

The authors disclosed research fellowships and support from foundations and federal agencies.

[email protected]

SOURCE: Josephson CB et al. JAMA Neurol. 2019 Jan 28. doi: 10.1001/jamaneurol.2018.4561.

Among patients with epilepsy, a simple model that incorporates factors such as a patient’s sex and history of depression, anxiety, and recreational drug use may help predict the risk of a psychiatric adverse effect from levetiracetam, according to a study published in JAMA Neurology.

“This study derived 2 simple models that predict the risk of a psychiatric adverse effect from levetiracetam” and can “guide prescription in clinical practice,” said Colin B. Josephson, MD, of the department of clinical neurosciences at the University of Calgary (Canada) and his research colleagues.

Levetiracetam is a commonly used first-line treatment for epilepsy because of its ease of use, broad spectrum of action, and safety profile, the researchers said. Still, psychiatric adverse reactions occur in as many as 16% of patients and frequently require treatment discontinuation.

To evaluate whether routine clinical data can predict which patients with epilepsy will experience a psychiatric adverse event from levetiracetam, the investigators analyzed data from The Health Improvement Network (THIN) database, which includes anonymized patient records from general practices in the United Kingdom. They assessed 21 variables for possible inclusion in prediction models. They identified these variables by searching the literature and weighing input from a panel of experts.

Their analysis included data from Jan. 1, 2000–May 31, 2012. Among the more than 11 million patients in THIN, the researchers identified 7,300 incident cases of epilepsy. The researchers examined when patients received a first prescription for levetiracetam and whether patients experienced a psychiatric symptom or disorder within 2 years of the prescription.

Among 1,173 patients with epilepsy receiving levetiracetam, the median age was 39 years; about half were women. In all, 14.1% experienced a psychiatric symptom or disorder within 2 years of prescription. Women were more likely to report a psychiatric symptom (odds ratio, 1.41), as were patients with a history of social deprivation (OR, 1.15), anxiety (OR, 1.74), recreational drug use (OR, 2.02), or depression (OR, 2.20).

The final model included female sex, history of depression, history of anxiety, and history of recreational drug use. Low socioeconomic status was not included because “it would be challenging to assign this score in clinic,” the authors said.

“There was a gradient in risk probabilities increasing from 8% for 0 risk factors to 11%-17% for 1, 17% to 31% for 2, 30%-42% for 3, and 49% when all risk factors were present,” Dr. Josephson and his colleagues indicated. “The discovered incremental probability of reporting a psychiatric sign can help generate an index of suspicion to counsel patients.”

Using the example of a woman patient with depression, the model “suggests she would be at risk,” with a 22% chance of a psychiatric adverse event in the 2 years after receiving a levetiracetam prescription.

The researchers created a second prediction algorithm based on data from patients without documentation of a mental health sign, symptom, or disorder prior to their levetiracetam prescription. This model incorporated age, sex, recreational drug use, and levetiracetam daily dose; it performed comparably well and might be used to determine safety of prescription, according to Dr. Josephson and his colleagues.

The authors noted that the study was limited by an inability to evaluate medication adherence and seizure type and frequency. One advantage of the study’s design is that it may have circumvented expectation bias because general practitioners were not prone to anticipating psychiatric adverse events or to have a lower threshold for diagnosing them.

The authors disclosed research fellowships and support from foundations and federal agencies.

[email protected]

SOURCE: Josephson CB et al. JAMA Neurol. 2019 Jan 28. doi: 10.1001/jamaneurol.2018.4561.

Among patients with epilepsy, a simple model that incorporates factors such as a patient’s sex and history of depression, anxiety, and recreational drug use may help predict the risk of a psychiatric adverse effect from levetiracetam, according to a study published in JAMA Neurology.

“This study derived 2 simple models that predict the risk of a psychiatric adverse effect from levetiracetam” and can “guide prescription in clinical practice,” said Colin B. Josephson, MD, of the department of clinical neurosciences at the University of Calgary (Canada) and his research colleagues.

Levetiracetam is a commonly used first-line treatment for epilepsy because of its ease of use, broad spectrum of action, and safety profile, the researchers said. Still, psychiatric adverse reactions occur in as many as 16% of patients and frequently require treatment discontinuation.

To evaluate whether routine clinical data can predict which patients with epilepsy will experience a psychiatric adverse event from levetiracetam, the investigators analyzed data from The Health Improvement Network (THIN) database, which includes anonymized patient records from general practices in the United Kingdom. They assessed 21 variables for possible inclusion in prediction models. They identified these variables by searching the literature and weighing input from a panel of experts.

Their analysis included data from Jan. 1, 2000–May 31, 2012. Among the more than 11 million patients in THIN, the researchers identified 7,300 incident cases of epilepsy. The researchers examined when patients received a first prescription for levetiracetam and whether patients experienced a psychiatric symptom or disorder within 2 years of the prescription.

Among 1,173 patients with epilepsy receiving levetiracetam, the median age was 39 years; about half were women. In all, 14.1% experienced a psychiatric symptom or disorder within 2 years of prescription. Women were more likely to report a psychiatric symptom (odds ratio, 1.41), as were patients with a history of social deprivation (OR, 1.15), anxiety (OR, 1.74), recreational drug use (OR, 2.02), or depression (OR, 2.20).

The final model included female sex, history of depression, history of anxiety, and history of recreational drug use. Low socioeconomic status was not included because “it would be challenging to assign this score in clinic,” the authors said.

“There was a gradient in risk probabilities increasing from 8% for 0 risk factors to 11%-17% for 1, 17% to 31% for 2, 30%-42% for 3, and 49% when all risk factors were present,” Dr. Josephson and his colleagues indicated. “The discovered incremental probability of reporting a psychiatric sign can help generate an index of suspicion to counsel patients.”

Using the example of a woman patient with depression, the model “suggests she would be at risk,” with a 22% chance of a psychiatric adverse event in the 2 years after receiving a levetiracetam prescription.

The researchers created a second prediction algorithm based on data from patients without documentation of a mental health sign, symptom, or disorder prior to their levetiracetam prescription. This model incorporated age, sex, recreational drug use, and levetiracetam daily dose; it performed comparably well and might be used to determine safety of prescription, according to Dr. Josephson and his colleagues.

The authors noted that the study was limited by an inability to evaluate medication adherence and seizure type and frequency. One advantage of the study’s design is that it may have circumvented expectation bias because general practitioners were not prone to anticipating psychiatric adverse events or to have a lower threshold for diagnosing them.

The authors disclosed research fellowships and support from foundations and federal agencies.

[email protected]

SOURCE: Josephson CB et al. JAMA Neurol. 2019 Jan 28. doi: 10.1001/jamaneurol.2018.4561.

When I was training to become a family physician, my mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation. I am not sure where that figure came from, but my 40 years of experience in family medicine supports that prediction. Of course, the flip-side of that coin is having the wisdom to make those referrals for patients who really need a specialist’s diagnostic or treatment skills. The “rub,” of course, is that when I do need a specialist’s help, the wait for an appointment is often unacceptably long—both for me and my patients.

One way to help alleviate the logjam of referrals is to manage more medical problems ourselves. Now I don’t mean holding on to patients who definitely need a referral. But I do think we should avoid being too quick to hand off a patient. Let me explain.

When I was Chair of Family Medicine at Cleveland Clinic, I asked my specialty colleagues what percentage of the referred patients they saw in their offices could be managed competently by a well-trained family physician. The usual answer—from a variety of specialists—was “about 30%.” If we took care of that 30% of patients ourselves, it would go a long way toward freeing up specialists’ schedules to see the patients who truly require their expertise.

My mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation.

Some public health systems, such as the University of California San Francisco Medical Center,¹ have implemented successful triage systems to alleviate the referral backlog. Patients are triaged by a specialist and assigned to 1 of 3 categories: 1) urgent—the patient will be seen right away, 2) non-urgent—the patient will be seen as soon as possible (usually within 2 weeks), or 3) phone/email consultation—the specialist provides diagnostic and management advice electronically, or by phone, but does not see the patient.

Continue to: The issue of referral comes to mind...

The issue of referral comes to mind this month in light of our cover story on migraine headache management. Migraine is one of those conditions that is often referred for specialist care, but can, in many cases, be competently managed by family physicians. The diagnosis of migraine is made almost entirely by history and physical exam, and there are many treatments for acute attacks and prevention that are effective and can be prescribed by family physicians and other primary health care professionals.

Yes, patients with more severe migraine may need a specialist consultation. But let’s remain cognizant of the fact that a good percentage of our patients will be best served staying right where they are—in the office of their family physician.

When I was training to become a family physician, my mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation. I am not sure where that figure came from, but my 40 years of experience in family medicine supports that prediction. Of course, the flip-side of that coin is having the wisdom to make those referrals for patients who really need a specialist’s diagnostic or treatment skills. The “rub,” of course, is that when I do need a specialist’s help, the wait for an appointment is often unacceptably long—both for me and my patients.

One way to help alleviate the logjam of referrals is to manage more medical problems ourselves. Now I don’t mean holding on to patients who definitely need a referral. But I do think we should avoid being too quick to hand off a patient. Let me explain.

When I was Chair of Family Medicine at Cleveland Clinic, I asked my specialty colleagues what percentage of the referred patients they saw in their offices could be managed competently by a well-trained family physician. The usual answer—from a variety of specialists—was “about 30%.” If we took care of that 30% of patients ourselves, it would go a long way toward freeing up specialists’ schedules to see the patients who truly require their expertise.

My mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation.

Some public health systems, such as the University of California San Francisco Medical Center,¹ have implemented successful triage systems to alleviate the referral backlog. Patients are triaged by a specialist and assigned to 1 of 3 categories: 1) urgent—the patient will be seen right away, 2) non-urgent—the patient will be seen as soon as possible (usually within 2 weeks), or 3) phone/email consultation—the specialist provides diagnostic and management advice electronically, or by phone, but does not see the patient.

Continue to: The issue of referral comes to mind...

The issue of referral comes to mind this month in light of our cover story on migraine headache management. Migraine is one of those conditions that is often referred for specialist care, but can, in many cases, be competently managed by family physicians. The diagnosis of migraine is made almost entirely by history and physical exam, and there are many treatments for acute attacks and prevention that are effective and can be prescribed by family physicians and other primary health care professionals.

Yes, patients with more severe migraine may need a specialist consultation. But let’s remain cognizant of the fact that a good percentage of our patients will be best served staying right where they are—in the office of their family physician.

When I was training to become a family physician, my mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation. I am not sure where that figure came from, but my 40 years of experience in family medicine supports that prediction. Of course, the flip-side of that coin is having the wisdom to make those referrals for patients who really need a specialist’s diagnostic or treatment skills. The “rub,” of course, is that when I do need a specialist’s help, the wait for an appointment is often unacceptably long—both for me and my patients.

One way to help alleviate the logjam of referrals is to manage more medical problems ourselves. Now I don’t mean holding on to patients who definitely need a referral. But I do think we should avoid being too quick to hand off a patient. Let me explain.

When I was Chair of Family Medicine at Cleveland Clinic, I asked my specialty colleagues what percentage of the referred patients they saw in their offices could be managed competently by a well-trained family physician. The usual answer—from a variety of specialists—was “about 30%.” If we took care of that 30% of patients ourselves, it would go a long way toward freeing up specialists’ schedules to see the patients who truly require their expertise.

My mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation.

Some public health systems, such as the University of California San Francisco Medical Center,¹ have implemented successful triage systems to alleviate the referral backlog. Patients are triaged by a specialist and assigned to 1 of 3 categories: 1) urgent—the patient will be seen right away, 2) non-urgent—the patient will be seen as soon as possible (usually within 2 weeks), or 3) phone/email consultation—the specialist provides diagnostic and management advice electronically, or by phone, but does not see the patient.

Continue to: The issue of referral comes to mind...

The issue of referral comes to mind this month in light of our cover story on migraine headache management. Migraine is one of those conditions that is often referred for specialist care, but can, in many cases, be competently managed by family physicians. The diagnosis of migraine is made almost entirely by history and physical exam, and there are many treatments for acute attacks and prevention that are effective and can be prescribed by family physicians and other primary health care professionals.

Yes, patients with more severe migraine may need a specialist consultation. But let’s remain cognizant of the fact that a good percentage of our patients will be best served staying right where they are—in the office of their family physician.

THE CASE

Ms. E, a 42-year-old woman, visited her new physician for a physical exam. When asked about alcohol intake, she reported that she drank 3 to 4 beers after work and sometimes 5 to 8 beers a day on the weekends. Occasionally, she exceeded those amounts, but she didn’t feel guilty about her drinking. She was often late to work and said her relationship with her boyfriend was strained. A review of systems was positive for fatigue, poor concentration, abdominal pain, and weight gain. Her body mass index was 41, pulse 100 beats/min, blood pressure 125/75 mm Hg, and she was afebrile. Her physical exam was otherwise within normal limits.

How would you proceed with this patient?

Alcohol use disorder (AUD) is a common and often untreated condition that is increasingly prevalent in the United States.¹ The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) characterizes AUD as a combination of signs and symptoms typifying alcohol abuse and dependence (discussed in a bit).²

Data from the 2015 National Survey on Drug Use and Health (NSDUH) showed 15.7 million Americans with AUD, affecting 6.2% of the population ages 18 years or older and 2.5% of adolescents ages 12 to 17 years.³

Alcohol use and AUD account for an estimated 3.8% of all global deaths and 4.6% of global disability-adjusted life years.⁴ AUD adversely affects several systems (TABLE 1⁵), and patients with AUD are sicker and more likely to die younger than those without AUD.⁴ In the United States, prevalence of AUD has increased in recent years among women, older adults, racial minorities, and individuals with a low education level.⁶

Screening for AUD is reasonable and straightforward, although diagnosis and treatment of AUD in primary care settings may be challenging due to competing clinical priorities; lack of training, resources, and support; and skepticism about the efficacy of behavioral and pharmacologic treatments.^7,8 However, family physicians are in an excellent position to diagnose and help address the complex biopsychosocial needs of patients with AUD, often in collaboration with colleagues and community organizations.

Signs and symptoms of AUD

In clinical practice, at least 2 of the following 11 behaviors or symptoms are required to diagnose AUD²:

• consuming larger amounts of alcohol over a longer period than intended
• persistent desire or unsuccessful efforts to cut down or control alcohol use
• making a significant effort to obtain, use, or recover from alcohol

In moderate-to-severe cases:

• cravings or urges to use alcohol
• recurrent failure to fulfill major work, school, or social obligations
• continued alcohol use despite recurrent social and interpersonal problems
• giving up social, occupational, and recreational activities due to alcohol
• using alcohol in physically dangerous situations
• continued alcohol use despite having physical or psychological problems
• tolerance to alcohol’s effects
• withdrawal symptoms.

Continue to: Patients meet criteria for mild AUD severity if...

Patients meet criteria for mild AUD severity if they exhibit 2 or 3 symptoms, moderate AUD with 4 or 5 symptoms, and severe AUD if there are 6 or more symptoms.²

USPSTF recommends screening for alcohol use disorder with the 10-question AUDIT, 3-question AUDIT-C, or single-question NIAAA tool.

Those who meet criteria for AUD and are able to stop using alcohol are deemed to be in early remission if the criteria have gone unfulfilled for at least 3 months and less than 12 months. Patients are considered to be in sustained remission if they have not met criteria for AUD at any time during a period of 12 months or longer.

How to detect AUD

Several clues in a patient’s history can suggest AUD (TABLE 2^9,10). Most imbibers are unaware of the dangers and may consider themselves merely “social drinkers.” Binge drinking may be an early indicator of vulnerability to AUD and should be assessed as part of a thorough clinical evaluation.¹¹ The US Preventive Services Task Force (USPSTF) recommends (Grade B) that clinicians screen adults ages 18 years or older for alcohol misuse.¹²

Studies demonstrate that both genetic and environmental factors play important roles in the development of AUD.¹³ A family history of excessive alcohol use increases the risk of AUD. Comorbidity of AUD and other mental health conditions is extremely common. For example, high rates of association between major depressive disorder and AUD have been observed.¹⁴

Tools to use in screening and diagnosing AUD

Screening for AUD during an office visit can be done fairly quickly. While 96% of primary care physicians screen for alcohol misuse in some way, only 38% use 1 of the 3 tools recommended by the USPSTF¹⁵—the Alcohol Use Disorders Identification Test (AUDIT), the abbreviated AUDIT-C, or the National Institute on Alcohol Abuse and Alcoholism (NIAAA) single question screen—which detect the full spectrum of alcohol misuse in adults.¹² Although the commonly used CAGE questionnaire is one of the most studied self-report tools, it has lower sensitivity at a lower level of alcohol intake.¹⁶

Continue to: The NIAAA single-question screen asks...

The NIAAA single-question screen asks how many times in the past year the patient had ≥4 drinks (women) or ≥5 drinks (men) in a day.¹⁵ The sensitivity and specificity of single-question screening are 82% to 87% and 61% to 79%, respectively, and the test has been validated in several different settings.¹² The AUDIT screening tool, freely available from the World Health Organization, is a 10-item questionnaire that probes an individual’s alcohol intake, alcohol dependence, and adverse consequences of alcohol use. Administration of the AUDIT typically requires only 2 minutes. AUDIT-C¹⁷ is an abbreviated version of the AUDIT questionnaire that asks 3 consumption questions to screen for AUD.

It was found that AUDIT scores in the range of 8 to 15 indicate a medium-level alcohol problem, whereas a score of ≥16 indicates a high-level alcohol problem. The AUDIT-C is scored from 0 to 12, with ≥4 indicating a problem in men and ≥3 a problem in women.

THE CASE

The physician had used the NIAAA single- question screen to determine that Ms. E drank more than 4 beers per day during social events and weekends, which occurred 2 to 3 times per month over the past year. She lives alone and said that she’d been seeing less and less of her boyfriend lately. Her score on the Patient Health Questionnaire (PHQ), which screens for depression, was 11, indicating moderate impairment. Her response on the CAGE questionnaire was negative for a problem with alcohol. However, her AUDIT score was 17, indicating a high-level alcohol problem. Based on these findings, her physician expressed concern that her alcohol use might be contributing to her symptoms and difficulties.

The CAGE questionnaire has lower sensitivity when alcohol intake is lower.

Although she did not have a history of increasing usage per day, a persistent desire to cut down, significant effort to obtain alcohol, or cravings, she was having work troubles and continued to drink even though it was straining relationships, promoting weight gain, and causing abdominal pain.

The physician asked her to schedule a return visit and ordered several blood studies. He also offered to connect her with a colleague with whom he collaborated who could speak with her about possible alcohol use disorders and depression.

Continue to: Selecting blood work in screening for AUD

Lab tests used to measure hepatic injury due to alcohol include gamma-glutamyl-transferase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and macrocytic volume, although the indices of hepatic damage have low specificity. Elevated serum ethanol levels can reveal recent alcohol use, and vitamin deficiencies and other abnormalities can be used to differentiate other causes of hepatic inflammation and co-existing health issues (TABLE 3^10,18). A number of as-yet-unvalidated biomarkers are being studied to assist in screening, diagnosing, and treating AUD.¹⁸

What treatment approaches work for AUD?

Family physicians can efficiently and productively address AUD by using alcohol screening and brief intervention, which have been shown to reduce risky drinking. Reimbursement for this service is covered by such CPT codes as 99408, 99409, or H0049, or with other evaluation and management (E/M) codes by using modifier 25.

Treatment of AUD varies and should be customized to each patient’s needs, readiness, preferences, and resources. Individual and group counseling approaches can be effective, and medications are available for inpatient and outpatient settings. Psychotherapy options include brief interventions, 12-step programs (eg, Alcoholics Anonymous—https://www.aa.org/pages/en_US/find-aa-resources),motivational enhancement therapy, and cognitive behavioral therapy. Although it is beyond the scope of this article to describe these options in detail, resources are available for those who wish to learn more.^19-21

Psychopharmacologic management includes US Food and Drug Administration (FDA)-approved medications such as disulfiram, naltrexone, and acamprosate, and off-label uses of other medications (TABLE 4⁹). Not enough empiric evidence is available to judge the effectiveness of these medications in adolescents, and the FDA has not approved them for such use. Evidence from meta-analyses comparing naltrexone and acamprosate have shown naltrexone to be more efficacious in reducing heavy drinking and cravings, while acamprosate is effective in promoting abstinence.^22,23 Naltrexone combined with behavioral intervention reduces the heavy drinking days and percentage of abstinence days.²⁴

Current guideline recommendations from the American Psychiatric Association²⁵ include:

• Naltrexone and acamprosate are recommended to treat patients with moderate-to-severe AUD in specific circumstances (eg, when nonpharmacologic approaches have failed to produce an effect or when patients prefer to use one of these medications).
• Topiramate and gabapentin are also suggested as medications for patients with moderate-to-severe AUD, but typically after first trying naltrexone and acamprosate.
• Disulfiram generally should not be used as first-line treatment. It produces physical reactions (eg, flushing) if alcohol is consumed within 12 to 24 hours of medication use.

Continue to: THE CASE

Ms. E was open to the idea of decreasing her alcohol use and agreed that she was depressed. Her lab tests at follow-up were normal other than an elevated AST/ALT of 90/80 U/L. She received brief counseling from her family physician combined with cognitive behavioral therapy by a psychologist colleague. A subsequent ultrasound of her liver showed mild hepatomegaly and moderate-to-severe steatosis with nodularity of the liver, raising the possibility of cirrhosis.

The NIAAA single-question screen asks how many times in the past year the patient had ≥4 drinks (women) or ≥5 drinks (men) in a day.

She continued to get counseling for her AUD and for her comorbid depression in addition to taking a selective serotonin reuptake inhibitor. She is now in early remission for her alcohol use.

CORRESPONDENCE
Jaividhya Dasarathy, MD, Department of Family Medicine, Metro Health Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109; [email protected].

THE CASE

Ms. E, a 42-year-old woman, visited her new physician for a physical exam. When asked about alcohol intake, she reported that she drank 3 to 4 beers after work and sometimes 5 to 8 beers a day on the weekends. Occasionally, she exceeded those amounts, but she didn’t feel guilty about her drinking. She was often late to work and said her relationship with her boyfriend was strained. A review of systems was positive for fatigue, poor concentration, abdominal pain, and weight gain. Her body mass index was 41, pulse 100 beats/min, blood pressure 125/75 mm Hg, and she was afebrile. Her physical exam was otherwise within normal limits.

How would you proceed with this patient?

Alcohol use disorder (AUD) is a common and often untreated condition that is increasingly prevalent in the United States.¹ The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) characterizes AUD as a combination of signs and symptoms typifying alcohol abuse and dependence (discussed in a bit).²

Data from the 2015 National Survey on Drug Use and Health (NSDUH) showed 15.7 million Americans with AUD, affecting 6.2% of the population ages 18 years or older and 2.5% of adolescents ages 12 to 17 years.³

Alcohol use and AUD account for an estimated 3.8% of all global deaths and 4.6% of global disability-adjusted life years.⁴ AUD adversely affects several systems (TABLE 1⁵), and patients with AUD are sicker and more likely to die younger than those without AUD.⁴ In the United States, prevalence of AUD has increased in recent years among women, older adults, racial minorities, and individuals with a low education level.⁶

Screening for AUD is reasonable and straightforward, although diagnosis and treatment of AUD in primary care settings may be challenging due to competing clinical priorities; lack of training, resources, and support; and skepticism about the efficacy of behavioral and pharmacologic treatments.^7,8 However, family physicians are in an excellent position to diagnose and help address the complex biopsychosocial needs of patients with AUD, often in collaboration with colleagues and community organizations.

Signs and symptoms of AUD

In clinical practice, at least 2 of the following 11 behaviors or symptoms are required to diagnose AUD²:

• consuming larger amounts of alcohol over a longer period than intended
• persistent desire or unsuccessful efforts to cut down or control alcohol use
• making a significant effort to obtain, use, or recover from alcohol

In moderate-to-severe cases:

• cravings or urges to use alcohol
• recurrent failure to fulfill major work, school, or social obligations
• continued alcohol use despite recurrent social and interpersonal problems
• giving up social, occupational, and recreational activities due to alcohol
• using alcohol in physically dangerous situations
• continued alcohol use despite having physical or psychological problems
• tolerance to alcohol’s effects
• withdrawal symptoms.

Continue to: Patients meet criteria for mild AUD severity if...

Patients meet criteria for mild AUD severity if they exhibit 2 or 3 symptoms, moderate AUD with 4 or 5 symptoms, and severe AUD if there are 6 or more symptoms.²

USPSTF recommends screening for alcohol use disorder with the 10-question AUDIT, 3-question AUDIT-C, or single-question NIAAA tool.

Those who meet criteria for AUD and are able to stop using alcohol are deemed to be in early remission if the criteria have gone unfulfilled for at least 3 months and less than 12 months. Patients are considered to be in sustained remission if they have not met criteria for AUD at any time during a period of 12 months or longer.

How to detect AUD

Several clues in a patient’s history can suggest AUD (TABLE 2^9,10). Most imbibers are unaware of the dangers and may consider themselves merely “social drinkers.” Binge drinking may be an early indicator of vulnerability to AUD and should be assessed as part of a thorough clinical evaluation.¹¹ The US Preventive Services Task Force (USPSTF) recommends (Grade B) that clinicians screen adults ages 18 years or older for alcohol misuse.¹²

Studies demonstrate that both genetic and environmental factors play important roles in the development of AUD.¹³ A family history of excessive alcohol use increases the risk of AUD. Comorbidity of AUD and other mental health conditions is extremely common. For example, high rates of association between major depressive disorder and AUD have been observed.¹⁴

Tools to use in screening and diagnosing AUD

Screening for AUD during an office visit can be done fairly quickly. While 96% of primary care physicians screen for alcohol misuse in some way, only 38% use 1 of the 3 tools recommended by the USPSTF¹⁵—the Alcohol Use Disorders Identification Test (AUDIT), the abbreviated AUDIT-C, or the National Institute on Alcohol Abuse and Alcoholism (NIAAA) single question screen—which detect the full spectrum of alcohol misuse in adults.¹² Although the commonly used CAGE questionnaire is one of the most studied self-report tools, it has lower sensitivity at a lower level of alcohol intake.¹⁶

Continue to: The NIAAA single-question screen asks...

The NIAAA single-question screen asks how many times in the past year the patient had ≥4 drinks (women) or ≥5 drinks (men) in a day.¹⁵ The sensitivity and specificity of single-question screening are 82% to 87% and 61% to 79%, respectively, and the test has been validated in several different settings.¹² The AUDIT screening tool, freely available from the World Health Organization, is a 10-item questionnaire that probes an individual’s alcohol intake, alcohol dependence, and adverse consequences of alcohol use. Administration of the AUDIT typically requires only 2 minutes. AUDIT-C¹⁷ is an abbreviated version of the AUDIT questionnaire that asks 3 consumption questions to screen for AUD.

It was found that AUDIT scores in the range of 8 to 15 indicate a medium-level alcohol problem, whereas a score of ≥16 indicates a high-level alcohol problem. The AUDIT-C is scored from 0 to 12, with ≥4 indicating a problem in men and ≥3 a problem in women.

THE CASE

The physician had used the NIAAA single- question screen to determine that Ms. E drank more than 4 beers per day during social events and weekends, which occurred 2 to 3 times per month over the past year. She lives alone and said that she’d been seeing less and less of her boyfriend lately. Her score on the Patient Health Questionnaire (PHQ), which screens for depression, was 11, indicating moderate impairment. Her response on the CAGE questionnaire was negative for a problem with alcohol. However, her AUDIT score was 17, indicating a high-level alcohol problem. Based on these findings, her physician expressed concern that her alcohol use might be contributing to her symptoms and difficulties.

The CAGE questionnaire has lower sensitivity when alcohol intake is lower.

Although she did not have a history of increasing usage per day, a persistent desire to cut down, significant effort to obtain alcohol, or cravings, she was having work troubles and continued to drink even though it was straining relationships, promoting weight gain, and causing abdominal pain.

The physician asked her to schedule a return visit and ordered several blood studies. He also offered to connect her with a colleague with whom he collaborated who could speak with her about possible alcohol use disorders and depression.

Continue to: Selecting blood work in screening for AUD

Lab tests used to measure hepatic injury due to alcohol include gamma-glutamyl-transferase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and macrocytic volume, although the indices of hepatic damage have low specificity. Elevated serum ethanol levels can reveal recent alcohol use, and vitamin deficiencies and other abnormalities can be used to differentiate other causes of hepatic inflammation and co-existing health issues (TABLE 3^10,18). A number of as-yet-unvalidated biomarkers are being studied to assist in screening, diagnosing, and treating AUD.¹⁸

What treatment approaches work for AUD?

Family physicians can efficiently and productively address AUD by using alcohol screening and brief intervention, which have been shown to reduce risky drinking. Reimbursement for this service is covered by such CPT codes as 99408, 99409, or H0049, or with other evaluation and management (E/M) codes by using modifier 25.

Treatment of AUD varies and should be customized to each patient’s needs, readiness, preferences, and resources. Individual and group counseling approaches can be effective, and medications are available for inpatient and outpatient settings. Psychotherapy options include brief interventions, 12-step programs (eg, Alcoholics Anonymous—https://www.aa.org/pages/en_US/find-aa-resources),motivational enhancement therapy, and cognitive behavioral therapy. Although it is beyond the scope of this article to describe these options in detail, resources are available for those who wish to learn more.^19-21

Psychopharmacologic management includes US Food and Drug Administration (FDA)-approved medications such as disulfiram, naltrexone, and acamprosate, and off-label uses of other medications (TABLE 4⁹). Not enough empiric evidence is available to judge the effectiveness of these medications in adolescents, and the FDA has not approved them for such use. Evidence from meta-analyses comparing naltrexone and acamprosate have shown naltrexone to be more efficacious in reducing heavy drinking and cravings, while acamprosate is effective in promoting abstinence.^22,23 Naltrexone combined with behavioral intervention reduces the heavy drinking days and percentage of abstinence days.²⁴

Current guideline recommendations from the American Psychiatric Association²⁵ include:

• Naltrexone and acamprosate are recommended to treat patients with moderate-to-severe AUD in specific circumstances (eg, when nonpharmacologic approaches have failed to produce an effect or when patients prefer to use one of these medications).
• Topiramate and gabapentin are also suggested as medications for patients with moderate-to-severe AUD, but typically after first trying naltrexone and acamprosate.
• Disulfiram generally should not be used as first-line treatment. It produces physical reactions (eg, flushing) if alcohol is consumed within 12 to 24 hours of medication use.

Continue to: THE CASE

Ms. E was open to the idea of decreasing her alcohol use and agreed that she was depressed. Her lab tests at follow-up were normal other than an elevated AST/ALT of 90/80 U/L. She received brief counseling from her family physician combined with cognitive behavioral therapy by a psychologist colleague. A subsequent ultrasound of her liver showed mild hepatomegaly and moderate-to-severe steatosis with nodularity of the liver, raising the possibility of cirrhosis.

The NIAAA single-question screen asks how many times in the past year the patient had ≥4 drinks (women) or ≥5 drinks (men) in a day.

She continued to get counseling for her AUD and for her comorbid depression in addition to taking a selective serotonin reuptake inhibitor. She is now in early remission for her alcohol use.

CORRESPONDENCE
Jaividhya Dasarathy, MD, Department of Family Medicine, Metro Health Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109; [email protected].

THE CASE

Ms. E, a 42-year-old woman, visited her new physician for a physical exam. When asked about alcohol intake, she reported that she drank 3 to 4 beers after work and sometimes 5 to 8 beers a day on the weekends. Occasionally, she exceeded those amounts, but she didn’t feel guilty about her drinking. She was often late to work and said her relationship with her boyfriend was strained. A review of systems was positive for fatigue, poor concentration, abdominal pain, and weight gain. Her body mass index was 41, pulse 100 beats/min, blood pressure 125/75 mm Hg, and she was afebrile. Her physical exam was otherwise within normal limits.

How would you proceed with this patient?

Alcohol use disorder (AUD) is a common and often untreated condition that is increasingly prevalent in the United States.¹ The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) characterizes AUD as a combination of signs and symptoms typifying alcohol abuse and dependence (discussed in a bit).²

Data from the 2015 National Survey on Drug Use and Health (NSDUH) showed 15.7 million Americans with AUD, affecting 6.2% of the population ages 18 years or older and 2.5% of adolescents ages 12 to 17 years.³

Alcohol use and AUD account for an estimated 3.8% of all global deaths and 4.6% of global disability-adjusted life years.⁴ AUD adversely affects several systems (TABLE 1⁵), and patients with AUD are sicker and more likely to die younger than those without AUD.⁴ In the United States, prevalence of AUD has increased in recent years among women, older adults, racial minorities, and individuals with a low education level.⁶

Screening for AUD is reasonable and straightforward, although diagnosis and treatment of AUD in primary care settings may be challenging due to competing clinical priorities; lack of training, resources, and support; and skepticism about the efficacy of behavioral and pharmacologic treatments.^7,8 However, family physicians are in an excellent position to diagnose and help address the complex biopsychosocial needs of patients with AUD, often in collaboration with colleagues and community organizations.

Signs and symptoms of AUD

In clinical practice, at least 2 of the following 11 behaviors or symptoms are required to diagnose AUD²:

• consuming larger amounts of alcohol over a longer period than intended
• persistent desire or unsuccessful efforts to cut down or control alcohol use
• making a significant effort to obtain, use, or recover from alcohol

In moderate-to-severe cases:

• cravings or urges to use alcohol
• recurrent failure to fulfill major work, school, or social obligations
• continued alcohol use despite recurrent social and interpersonal problems
• giving up social, occupational, and recreational activities due to alcohol
• using alcohol in physically dangerous situations
• continued alcohol use despite having physical or psychological problems
• tolerance to alcohol’s effects
• withdrawal symptoms.

Continue to: Patients meet criteria for mild AUD severity if...

Patients meet criteria for mild AUD severity if they exhibit 2 or 3 symptoms, moderate AUD with 4 or 5 symptoms, and severe AUD if there are 6 or more symptoms.²

USPSTF recommends screening for alcohol use disorder with the 10-question AUDIT, 3-question AUDIT-C, or single-question NIAAA tool.

Those who meet criteria for AUD and are able to stop using alcohol are deemed to be in early remission if the criteria have gone unfulfilled for at least 3 months and less than 12 months. Patients are considered to be in sustained remission if they have not met criteria for AUD at any time during a period of 12 months or longer.

How to detect AUD

Several clues in a patient’s history can suggest AUD (TABLE 2^9,10). Most imbibers are unaware of the dangers and may consider themselves merely “social drinkers.” Binge drinking may be an early indicator of vulnerability to AUD and should be assessed as part of a thorough clinical evaluation.¹¹ The US Preventive Services Task Force (USPSTF) recommends (Grade B) that clinicians screen adults ages 18 years or older for alcohol misuse.¹²

Studies demonstrate that both genetic and environmental factors play important roles in the development of AUD.¹³ A family history of excessive alcohol use increases the risk of AUD. Comorbidity of AUD and other mental health conditions is extremely common. For example, high rates of association between major depressive disorder and AUD have been observed.¹⁴

Tools to use in screening and diagnosing AUD

Screening for AUD during an office visit can be done fairly quickly. While 96% of primary care physicians screen for alcohol misuse in some way, only 38% use 1 of the 3 tools recommended by the USPSTF¹⁵—the Alcohol Use Disorders Identification Test (AUDIT), the abbreviated AUDIT-C, or the National Institute on Alcohol Abuse and Alcoholism (NIAAA) single question screen—which detect the full spectrum of alcohol misuse in adults.¹² Although the commonly used CAGE questionnaire is one of the most studied self-report tools, it has lower sensitivity at a lower level of alcohol intake.¹⁶

Continue to: The NIAAA single-question screen asks...

The NIAAA single-question screen asks how many times in the past year the patient had ≥4 drinks (women) or ≥5 drinks (men) in a day.¹⁵ The sensitivity and specificity of single-question screening are 82% to 87% and 61% to 79%, respectively, and the test has been validated in several different settings.¹² The AUDIT screening tool, freely available from the World Health Organization, is a 10-item questionnaire that probes an individual’s alcohol intake, alcohol dependence, and adverse consequences of alcohol use. Administration of the AUDIT typically requires only 2 minutes. AUDIT-C¹⁷ is an abbreviated version of the AUDIT questionnaire that asks 3 consumption questions to screen for AUD.

It was found that AUDIT scores in the range of 8 to 15 indicate a medium-level alcohol problem, whereas a score of ≥16 indicates a high-level alcohol problem. The AUDIT-C is scored from 0 to 12, with ≥4 indicating a problem in men and ≥3 a problem in women.

THE CASE

The physician had used the NIAAA single- question screen to determine that Ms. E drank more than 4 beers per day during social events and weekends, which occurred 2 to 3 times per month over the past year. She lives alone and said that she’d been seeing less and less of her boyfriend lately. Her score on the Patient Health Questionnaire (PHQ), which screens for depression, was 11, indicating moderate impairment. Her response on the CAGE questionnaire was negative for a problem with alcohol. However, her AUDIT score was 17, indicating a high-level alcohol problem. Based on these findings, her physician expressed concern that her alcohol use might be contributing to her symptoms and difficulties.

The CAGE questionnaire has lower sensitivity when alcohol intake is lower.

Although she did not have a history of increasing usage per day, a persistent desire to cut down, significant effort to obtain alcohol, or cravings, she was having work troubles and continued to drink even though it was straining relationships, promoting weight gain, and causing abdominal pain.

The physician asked her to schedule a return visit and ordered several blood studies. He also offered to connect her with a colleague with whom he collaborated who could speak with her about possible alcohol use disorders and depression.

Continue to: Selecting blood work in screening for AUD

Lab tests used to measure hepatic injury due to alcohol include gamma-glutamyl-transferase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and macrocytic volume, although the indices of hepatic damage have low specificity. Elevated serum ethanol levels can reveal recent alcohol use, and vitamin deficiencies and other abnormalities can be used to differentiate other causes of hepatic inflammation and co-existing health issues (TABLE 3^10,18). A number of as-yet-unvalidated biomarkers are being studied to assist in screening, diagnosing, and treating AUD.¹⁸

What treatment approaches work for AUD?

Family physicians can efficiently and productively address AUD by using alcohol screening and brief intervention, which have been shown to reduce risky drinking. Reimbursement for this service is covered by such CPT codes as 99408, 99409, or H0049, or with other evaluation and management (E/M) codes by using modifier 25.

Treatment of AUD varies and should be customized to each patient’s needs, readiness, preferences, and resources. Individual and group counseling approaches can be effective, and medications are available for inpatient and outpatient settings. Psychotherapy options include brief interventions, 12-step programs (eg, Alcoholics Anonymous—https://www.aa.org/pages/en_US/find-aa-resources),motivational enhancement therapy, and cognitive behavioral therapy. Although it is beyond the scope of this article to describe these options in detail, resources are available for those who wish to learn more.^19-21

Psychopharmacologic management includes US Food and Drug Administration (FDA)-approved medications such as disulfiram, naltrexone, and acamprosate, and off-label uses of other medications (TABLE 4⁹). Not enough empiric evidence is available to judge the effectiveness of these medications in adolescents, and the FDA has not approved them for such use. Evidence from meta-analyses comparing naltrexone and acamprosate have shown naltrexone to be more efficacious in reducing heavy drinking and cravings, while acamprosate is effective in promoting abstinence.^22,23 Naltrexone combined with behavioral intervention reduces the heavy drinking days and percentage of abstinence days.²⁴

Current guideline recommendations from the American Psychiatric Association²⁵ include:

• Naltrexone and acamprosate are recommended to treat patients with moderate-to-severe AUD in specific circumstances (eg, when nonpharmacologic approaches have failed to produce an effect or when patients prefer to use one of these medications).
• Topiramate and gabapentin are also suggested as medications for patients with moderate-to-severe AUD, but typically after first trying naltrexone and acamprosate.
• Disulfiram generally should not be used as first-line treatment. It produces physical reactions (eg, flushing) if alcohol is consumed within 12 to 24 hours of medication use.

Continue to: THE CASE

Ms. E was open to the idea of decreasing her alcohol use and agreed that she was depressed. Her lab tests at follow-up were normal other than an elevated AST/ALT of 90/80 U/L. She received brief counseling from her family physician combined with cognitive behavioral therapy by a psychologist colleague. A subsequent ultrasound of her liver showed mild hepatomegaly and moderate-to-severe steatosis with nodularity of the liver, raising the possibility of cirrhosis.

The NIAAA single-question screen asks how many times in the past year the patient had ≥4 drinks (women) or ≥5 drinks (men) in a day.

She continued to get counseling for her AUD and for her comorbid depression in addition to taking a selective serotonin reuptake inhibitor. She is now in early remission for her alcohol use.

CORRESPONDENCE
Jaividhya Dasarathy, MD, Department of Family Medicine, Metro Health Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109; [email protected].

Migraine is a highly disabling primary headache disorder that affects more than 44 million Americans annually.¹ The disorder causes pain, photophobia, phonophobia, and nausea that can last for hours, even days. Migraine headaches are 2 times more common in women than in men; although migraine is most common in people 30 to 39 years of age, all ages are affected.^2,3 Frequency of migraine headache is variable; chronic migraineurs experience more than 15 headache days a month.

©Cath Riley/Science Source

Recent estimates indicate that the cost of acute and chronic migraine headaches reaches approximately $78 million a year in the United States. ⁴ This high burden of disease has made effective migraine treatment options absolutely essential. Recent advances in our understanding of migraine pathophysiology have led to new therapeutic targets; there are now many novel treatment approaches on the horizon.

In this article, we review the diagnosis and management of migraine in detail. Our emphasis is on evidence-based approaches to acute and prophylactic treatment, including tried-and-true options and newly emerging therapies.

Neuronal dysfunction and a genetic predisposition

Although migraine was once thought to be caused by abnormalities of vasodilation, current research suggests that the disorder has its origins in primary neuronal dysfunction. There appears to be a genetic predisposition toward widespread neuronal hyperexcitability in migraineurs.⁵ In addition, hypothalamic neurons are thought to initiate migraine by responding to changes in brain homeostasis. Increased parasympathetic tone might activate meningeal pain receptors or lower the threshold for transmitting pain signals from the thalamus to the cortex.⁶

Prodromal symptoms and aura appear to originate from multiple areas across the brain, including the hypothalamus, cortex, limbic system, and brainstem. This widespread brain involvement might explain why some headache sufferers concurrently experience a variety of symptoms, including fatigue, depression, muscle pain, and an abnormal sensitivity to light, sound, and smell.^6,7

After taking the initial history (headache onset, location, duration, associated symptoms), focus attention on assessing the risk of intracranial pathology.

Although the exact mechanisms behind each of these symptoms have yet to be defined precisely, waves of neuronal depolarization—known as cortical spreading depression—are suspected to cause migraine aura.^8-10 Cortical spreading depression activates the trigeminal pain pathway and leads to the release of pro-inflammatory markers such as calcitonin gene-related protein (CGRP).⁶ A better understanding of these complex signaling pathways has helped provide potential therapeutic targets for new migraine drugs.

Diagnosis: Close patient inquiry is most helpful

The International Headache Society (IHS) criteria for primary headache disorders serve as the basis for the diagnosis of migraine and its subtypes, which include migraine without aura and migraine with aura. Due to variability of presentation, migraine with aura is further subdivided into migraine with typical aura (with and without headache), migraine with brainstem aura, hemiplegic migraine, and retinal migraine.¹¹

Continue to: How is migraine defined?

How is migraine defined? Simply, migraine is classically defined as a unilateral, pulsating headache of moderate to severe intensity lasting 4 to 72 hours, associated with photophobia and phonophobia or nausea and vomiting, or both.¹¹ Often visual in nature, aura is a set of neurologic symptoms that lasts for minutes and precedes the onset of the headache. The visual aura is often described as a scintillating scotoma that begins near the point of visual fixation and then spreads left or right. Other aura symptoms include tingling or numbness (second most common), speech disturbance (aphasia), motor changes and, in rare cases, a combination of these in succession. By definition, all of these symptoms fully resolve between attacks.¹¹

Validated valuable questionnaires. To help with accurate and timely diagnosis, researchers have developed and validated simplified questionnaires that can be completed independently by patients presenting to primary care (TABLE 1^12,13):

• ID Migraine is a set of 3 questions that scores positive when a patient endorses at least 2 of the 3 symptoms. ¹²
• MS-Q is similar to the ID Migraine but includes 5 items. A score of ≥4 is a positive screen. ¹³

The sensitivity and specificity of MS-Q (0.93 and 0.81, respectively) are slightly higher than those of ID Migraine (0.81 and 0.75).¹³

Remember POUND. This mnemonic device can also be used during history-taking to aid in diagnostic accuracy. Migraine is highly likely (92%) in patients who endorse 4 of the following 5 symptoms and unlikely (17%) in those who endorse ≤2 symptoms¹⁴: Pulsatile quality of headache 4 to 72 hOurs in duration, Unilateral location, Nausea or vomiting, and Disabling intensity.

Differential Dx. Although the differential diagnosis of headache is broad (TABLE 2^14,15), the history alone can often guide clinicians towards the correct assessment. After taking the initial history (headache onset, location, duration, and associated symptoms), focus your attention on assessing the risk of intracranial pathology. This is best accomplished by assessing specific details of the history (TABLE 3¹⁴) and findings on physical examination¹⁵:

• blood pressure measurement (seated, legs uncrossed, feet flat on the floor; having rested for 5 minutes; arm well supported)
• cranial nerve exam
• extremity strength testing
• eye exam (vision, extra-ocular muscles, visual fields, pupillary reactivity, and funduscopic exam)
• gait (tandem walk)
• reflexes.

Continue to: Further testing needed?

Further testing needed? Neuroimaging should be considered only in patients with an abnormal neurologic exam, atypical headache features, or certain risk factors, such as an immune deficiency. There is no role for electroencephalography or other diagnostic testing in migraine.¹⁶

Take a multipronged approach to treatment

As with other complex, chronic conditions, the treatment of migraine should take a multifaceted approach, including management of acute symptoms as well as prevention of future headaches. In 2015, the American Headache Society published a systematic review that specified particular treatment goals for migraine sufferers. ¹⁷ These goals include:

• headache reduction
• headache relief
• decreased disability from headache
• elimination of nausea and vomiting
• elimination of photophobia and phonophobia.

Our review, which follows, of therapeutic options focuses on the management of migraine in adults. Approaches in special populations (older adults, pregnant women, and children) are discussed afterward.

Pharmacotherapy for acute migraine

Acute migraine should be treated with an abortive medication at the onset of headache. The immediate goal is to relieve pain within 2 hours and prevent its recurrence within the subsequent 48 hours (TABLE 4^12,18-20).

Electroencephalography and other diagnostic testing have no role in the workup of migraine.

In the general population, mild, infrequent migraines can be managed with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).²¹

Continue to: For moderate-to-severe migraine...

For moderate-to-severe migraine, triptans, which target serotonin receptors, are the drug of choice for most patients.²¹ Triptans are superior to placebo in achieving a pain-free state at 2 and 24 hours after administration; eletriptan has the most desirable outcome, with 68% of patients pain free at 2 hours and 54% pain free at 24 hours.²² Triptans are available as sublingual tablets and nasal sprays, as well as subcutaneous injections for patients with significant associated nausea and vomiting. Avoid prescribing triptans for patients with known vascular disease (eg, history of stroke, myocardial infarction, peripheral vascular disease, uncontrolled hypertension, or signs and symptoms of these conditions), as well as for patients with severe hepatic impairment.

Treat migraine with a multifaceted approach, including management of acute symptoms and prevention of future headaches.

Importantly, although triptans all have a similar mechanism of action, patients might respond differently to different drugs within the class. If a patient does not get adequate headache relief from an appropriate dosage of a given triptan during a particular migraine episode, a different triptan can be tried during the next migraine.²² Additionally, if a patient experiences an adverse effect from one triptan, this does not necessarily mean that a trial of another triptan at a later time is contraindicated.

For patients who have an incomplete response to migraine treatment or for those with frequent recurrence, the combination formulation of sumatriptan, 85 mg, and naproxen, 500 mg, showed the highest rate of resolution of headache within 2 hours compared with either drug alone.²³ A similar result might be found by combining a triptan known to be effective for a patient and an NSAID other than naproxen. If migraine persists despite initial treatment of an attack, a different class of medication should be tried during the course of that attack to attain relief of symptoms of that migraine.²¹

When a patient is seen in an acute care setting (eg, emergency department, urgent care center) while suffering a migraine, additional treatment options are available. Intravenous (IV) anti-emetics are useful for relieving the pain of migraine and nausea, and can be used in combination with an IV NSAID (eg, ketorolac).²¹ The most effective anti-emetics are dopamine receptor type-2 blockers, including chlorpromazine, droperidol, metoclopramide, and prochlorperazine, which has the highest level of efficacy.²⁴ Note that these medications do present the risk of a dystonic reaction; diphenhydramine is therefore often used in tandem to mitigate such a response.

Looking ahead. Although triptans are the current first-line therapy for acute migraine, their effectiveness is limited. Only 20% of patients report sustained relief of pain in the 2 to 24 hours after treatment, and the response can vary from episode to episode.²⁵

Continue to: With better understading of the pathophysiology of migraine...

With better understanding of the pathophysiology of migraine, a host of novel anti-migraine drugs are on the horizon.

CGRP receptor antagonists. The neuropeptide CGRP, which mediates central and peripheral nervous system pain signaling, has been noted to be elevated during acute migraine attacks²⁶; clinical trials are therefore underway to evaluate the safety and efficacy of CGRP receptor antagonists.¹⁸ These agents appear to be better tolerated than triptans, have fewer vascular and central nervous system adverse effects, and present less of a risk of medication overuse headache.¹⁸ Liver toxicity has been seen with some medications in this class and remains an important concern in their development.¹⁹

Phase 3 clinical trials for 1 drug in this class, ubrogepant, were completed in late 2017; full analysis of the data is not yet available. Primary outcomes being evaluated include relief of pain at 2 hours and relief from the most bothersome symptoms again at 2 hours.²⁷

Selective serotonin-HT_1f receptor agonists, such as lasmiditan, offer another potential approach. Although the exact mechanism of action of these agents is not entirely clear, clinical trials have supported their efficacy and safety.²⁰ Importantly, ongoing trials are specifically targeting patients with known cardiovascular risk factors because they are most likely to benefit from the nonvasoconstrictive mechanism of action.^28,29 Adverse effects reported primarily include dizziness, fatigue, and vertigo.

Strategies for managing recurrent episodic migraine

Because of the risk of medication overuse headache with acute treatment, daily preventive therapy for migraine is indicated for any patient with ³⁰ :

• ≥6 headache days a month
• ≥4 headache days a month with some impairment
• ≥3 headache days a month with severe impairment.

Continue to: Treatment begins by having patients identify...

Treatment begins by having patients identify, and then avoid, migraine triggers (TABLE 5). This can be accomplished by having patients keep a headache diary, in which they can enter notations about personal and environmental situations that precede a headache.

For the individual patient, some triggers are modifiable; others are not. Helping a patient develop strategies for coping with triggers, rather than aiming for complete avoidance, might help her (him) manage those that are inescapable (eg stress, menstruation, etc).³¹ For many patients, however, this is not an adequate intervention and other approaches must be explored. When considering which therapy might be best for a given patient, evaluate her (his) comorbidities and assess that particular treatment for potential secondary benefits and the possibility of adverse effects. Pay attention to the choice of preventive therapy in women who are considering pregnancy because many available treatments are potentially teratogenic.

Oral medications. Oral agents from several classes of drugs can be used for migraine prophylaxis, including anti-epileptics,antidepressants, and antihypertensives (TABLE 6^{20,29,30,32-41}). Selected anti-epileptics (divalproex sodium, sodium valproate, topiramate) and beta-blockers (metoprolol, propranolol, and timolol) have the strongest evidence to support their use.³² Overall, regular use of prophylactic medications can reduce headache frequency by 50% for approximately 40% to 45% of patients who take them.²⁹ However, adherence may be limited by adverse effects or perceived lack of efficacy, thus reducing their potential for benefit.⁴²

OnabotulinumtoxinA. In patients with chronic migraine (≥15 headache days a month for at least 3 months) who have failed oral medications, the American Academy of Neurology (AAN) recommends the use of onabotulinumtoxinA.³⁰ The treatment regimen comprises 31 injections at various sites on the head, neck, and shoulders every 3 months.³³

A 2010 large randomized controlled trial showed a decrease in the frequency of headache days for patients receiving onabotulinumtoxinA compared to placebo after a 24-week treatment period (7.8 fewer headache days a month, compared to 6.4 fewer in the placebo group).³³ A recent systematic review also noted a reduction of 2 headache days a month compared with placebo; the authors cautioned, however, that data with which to evaluate onabotulinumtoxinA in comparison to other prophylactic agents are limited.⁴³

Continue to: In both studies...

In both studies, the risk of adverse drug events due to onabotulinumtoxinA was high and led to a significant rate of discontinuation.^33,43 Despite this, onabotulinumtoxinA remains the only Food and Drug Administration (FDA)–approved treatment for chronic migraine, making it reasonable to consider for appropriate patients.

Acupuncture. A 2016 Cochrane review found benefit for patients using acupuncture compared with sham acupuncture.³⁴ When acupuncture was compared with prophylactic agents such as beta-blockers, calcium-channel blockers, and anti-epileptics, however, there was no significant difference between the procedure and pharmacotherapy. Patients willing and able to try acupuncture might see a reduction in the overall number of headaches. Acupuncture has few adverse effects; however, long-term data are lacking.³⁴

Exercise is not supported by robust data for its role as a prophylactic treatment. It is generally considered safe in most populations, however, and can be pursued with little out-of-pocket cost.³⁵

Cognitive behavioral therapy (CBT). The AAN recommends CBT, relaxation therapy, and biofeedback therapy. Accessibility of these services remains limited for many patients, and cost can be prohibitive.¹⁶

Supplements used to help prevent migraine include the root of Petasites hybridus (butterbur), magnesium, vitamin B2 (riboflavin), Tanacetum parthenium (feverfew), and coenzyme Q10.¹⁶ Although the strength of evidence for these therapies is limited by small trials, their overall risk of adverse effects is low, and they might be easier for patients to obtain than acupuncture or CBT.

Continue to: Butterbur, in particular...

Butterbur, in particular, has been found to be beneficial for migraine prevention in 2 small placebo-controlled trials. In a randomized controlled study of 245 patients P hybridus, (specifically, the German formulation, Petadolex), 75 mg BID, reduced the frequency of migraine attack by 48% at 4 months, compared to placebo (number needed to treat, 5.3).⁴⁴ No difference was found at lower dosages. The most common reported adverse effect was burping.

Regrettably, unpurified butterbur extract contains pyrrolizidine alkaloids, potentially hepatotoxic and carcinogenic compounds. Because of variations in purification in production facilities in the United States, butterbur supplements might not have all of these compounds removed—and so should be used with caution.⁴¹

Magnesium. Studies evaluating the use of magnesium have demonstrated varied results; differences in methods and dosing have limited broad application of findings. As with most supplements considered for prophylactic treatment, magnesium dosing is poorly understood, and bioavailability varies in its different forms. Oral supplementation can be given as magnesium dicitrate, 600 mg/d.⁴⁵

Recently, products containing various combinations of feverfew, coenzyme Q10, riboflavin, magnesium, and other supplements have shown benefit in early clinical trials.^36,37

Neural stimulation. Over the past few years, a variety of transcutaneous nerve stimulator devices have gained FDA approval for use in migraine prophylaxis. The long-term safety and efficacy of these devices is not yet well understood, but they appear to provide headache relief in the short term and decrease the frequency of headache.³⁸ Use of the noninvasive stimulators is limited today by high cost and poor coverage by US health care insurers.

Continue to: Newly available medical therapy

Newly available medical therapy. The FDA recently approved erenumab, a fully human monoclonal antibody for prevention of migraine in adults. This is the first drug in the CGRP antagonist class to be approved for this indication. Trials of this once-monthly, self-injectable drug show promising results for patients whose migraines have been refractory to other therapies.

A recent large trial evaluated 955 adults with migraine, randomizing them to receive erenumab, 70 mg; erenumab, 140 mg; or placebo over 28 weeks.³⁹ The groups receiving erenumab had a nearly 2-fold higher odds of having their migraine reduced by 50%, compared with placebo (number needed to treat with the 140-mg dose, 4.27). Similar numbers of participants from all groups discontinued the study.³⁹ Phase 3 trials that are not yet formally published have produced similarly beneficial results.^40,46 The FDA has listed injection site reaction and constipation as the most reported adverse effects.⁴⁰

Three other anti-CGRP antibodies are likely to be approved in the near future: fremanezumab, galcanezumab, and eptinezumab.

The approach to migraine in special populations

Management of acute and chronic migraine in children, pregnant women, and older adults requires special attention: Treatment approaches are different than they are for adults 19 to 65 years of age.

Pediatric patients. Migraine is the most common acute and recurrent headache syndrome in children. Headaches differ from those of adult migraine as a result of variations in brain maturation, plasticity, and cognitive development.⁴⁷ Migraine attacks are often of shorter duration in children, lasting 1 to 2 hours, but can still be preceded by visual aura.⁴⁸ Just as with adults, imaging, electroencephalography, lumbar puncture, and routine labs should be considered only if a child has an abnormal neurological exam or other concerning features (TABLE 2^14,15).

Continue to: The general approach to migraine treatment...

The general approach to migraine treatment in the pediatric population includes education of the child and family about symptom management. Acetaminophen, NSAIDs, and triptans are approved for abortive therapy in children and should be used for acute headache relief in the same way that they are used in adults. Oral rizatriptan, the most well studied triptan in the pediatric population, is approved for use in children as young as 6 years⁴⁹; the pediatric dosage is 5 mg/d for patients weighing 20 to 39 kg and 10 mg/d for patients weighing more than 40 kg (same as the adult dosage).

Don’t prescribe triptans for patients with known vascular disease or severe hepatic impairment.

Oral almotriptan and zolmitriptan are also approved for use in children 12 to 17 years of age. Usual dosages are: almotriptan, 12.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 25 mg/d); and zolmitriptan, 2.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 10 mg/d).⁵⁰

For children who are unable to swallow pills or who are vomiting, a non-oral route of administration is preferable. Rizatriptan is available as an orally disintegrating tablet. Zolmitriptan is available in a nasal spray at a dose of 5 mg for children 12 years and older. Sumatriptan is not approved for use in patients younger than 18 years; however, recent studies have shown that it might have good efficacy and tolerability.⁵⁰

Daily prophylactic treatment for recurrent migraine in the pediatric population is an evolving subject; published guidelines do not exist. It is reasonable to consider treatment using the same guidelines as those in place for adults.⁵¹ Topiramate, 1 to 2 mg/kg/d, is the only therapy approved by the FDA for episodic migraine preventive therapy in adolescents.⁵⁰

If a patient doesn’t get adequate headache relief from an appropriate dosage of a given triptan, try a different triptan during the next migraine.

Notably, a nonpharmacotherapeutic approach may be more effective for pediatric prevention. In 2017, a large double-blind, placebo-controlled trial investigated the use of amitriptyline, topiramate, and placebo for the treatment of recurrent migraine in children 8 to 17 years of age. An interim analysis of the 328 children enrolled found no significant differences in reduction of headache frequency with treatment compared with placebo over a 24-week period; the trial was stopped early due to futility.⁵²

Continue to: The study did show...

The study did show, however, that reducing migraine triggers provided a high level of benefit to study participants. Stress is one of the most common migraine triggers in children; lack of sleep, exposure to a warm climate, and exposure to video games are also notable triggers.⁵³ CBT may augment the efficacy of standard migraine medications in the pediatric population and may help prevent recurrence of episodes.⁵⁴

Pregnancy. The treatment of migraine is different in pregnant women than it is in nonpregnant adults because of a concern over adverse effects on fetal development. For acute headache treatment, first-line therapies include trigger avoidance and acetaminophen, 1000 mg (maximum dosage, 4000 mg/d).⁵⁵ If this is ineffective, a 10-mg dose of metoclopramide, as often as every 6 hours (not an FDA-approved indication), can be considered. During the second trimester, NSAIDs can be considered second-line therapy.

Triptans—specifically, sumatriptan and rizatriptan—can also be considered if first-line therapies fail.⁵⁶ Triptan-exposed pregnant women with migraine have a rate of congenital malformations, spontaneous abortions, and prematurity that is similar to what is seen in pregnant women with migraine who have not been exposed to triptans. However, when triptan-exposed women are compared with healthy, non-migraine-suffering women, the rate of spontaneous abortion appears to be increased in the triptan-exposed population.⁵⁷

Ergotamine is contraindicated during pregnancy because of its potential to induce uterine contractions and vasospasm, which can be detrimental to the fetus.⁵⁶Nonpharmacotherapeutic interventions such as heat, ice, massage, rest, and avoidance of triggers are as successful in the pregnant population as in the nonpregnant population. For migraine prevention, coenzyme Q10, vitamins B2 and B6 (pyridoxine), and oral magnesium can be considered. Feverfew and butterbur should be avoided because of concerns about fetal malformation and preterm labor.⁵⁸

Older adults. Choosing appropriate migraine therapy for older adults requires special consideration because of changes in drug metabolism and risks associated with drug adverse effects. Additionally, few studies of migraine drugs have included large populations of adults older than 65 years; medications should therefore be prescribed cautiously in this population, with particular attention to drug–drug interactions.

Continue to: Just as for younger adults...

Just as for younger adults, mild symptoms can be managed effectively with acetaminophen. NSAIDs may be used as well, but carry increased risks of gastric bleeding and elevation in blood pressure.⁵⁹ The use of triptans is acceptable for the appropriate patient, but should be avoided in patients with known vascular disease.⁶⁰ Antiemetics present an increased risk of extrapyramidal adverse effects in the elderly and should be used with caution at the lowest effective dosage.⁵⁹ Novel mechanisms of action make some of the newer agents potentially safer for use in older adults when treating acute migraine.

Stress is one of the most common migraine triggers in children.

For migraine prevention in older adults, particular attention should be paid to reducing triggers and minimizing polypharmacy.

More and more, successful treatment is within reach

With many clinical trials evaluating novel drugs underway, and additional studies contributing to our understanding of nonpharmacotherapeutic approaches to migraine treatment, improved headache control may become increasingly common over the next few years.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Thomas Jefferson University, 1015 Walnut St, Philadelphia PA 19107; [email protected].

Migraine is a highly disabling primary headache disorder that affects more than 44 million Americans annually.¹ The disorder causes pain, photophobia, phonophobia, and nausea that can last for hours, even days. Migraine headaches are 2 times more common in women than in men; although migraine is most common in people 30 to 39 years of age, all ages are affected.^2,3 Frequency of migraine headache is variable; chronic migraineurs experience more than 15 headache days a month.

©Cath Riley/Science Source

Recent estimates indicate that the cost of acute and chronic migraine headaches reaches approximately $78 million a year in the United States. ⁴ This high burden of disease has made effective migraine treatment options absolutely essential. Recent advances in our understanding of migraine pathophysiology have led to new therapeutic targets; there are now many novel treatment approaches on the horizon.

In this article, we review the diagnosis and management of migraine in detail. Our emphasis is on evidence-based approaches to acute and prophylactic treatment, including tried-and-true options and newly emerging therapies.

Neuronal dysfunction and a genetic predisposition

Although migraine was once thought to be caused by abnormalities of vasodilation, current research suggests that the disorder has its origins in primary neuronal dysfunction. There appears to be a genetic predisposition toward widespread neuronal hyperexcitability in migraineurs.⁵ In addition, hypothalamic neurons are thought to initiate migraine by responding to changes in brain homeostasis. Increased parasympathetic tone might activate meningeal pain receptors or lower the threshold for transmitting pain signals from the thalamus to the cortex.⁶

Prodromal symptoms and aura appear to originate from multiple areas across the brain, including the hypothalamus, cortex, limbic system, and brainstem. This widespread brain involvement might explain why some headache sufferers concurrently experience a variety of symptoms, including fatigue, depression, muscle pain, and an abnormal sensitivity to light, sound, and smell.^6,7

After taking the initial history (headache onset, location, duration, associated symptoms), focus attention on assessing the risk of intracranial pathology.

Although the exact mechanisms behind each of these symptoms have yet to be defined precisely, waves of neuronal depolarization—known as cortical spreading depression—are suspected to cause migraine aura.^8-10 Cortical spreading depression activates the trigeminal pain pathway and leads to the release of pro-inflammatory markers such as calcitonin gene-related protein (CGRP).⁶ A better understanding of these complex signaling pathways has helped provide potential therapeutic targets for new migraine drugs.

Diagnosis: Close patient inquiry is most helpful

The International Headache Society (IHS) criteria for primary headache disorders serve as the basis for the diagnosis of migraine and its subtypes, which include migraine without aura and migraine with aura. Due to variability of presentation, migraine with aura is further subdivided into migraine with typical aura (with and without headache), migraine with brainstem aura, hemiplegic migraine, and retinal migraine.¹¹

Continue to: How is migraine defined?

How is migraine defined? Simply, migraine is classically defined as a unilateral, pulsating headache of moderate to severe intensity lasting 4 to 72 hours, associated with photophobia and phonophobia or nausea and vomiting, or both.¹¹ Often visual in nature, aura is a set of neurologic symptoms that lasts for minutes and precedes the onset of the headache. The visual aura is often described as a scintillating scotoma that begins near the point of visual fixation and then spreads left or right. Other aura symptoms include tingling or numbness (second most common), speech disturbance (aphasia), motor changes and, in rare cases, a combination of these in succession. By definition, all of these symptoms fully resolve between attacks.¹¹

Validated valuable questionnaires. To help with accurate and timely diagnosis, researchers have developed and validated simplified questionnaires that can be completed independently by patients presenting to primary care (TABLE 1^12,13):

• ID Migraine is a set of 3 questions that scores positive when a patient endorses at least 2 of the 3 symptoms. ¹²
• MS-Q is similar to the ID Migraine but includes 5 items. A score of ≥4 is a positive screen. ¹³

The sensitivity and specificity of MS-Q (0.93 and 0.81, respectively) are slightly higher than those of ID Migraine (0.81 and 0.75).¹³

Remember POUND. This mnemonic device can also be used during history-taking to aid in diagnostic accuracy. Migraine is highly likely (92%) in patients who endorse 4 of the following 5 symptoms and unlikely (17%) in those who endorse ≤2 symptoms¹⁴: Pulsatile quality of headache 4 to 72 hOurs in duration, Unilateral location, Nausea or vomiting, and Disabling intensity.

Differential Dx. Although the differential diagnosis of headache is broad (TABLE 2^14,15), the history alone can often guide clinicians towards the correct assessment. After taking the initial history (headache onset, location, duration, and associated symptoms), focus your attention on assessing the risk of intracranial pathology. This is best accomplished by assessing specific details of the history (TABLE 3¹⁴) and findings on physical examination¹⁵:

• blood pressure measurement (seated, legs uncrossed, feet flat on the floor; having rested for 5 minutes; arm well supported)
• cranial nerve exam
• extremity strength testing
• eye exam (vision, extra-ocular muscles, visual fields, pupillary reactivity, and funduscopic exam)
• gait (tandem walk)
• reflexes.

Continue to: Further testing needed?

Further testing needed? Neuroimaging should be considered only in patients with an abnormal neurologic exam, atypical headache features, or certain risk factors, such as an immune deficiency. There is no role for electroencephalography or other diagnostic testing in migraine.¹⁶

Take a multipronged approach to treatment

As with other complex, chronic conditions, the treatment of migraine should take a multifaceted approach, including management of acute symptoms as well as prevention of future headaches. In 2015, the American Headache Society published a systematic review that specified particular treatment goals for migraine sufferers. ¹⁷ These goals include:

• headache reduction
• headache relief
• decreased disability from headache
• elimination of nausea and vomiting
• elimination of photophobia and phonophobia.

Our review, which follows, of therapeutic options focuses on the management of migraine in adults. Approaches in special populations (older adults, pregnant women, and children) are discussed afterward.

Pharmacotherapy for acute migraine

Acute migraine should be treated with an abortive medication at the onset of headache. The immediate goal is to relieve pain within 2 hours and prevent its recurrence within the subsequent 48 hours (TABLE 4^12,18-20).

Electroencephalography and other diagnostic testing have no role in the workup of migraine.

In the general population, mild, infrequent migraines can be managed with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).²¹

Continue to: For moderate-to-severe migraine...

For moderate-to-severe migraine, triptans, which target serotonin receptors, are the drug of choice for most patients.²¹ Triptans are superior to placebo in achieving a pain-free state at 2 and 24 hours after administration; eletriptan has the most desirable outcome, with 68% of patients pain free at 2 hours and 54% pain free at 24 hours.²² Triptans are available as sublingual tablets and nasal sprays, as well as subcutaneous injections for patients with significant associated nausea and vomiting. Avoid prescribing triptans for patients with known vascular disease (eg, history of stroke, myocardial infarction, peripheral vascular disease, uncontrolled hypertension, or signs and symptoms of these conditions), as well as for patients with severe hepatic impairment.

Treat migraine with a multifaceted approach, including management of acute symptoms and prevention of future headaches.

Importantly, although triptans all have a similar mechanism of action, patients might respond differently to different drugs within the class. If a patient does not get adequate headache relief from an appropriate dosage of a given triptan during a particular migraine episode, a different triptan can be tried during the next migraine.²² Additionally, if a patient experiences an adverse effect from one triptan, this does not necessarily mean that a trial of another triptan at a later time is contraindicated.

For patients who have an incomplete response to migraine treatment or for those with frequent recurrence, the combination formulation of sumatriptan, 85 mg, and naproxen, 500 mg, showed the highest rate of resolution of headache within 2 hours compared with either drug alone.²³ A similar result might be found by combining a triptan known to be effective for a patient and an NSAID other than naproxen. If migraine persists despite initial treatment of an attack, a different class of medication should be tried during the course of that attack to attain relief of symptoms of that migraine.²¹

When a patient is seen in an acute care setting (eg, emergency department, urgent care center) while suffering a migraine, additional treatment options are available. Intravenous (IV) anti-emetics are useful for relieving the pain of migraine and nausea, and can be used in combination with an IV NSAID (eg, ketorolac).²¹ The most effective anti-emetics are dopamine receptor type-2 blockers, including chlorpromazine, droperidol, metoclopramide, and prochlorperazine, which has the highest level of efficacy.²⁴ Note that these medications do present the risk of a dystonic reaction; diphenhydramine is therefore often used in tandem to mitigate such a response.

Looking ahead. Although triptans are the current first-line therapy for acute migraine, their effectiveness is limited. Only 20% of patients report sustained relief of pain in the 2 to 24 hours after treatment, and the response can vary from episode to episode.²⁵

Continue to: With better understading of the pathophysiology of migraine...

With better understanding of the pathophysiology of migraine, a host of novel anti-migraine drugs are on the horizon.

CGRP receptor antagonists. The neuropeptide CGRP, which mediates central and peripheral nervous system pain signaling, has been noted to be elevated during acute migraine attacks²⁶; clinical trials are therefore underway to evaluate the safety and efficacy of CGRP receptor antagonists.¹⁸ These agents appear to be better tolerated than triptans, have fewer vascular and central nervous system adverse effects, and present less of a risk of medication overuse headache.¹⁸ Liver toxicity has been seen with some medications in this class and remains an important concern in their development.¹⁹

Phase 3 clinical trials for 1 drug in this class, ubrogepant, were completed in late 2017; full analysis of the data is not yet available. Primary outcomes being evaluated include relief of pain at 2 hours and relief from the most bothersome symptoms again at 2 hours.²⁷

Selective serotonin-HT_1f receptor agonists, such as lasmiditan, offer another potential approach. Although the exact mechanism of action of these agents is not entirely clear, clinical trials have supported their efficacy and safety.²⁰ Importantly, ongoing trials are specifically targeting patients with known cardiovascular risk factors because they are most likely to benefit from the nonvasoconstrictive mechanism of action.^28,29 Adverse effects reported primarily include dizziness, fatigue, and vertigo.

Strategies for managing recurrent episodic migraine

Because of the risk of medication overuse headache with acute treatment, daily preventive therapy for migraine is indicated for any patient with ³⁰ :

• ≥6 headache days a month
• ≥4 headache days a month with some impairment
• ≥3 headache days a month with severe impairment.

Continue to: Treatment begins by having patients identify...

Treatment begins by having patients identify, and then avoid, migraine triggers (TABLE 5). This can be accomplished by having patients keep a headache diary, in which they can enter notations about personal and environmental situations that precede a headache.

For the individual patient, some triggers are modifiable; others are not. Helping a patient develop strategies for coping with triggers, rather than aiming for complete avoidance, might help her (him) manage those that are inescapable (eg stress, menstruation, etc).³¹ For many patients, however, this is not an adequate intervention and other approaches must be explored. When considering which therapy might be best for a given patient, evaluate her (his) comorbidities and assess that particular treatment for potential secondary benefits and the possibility of adverse effects. Pay attention to the choice of preventive therapy in women who are considering pregnancy because many available treatments are potentially teratogenic.

Oral medications. Oral agents from several classes of drugs can be used for migraine prophylaxis, including anti-epileptics,antidepressants, and antihypertensives (TABLE 6^{20,29,30,32-41}). Selected anti-epileptics (divalproex sodium, sodium valproate, topiramate) and beta-blockers (metoprolol, propranolol, and timolol) have the strongest evidence to support their use.³² Overall, regular use of prophylactic medications can reduce headache frequency by 50% for approximately 40% to 45% of patients who take them.²⁹ However, adherence may be limited by adverse effects or perceived lack of efficacy, thus reducing their potential for benefit.⁴²

OnabotulinumtoxinA. In patients with chronic migraine (≥15 headache days a month for at least 3 months) who have failed oral medications, the American Academy of Neurology (AAN) recommends the use of onabotulinumtoxinA.³⁰ The treatment regimen comprises 31 injections at various sites on the head, neck, and shoulders every 3 months.³³

A 2010 large randomized controlled trial showed a decrease in the frequency of headache days for patients receiving onabotulinumtoxinA compared to placebo after a 24-week treatment period (7.8 fewer headache days a month, compared to 6.4 fewer in the placebo group).³³ A recent systematic review also noted a reduction of 2 headache days a month compared with placebo; the authors cautioned, however, that data with which to evaluate onabotulinumtoxinA in comparison to other prophylactic agents are limited.⁴³

Continue to: In both studies...

In both studies, the risk of adverse drug events due to onabotulinumtoxinA was high and led to a significant rate of discontinuation.^33,43 Despite this, onabotulinumtoxinA remains the only Food and Drug Administration (FDA)–approved treatment for chronic migraine, making it reasonable to consider for appropriate patients.

Acupuncture. A 2016 Cochrane review found benefit for patients using acupuncture compared with sham acupuncture.³⁴ When acupuncture was compared with prophylactic agents such as beta-blockers, calcium-channel blockers, and anti-epileptics, however, there was no significant difference between the procedure and pharmacotherapy. Patients willing and able to try acupuncture might see a reduction in the overall number of headaches. Acupuncture has few adverse effects; however, long-term data are lacking.³⁴

Exercise is not supported by robust data for its role as a prophylactic treatment. It is generally considered safe in most populations, however, and can be pursued with little out-of-pocket cost.³⁵

Cognitive behavioral therapy (CBT). The AAN recommends CBT, relaxation therapy, and biofeedback therapy. Accessibility of these services remains limited for many patients, and cost can be prohibitive.¹⁶

Supplements used to help prevent migraine include the root of Petasites hybridus (butterbur), magnesium, vitamin B2 (riboflavin), Tanacetum parthenium (feverfew), and coenzyme Q10.¹⁶ Although the strength of evidence for these therapies is limited by small trials, their overall risk of adverse effects is low, and they might be easier for patients to obtain than acupuncture or CBT.

Continue to: Butterbur, in particular...

Butterbur, in particular, has been found to be beneficial for migraine prevention in 2 small placebo-controlled trials. In a randomized controlled study of 245 patients P hybridus, (specifically, the German formulation, Petadolex), 75 mg BID, reduced the frequency of migraine attack by 48% at 4 months, compared to placebo (number needed to treat, 5.3).⁴⁴ No difference was found at lower dosages. The most common reported adverse effect was burping.

Regrettably, unpurified butterbur extract contains pyrrolizidine alkaloids, potentially hepatotoxic and carcinogenic compounds. Because of variations in purification in production facilities in the United States, butterbur supplements might not have all of these compounds removed—and so should be used with caution.⁴¹

Magnesium. Studies evaluating the use of magnesium have demonstrated varied results; differences in methods and dosing have limited broad application of findings. As with most supplements considered for prophylactic treatment, magnesium dosing is poorly understood, and bioavailability varies in its different forms. Oral supplementation can be given as magnesium dicitrate, 600 mg/d.⁴⁵

Recently, products containing various combinations of feverfew, coenzyme Q10, riboflavin, magnesium, and other supplements have shown benefit in early clinical trials.^36,37

Neural stimulation. Over the past few years, a variety of transcutaneous nerve stimulator devices have gained FDA approval for use in migraine prophylaxis. The long-term safety and efficacy of these devices is not yet well understood, but they appear to provide headache relief in the short term and decrease the frequency of headache.³⁸ Use of the noninvasive stimulators is limited today by high cost and poor coverage by US health care insurers.

Continue to: Newly available medical therapy

Newly available medical therapy. The FDA recently approved erenumab, a fully human monoclonal antibody for prevention of migraine in adults. This is the first drug in the CGRP antagonist class to be approved for this indication. Trials of this once-monthly, self-injectable drug show promising results for patients whose migraines have been refractory to other therapies.

A recent large trial evaluated 955 adults with migraine, randomizing them to receive erenumab, 70 mg; erenumab, 140 mg; or placebo over 28 weeks.³⁹ The groups receiving erenumab had a nearly 2-fold higher odds of having their migraine reduced by 50%, compared with placebo (number needed to treat with the 140-mg dose, 4.27). Similar numbers of participants from all groups discontinued the study.³⁹ Phase 3 trials that are not yet formally published have produced similarly beneficial results.^40,46 The FDA has listed injection site reaction and constipation as the most reported adverse effects.⁴⁰

Three other anti-CGRP antibodies are likely to be approved in the near future: fremanezumab, galcanezumab, and eptinezumab.

The approach to migraine in special populations

Management of acute and chronic migraine in children, pregnant women, and older adults requires special attention: Treatment approaches are different than they are for adults 19 to 65 years of age.

Pediatric patients. Migraine is the most common acute and recurrent headache syndrome in children. Headaches differ from those of adult migraine as a result of variations in brain maturation, plasticity, and cognitive development.⁴⁷ Migraine attacks are often of shorter duration in children, lasting 1 to 2 hours, but can still be preceded by visual aura.⁴⁸ Just as with adults, imaging, electroencephalography, lumbar puncture, and routine labs should be considered only if a child has an abnormal neurological exam or other concerning features (TABLE 2^14,15).

Continue to: The general approach to migraine treatment...

The general approach to migraine treatment in the pediatric population includes education of the child and family about symptom management. Acetaminophen, NSAIDs, and triptans are approved for abortive therapy in children and should be used for acute headache relief in the same way that they are used in adults. Oral rizatriptan, the most well studied triptan in the pediatric population, is approved for use in children as young as 6 years⁴⁹; the pediatric dosage is 5 mg/d for patients weighing 20 to 39 kg and 10 mg/d for patients weighing more than 40 kg (same as the adult dosage).

Don’t prescribe triptans for patients with known vascular disease or severe hepatic impairment.

Oral almotriptan and zolmitriptan are also approved for use in children 12 to 17 years of age. Usual dosages are: almotriptan, 12.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 25 mg/d); and zolmitriptan, 2.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 10 mg/d).⁵⁰

For children who are unable to swallow pills or who are vomiting, a non-oral route of administration is preferable. Rizatriptan is available as an orally disintegrating tablet. Zolmitriptan is available in a nasal spray at a dose of 5 mg for children 12 years and older. Sumatriptan is not approved for use in patients younger than 18 years; however, recent studies have shown that it might have good efficacy and tolerability.⁵⁰

Daily prophylactic treatment for recurrent migraine in the pediatric population is an evolving subject; published guidelines do not exist. It is reasonable to consider treatment using the same guidelines as those in place for adults.⁵¹ Topiramate, 1 to 2 mg/kg/d, is the only therapy approved by the FDA for episodic migraine preventive therapy in adolescents.⁵⁰

If a patient doesn’t get adequate headache relief from an appropriate dosage of a given triptan, try a different triptan during the next migraine.

Notably, a nonpharmacotherapeutic approach may be more effective for pediatric prevention. In 2017, a large double-blind, placebo-controlled trial investigated the use of amitriptyline, topiramate, and placebo for the treatment of recurrent migraine in children 8 to 17 years of age. An interim analysis of the 328 children enrolled found no significant differences in reduction of headache frequency with treatment compared with placebo over a 24-week period; the trial was stopped early due to futility.⁵²

Continue to: The study did show...

The study did show, however, that reducing migraine triggers provided a high level of benefit to study participants. Stress is one of the most common migraine triggers in children; lack of sleep, exposure to a warm climate, and exposure to video games are also notable triggers.⁵³ CBT may augment the efficacy of standard migraine medications in the pediatric population and may help prevent recurrence of episodes.⁵⁴

Pregnancy. The treatment of migraine is different in pregnant women than it is in nonpregnant adults because of a concern over adverse effects on fetal development. For acute headache treatment, first-line therapies include trigger avoidance and acetaminophen, 1000 mg (maximum dosage, 4000 mg/d).⁵⁵ If this is ineffective, a 10-mg dose of metoclopramide, as often as every 6 hours (not an FDA-approved indication), can be considered. During the second trimester, NSAIDs can be considered second-line therapy.

Triptans—specifically, sumatriptan and rizatriptan—can also be considered if first-line therapies fail.⁵⁶ Triptan-exposed pregnant women with migraine have a rate of congenital malformations, spontaneous abortions, and prematurity that is similar to what is seen in pregnant women with migraine who have not been exposed to triptans. However, when triptan-exposed women are compared with healthy, non-migraine-suffering women, the rate of spontaneous abortion appears to be increased in the triptan-exposed population.⁵⁷

Ergotamine is contraindicated during pregnancy because of its potential to induce uterine contractions and vasospasm, which can be detrimental to the fetus.⁵⁶Nonpharmacotherapeutic interventions such as heat, ice, massage, rest, and avoidance of triggers are as successful in the pregnant population as in the nonpregnant population. For migraine prevention, coenzyme Q10, vitamins B2 and B6 (pyridoxine), and oral magnesium can be considered. Feverfew and butterbur should be avoided because of concerns about fetal malformation and preterm labor.⁵⁸

Older adults. Choosing appropriate migraine therapy for older adults requires special consideration because of changes in drug metabolism and risks associated with drug adverse effects. Additionally, few studies of migraine drugs have included large populations of adults older than 65 years; medications should therefore be prescribed cautiously in this population, with particular attention to drug–drug interactions.

Continue to: Just as for younger adults...

Just as for younger adults, mild symptoms can be managed effectively with acetaminophen. NSAIDs may be used as well, but carry increased risks of gastric bleeding and elevation in blood pressure.⁵⁹ The use of triptans is acceptable for the appropriate patient, but should be avoided in patients with known vascular disease.⁶⁰ Antiemetics present an increased risk of extrapyramidal adverse effects in the elderly and should be used with caution at the lowest effective dosage.⁵⁹ Novel mechanisms of action make some of the newer agents potentially safer for use in older adults when treating acute migraine.

Stress is one of the most common migraine triggers in children.

For migraine prevention in older adults, particular attention should be paid to reducing triggers and minimizing polypharmacy.

More and more, successful treatment is within reach

With many clinical trials evaluating novel drugs underway, and additional studies contributing to our understanding of nonpharmacotherapeutic approaches to migraine treatment, improved headache control may become increasingly common over the next few years.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Thomas Jefferson University, 1015 Walnut St, Philadelphia PA 19107; [email protected].

Migraine is a highly disabling primary headache disorder that affects more than 44 million Americans annually.¹ The disorder causes pain, photophobia, phonophobia, and nausea that can last for hours, even days. Migraine headaches are 2 times more common in women than in men; although migraine is most common in people 30 to 39 years of age, all ages are affected.^2,3 Frequency of migraine headache is variable; chronic migraineurs experience more than 15 headache days a month.

©Cath Riley/Science Source

Recent estimates indicate that the cost of acute and chronic migraine headaches reaches approximately $78 million a year in the United States. ⁴ This high burden of disease has made effective migraine treatment options absolutely essential. Recent advances in our understanding of migraine pathophysiology have led to new therapeutic targets; there are now many novel treatment approaches on the horizon.

In this article, we review the diagnosis and management of migraine in detail. Our emphasis is on evidence-based approaches to acute and prophylactic treatment, including tried-and-true options and newly emerging therapies.

Neuronal dysfunction and a genetic predisposition

Although migraine was once thought to be caused by abnormalities of vasodilation, current research suggests that the disorder has its origins in primary neuronal dysfunction. There appears to be a genetic predisposition toward widespread neuronal hyperexcitability in migraineurs.⁵ In addition, hypothalamic neurons are thought to initiate migraine by responding to changes in brain homeostasis. Increased parasympathetic tone might activate meningeal pain receptors or lower the threshold for transmitting pain signals from the thalamus to the cortex.⁶

Prodromal symptoms and aura appear to originate from multiple areas across the brain, including the hypothalamus, cortex, limbic system, and brainstem. This widespread brain involvement might explain why some headache sufferers concurrently experience a variety of symptoms, including fatigue, depression, muscle pain, and an abnormal sensitivity to light, sound, and smell.^6,7

After taking the initial history (headache onset, location, duration, associated symptoms), focus attention on assessing the risk of intracranial pathology.

Although the exact mechanisms behind each of these symptoms have yet to be defined precisely, waves of neuronal depolarization—known as cortical spreading depression—are suspected to cause migraine aura.^8-10 Cortical spreading depression activates the trigeminal pain pathway and leads to the release of pro-inflammatory markers such as calcitonin gene-related protein (CGRP).⁶ A better understanding of these complex signaling pathways has helped provide potential therapeutic targets for new migraine drugs.

Diagnosis: Close patient inquiry is most helpful

The International Headache Society (IHS) criteria for primary headache disorders serve as the basis for the diagnosis of migraine and its subtypes, which include migraine without aura and migraine with aura. Due to variability of presentation, migraine with aura is further subdivided into migraine with typical aura (with and without headache), migraine with brainstem aura, hemiplegic migraine, and retinal migraine.¹¹

Continue to: How is migraine defined?

How is migraine defined? Simply, migraine is classically defined as a unilateral, pulsating headache of moderate to severe intensity lasting 4 to 72 hours, associated with photophobia and phonophobia or nausea and vomiting, or both.¹¹ Often visual in nature, aura is a set of neurologic symptoms that lasts for minutes and precedes the onset of the headache. The visual aura is often described as a scintillating scotoma that begins near the point of visual fixation and then spreads left or right. Other aura symptoms include tingling or numbness (second most common), speech disturbance (aphasia), motor changes and, in rare cases, a combination of these in succession. By definition, all of these symptoms fully resolve between attacks.¹¹

Validated valuable questionnaires. To help with accurate and timely diagnosis, researchers have developed and validated simplified questionnaires that can be completed independently by patients presenting to primary care (TABLE 1^12,13):

• ID Migraine is a set of 3 questions that scores positive when a patient endorses at least 2 of the 3 symptoms. ¹²
• MS-Q is similar to the ID Migraine but includes 5 items. A score of ≥4 is a positive screen. ¹³

The sensitivity and specificity of MS-Q (0.93 and 0.81, respectively) are slightly higher than those of ID Migraine (0.81 and 0.75).¹³

Remember POUND. This mnemonic device can also be used during history-taking to aid in diagnostic accuracy. Migraine is highly likely (92%) in patients who endorse 4 of the following 5 symptoms and unlikely (17%) in those who endorse ≤2 symptoms¹⁴: Pulsatile quality of headache 4 to 72 hOurs in duration, Unilateral location, Nausea or vomiting, and Disabling intensity.

Differential Dx. Although the differential diagnosis of headache is broad (TABLE 2^14,15), the history alone can often guide clinicians towards the correct assessment. After taking the initial history (headache onset, location, duration, and associated symptoms), focus your attention on assessing the risk of intracranial pathology. This is best accomplished by assessing specific details of the history (TABLE 3¹⁴) and findings on physical examination¹⁵:

• blood pressure measurement (seated, legs uncrossed, feet flat on the floor; having rested for 5 minutes; arm well supported)
• cranial nerve exam
• extremity strength testing
• eye exam (vision, extra-ocular muscles, visual fields, pupillary reactivity, and funduscopic exam)
• gait (tandem walk)
• reflexes.

Continue to: Further testing needed?

Further testing needed? Neuroimaging should be considered only in patients with an abnormal neurologic exam, atypical headache features, or certain risk factors, such as an immune deficiency. There is no role for electroencephalography or other diagnostic testing in migraine.¹⁶

Take a multipronged approach to treatment

As with other complex, chronic conditions, the treatment of migraine should take a multifaceted approach, including management of acute symptoms as well as prevention of future headaches. In 2015, the American Headache Society published a systematic review that specified particular treatment goals for migraine sufferers. ¹⁷ These goals include:

• headache reduction
• headache relief
• decreased disability from headache
• elimination of nausea and vomiting
• elimination of photophobia and phonophobia.

Our review, which follows, of therapeutic options focuses on the management of migraine in adults. Approaches in special populations (older adults, pregnant women, and children) are discussed afterward.

Pharmacotherapy for acute migraine

Acute migraine should be treated with an abortive medication at the onset of headache. The immediate goal is to relieve pain within 2 hours and prevent its recurrence within the subsequent 48 hours (TABLE 4^12,18-20).

Electroencephalography and other diagnostic testing have no role in the workup of migraine.

In the general population, mild, infrequent migraines can be managed with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).²¹

Continue to: For moderate-to-severe migraine...

For moderate-to-severe migraine, triptans, which target serotonin receptors, are the drug of choice for most patients.²¹ Triptans are superior to placebo in achieving a pain-free state at 2 and 24 hours after administration; eletriptan has the most desirable outcome, with 68% of patients pain free at 2 hours and 54% pain free at 24 hours.²² Triptans are available as sublingual tablets and nasal sprays, as well as subcutaneous injections for patients with significant associated nausea and vomiting. Avoid prescribing triptans for patients with known vascular disease (eg, history of stroke, myocardial infarction, peripheral vascular disease, uncontrolled hypertension, or signs and symptoms of these conditions), as well as for patients with severe hepatic impairment.

Treat migraine with a multifaceted approach, including management of acute symptoms and prevention of future headaches.

Importantly, although triptans all have a similar mechanism of action, patients might respond differently to different drugs within the class. If a patient does not get adequate headache relief from an appropriate dosage of a given triptan during a particular migraine episode, a different triptan can be tried during the next migraine.²² Additionally, if a patient experiences an adverse effect from one triptan, this does not necessarily mean that a trial of another triptan at a later time is contraindicated.

For patients who have an incomplete response to migraine treatment or for those with frequent recurrence, the combination formulation of sumatriptan, 85 mg, and naproxen, 500 mg, showed the highest rate of resolution of headache within 2 hours compared with either drug alone.²³ A similar result might be found by combining a triptan known to be effective for a patient and an NSAID other than naproxen. If migraine persists despite initial treatment of an attack, a different class of medication should be tried during the course of that attack to attain relief of symptoms of that migraine.²¹

When a patient is seen in an acute care setting (eg, emergency department, urgent care center) while suffering a migraine, additional treatment options are available. Intravenous (IV) anti-emetics are useful for relieving the pain of migraine and nausea, and can be used in combination with an IV NSAID (eg, ketorolac).²¹ The most effective anti-emetics are dopamine receptor type-2 blockers, including chlorpromazine, droperidol, metoclopramide, and prochlorperazine, which has the highest level of efficacy.²⁴ Note that these medications do present the risk of a dystonic reaction; diphenhydramine is therefore often used in tandem to mitigate such a response.

Looking ahead. Although triptans are the current first-line therapy for acute migraine, their effectiveness is limited. Only 20% of patients report sustained relief of pain in the 2 to 24 hours after treatment, and the response can vary from episode to episode.²⁵

Continue to: With better understading of the pathophysiology of migraine...

With better understanding of the pathophysiology of migraine, a host of novel anti-migraine drugs are on the horizon.

CGRP receptor antagonists. The neuropeptide CGRP, which mediates central and peripheral nervous system pain signaling, has been noted to be elevated during acute migraine attacks²⁶; clinical trials are therefore underway to evaluate the safety and efficacy of CGRP receptor antagonists.¹⁸ These agents appear to be better tolerated than triptans, have fewer vascular and central nervous system adverse effects, and present less of a risk of medication overuse headache.¹⁸ Liver toxicity has been seen with some medications in this class and remains an important concern in their development.¹⁹

Phase 3 clinical trials for 1 drug in this class, ubrogepant, were completed in late 2017; full analysis of the data is not yet available. Primary outcomes being evaluated include relief of pain at 2 hours and relief from the most bothersome symptoms again at 2 hours.²⁷

Selective serotonin-HT_1f receptor agonists, such as lasmiditan, offer another potential approach. Although the exact mechanism of action of these agents is not entirely clear, clinical trials have supported their efficacy and safety.²⁰ Importantly, ongoing trials are specifically targeting patients with known cardiovascular risk factors because they are most likely to benefit from the nonvasoconstrictive mechanism of action.^28,29 Adverse effects reported primarily include dizziness, fatigue, and vertigo.

Strategies for managing recurrent episodic migraine

Because of the risk of medication overuse headache with acute treatment, daily preventive therapy for migraine is indicated for any patient with ³⁰ :

• ≥6 headache days a month
• ≥4 headache days a month with some impairment
• ≥3 headache days a month with severe impairment.

Continue to: Treatment begins by having patients identify...

Treatment begins by having patients identify, and then avoid, migraine triggers (TABLE 5). This can be accomplished by having patients keep a headache diary, in which they can enter notations about personal and environmental situations that precede a headache.

For the individual patient, some triggers are modifiable; others are not. Helping a patient develop strategies for coping with triggers, rather than aiming for complete avoidance, might help her (him) manage those that are inescapable (eg stress, menstruation, etc).³¹ For many patients, however, this is not an adequate intervention and other approaches must be explored. When considering which therapy might be best for a given patient, evaluate her (his) comorbidities and assess that particular treatment for potential secondary benefits and the possibility of adverse effects. Pay attention to the choice of preventive therapy in women who are considering pregnancy because many available treatments are potentially teratogenic.

Oral medications. Oral agents from several classes of drugs can be used for migraine prophylaxis, including anti-epileptics,antidepressants, and antihypertensives (TABLE 6^{20,29,30,32-41}). Selected anti-epileptics (divalproex sodium, sodium valproate, topiramate) and beta-blockers (metoprolol, propranolol, and timolol) have the strongest evidence to support their use.³² Overall, regular use of prophylactic medications can reduce headache frequency by 50% for approximately 40% to 45% of patients who take them.²⁹ However, adherence may be limited by adverse effects or perceived lack of efficacy, thus reducing their potential for benefit.⁴²

OnabotulinumtoxinA. In patients with chronic migraine (≥15 headache days a month for at least 3 months) who have failed oral medications, the American Academy of Neurology (AAN) recommends the use of onabotulinumtoxinA.³⁰ The treatment regimen comprises 31 injections at various sites on the head, neck, and shoulders every 3 months.³³

A 2010 large randomized controlled trial showed a decrease in the frequency of headache days for patients receiving onabotulinumtoxinA compared to placebo after a 24-week treatment period (7.8 fewer headache days a month, compared to 6.4 fewer in the placebo group).³³ A recent systematic review also noted a reduction of 2 headache days a month compared with placebo; the authors cautioned, however, that data with which to evaluate onabotulinumtoxinA in comparison to other prophylactic agents are limited.⁴³

Continue to: In both studies...

In both studies, the risk of adverse drug events due to onabotulinumtoxinA was high and led to a significant rate of discontinuation.^33,43 Despite this, onabotulinumtoxinA remains the only Food and Drug Administration (FDA)–approved treatment for chronic migraine, making it reasonable to consider for appropriate patients.

Acupuncture. A 2016 Cochrane review found benefit for patients using acupuncture compared with sham acupuncture.³⁴ When acupuncture was compared with prophylactic agents such as beta-blockers, calcium-channel blockers, and anti-epileptics, however, there was no significant difference between the procedure and pharmacotherapy. Patients willing and able to try acupuncture might see a reduction in the overall number of headaches. Acupuncture has few adverse effects; however, long-term data are lacking.³⁴

Exercise is not supported by robust data for its role as a prophylactic treatment. It is generally considered safe in most populations, however, and can be pursued with little out-of-pocket cost.³⁵

Cognitive behavioral therapy (CBT). The AAN recommends CBT, relaxation therapy, and biofeedback therapy. Accessibility of these services remains limited for many patients, and cost can be prohibitive.¹⁶

Supplements used to help prevent migraine include the root of Petasites hybridus (butterbur), magnesium, vitamin B2 (riboflavin), Tanacetum parthenium (feverfew), and coenzyme Q10.¹⁶ Although the strength of evidence for these therapies is limited by small trials, their overall risk of adverse effects is low, and they might be easier for patients to obtain than acupuncture or CBT.

Continue to: Butterbur, in particular...

Butterbur, in particular, has been found to be beneficial for migraine prevention in 2 small placebo-controlled trials. In a randomized controlled study of 245 patients P hybridus, (specifically, the German formulation, Petadolex), 75 mg BID, reduced the frequency of migraine attack by 48% at 4 months, compared to placebo (number needed to treat, 5.3).⁴⁴ No difference was found at lower dosages. The most common reported adverse effect was burping.

Regrettably, unpurified butterbur extract contains pyrrolizidine alkaloids, potentially hepatotoxic and carcinogenic compounds. Because of variations in purification in production facilities in the United States, butterbur supplements might not have all of these compounds removed—and so should be used with caution.⁴¹

Magnesium. Studies evaluating the use of magnesium have demonstrated varied results; differences in methods and dosing have limited broad application of findings. As with most supplements considered for prophylactic treatment, magnesium dosing is poorly understood, and bioavailability varies in its different forms. Oral supplementation can be given as magnesium dicitrate, 600 mg/d.⁴⁵

Recently, products containing various combinations of feverfew, coenzyme Q10, riboflavin, magnesium, and other supplements have shown benefit in early clinical trials.^36,37

Neural stimulation. Over the past few years, a variety of transcutaneous nerve stimulator devices have gained FDA approval for use in migraine prophylaxis. The long-term safety and efficacy of these devices is not yet well understood, but they appear to provide headache relief in the short term and decrease the frequency of headache.³⁸ Use of the noninvasive stimulators is limited today by high cost and poor coverage by US health care insurers.

Continue to: Newly available medical therapy

Newly available medical therapy. The FDA recently approved erenumab, a fully human monoclonal antibody for prevention of migraine in adults. This is the first drug in the CGRP antagonist class to be approved for this indication. Trials of this once-monthly, self-injectable drug show promising results for patients whose migraines have been refractory to other therapies.

A recent large trial evaluated 955 adults with migraine, randomizing them to receive erenumab, 70 mg; erenumab, 140 mg; or placebo over 28 weeks.³⁹ The groups receiving erenumab had a nearly 2-fold higher odds of having their migraine reduced by 50%, compared with placebo (number needed to treat with the 140-mg dose, 4.27). Similar numbers of participants from all groups discontinued the study.³⁹ Phase 3 trials that are not yet formally published have produced similarly beneficial results.^40,46 The FDA has listed injection site reaction and constipation as the most reported adverse effects.⁴⁰

Three other anti-CGRP antibodies are likely to be approved in the near future: fremanezumab, galcanezumab, and eptinezumab.

The approach to migraine in special populations

Management of acute and chronic migraine in children, pregnant women, and older adults requires special attention: Treatment approaches are different than they are for adults 19 to 65 years of age.

Pediatric patients. Migraine is the most common acute and recurrent headache syndrome in children. Headaches differ from those of adult migraine as a result of variations in brain maturation, plasticity, and cognitive development.⁴⁷ Migraine attacks are often of shorter duration in children, lasting 1 to 2 hours, but can still be preceded by visual aura.⁴⁸ Just as with adults, imaging, electroencephalography, lumbar puncture, and routine labs should be considered only if a child has an abnormal neurological exam or other concerning features (TABLE 2^14,15).

Continue to: The general approach to migraine treatment...

The general approach to migraine treatment in the pediatric population includes education of the child and family about symptom management. Acetaminophen, NSAIDs, and triptans are approved for abortive therapy in children and should be used for acute headache relief in the same way that they are used in adults. Oral rizatriptan, the most well studied triptan in the pediatric population, is approved for use in children as young as 6 years⁴⁹; the pediatric dosage is 5 mg/d for patients weighing 20 to 39 kg and 10 mg/d for patients weighing more than 40 kg (same as the adult dosage).

Don’t prescribe triptans for patients with known vascular disease or severe hepatic impairment.

Oral almotriptan and zolmitriptan are also approved for use in children 12 to 17 years of age. Usual dosages are: almotriptan, 12.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 25 mg/d); and zolmitriptan, 2.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 10 mg/d).⁵⁰

For children who are unable to swallow pills or who are vomiting, a non-oral route of administration is preferable. Rizatriptan is available as an orally disintegrating tablet. Zolmitriptan is available in a nasal spray at a dose of 5 mg for children 12 years and older. Sumatriptan is not approved for use in patients younger than 18 years; however, recent studies have shown that it might have good efficacy and tolerability.⁵⁰

Daily prophylactic treatment for recurrent migraine in the pediatric population is an evolving subject; published guidelines do not exist. It is reasonable to consider treatment using the same guidelines as those in place for adults.⁵¹ Topiramate, 1 to 2 mg/kg/d, is the only therapy approved by the FDA for episodic migraine preventive therapy in adolescents.⁵⁰

If a patient doesn’t get adequate headache relief from an appropriate dosage of a given triptan, try a different triptan during the next migraine.

Notably, a nonpharmacotherapeutic approach may be more effective for pediatric prevention. In 2017, a large double-blind, placebo-controlled trial investigated the use of amitriptyline, topiramate, and placebo for the treatment of recurrent migraine in children 8 to 17 years of age. An interim analysis of the 328 children enrolled found no significant differences in reduction of headache frequency with treatment compared with placebo over a 24-week period; the trial was stopped early due to futility.⁵²

Continue to: The study did show...

The study did show, however, that reducing migraine triggers provided a high level of benefit to study participants. Stress is one of the most common migraine triggers in children; lack of sleep, exposure to a warm climate, and exposure to video games are also notable triggers.⁵³ CBT may augment the efficacy of standard migraine medications in the pediatric population and may help prevent recurrence of episodes.⁵⁴

Pregnancy. The treatment of migraine is different in pregnant women than it is in nonpregnant adults because of a concern over adverse effects on fetal development. For acute headache treatment, first-line therapies include trigger avoidance and acetaminophen, 1000 mg (maximum dosage, 4000 mg/d).⁵⁵ If this is ineffective, a 10-mg dose of metoclopramide, as often as every 6 hours (not an FDA-approved indication), can be considered. During the second trimester, NSAIDs can be considered second-line therapy.

Triptans—specifically, sumatriptan and rizatriptan—can also be considered if first-line therapies fail.⁵⁶ Triptan-exposed pregnant women with migraine have a rate of congenital malformations, spontaneous abortions, and prematurity that is similar to what is seen in pregnant women with migraine who have not been exposed to triptans. However, when triptan-exposed women are compared with healthy, non-migraine-suffering women, the rate of spontaneous abortion appears to be increased in the triptan-exposed population.⁵⁷

Ergotamine is contraindicated during pregnancy because of its potential to induce uterine contractions and vasospasm, which can be detrimental to the fetus.⁵⁶Nonpharmacotherapeutic interventions such as heat, ice, massage, rest, and avoidance of triggers are as successful in the pregnant population as in the nonpregnant population. For migraine prevention, coenzyme Q10, vitamins B2 and B6 (pyridoxine), and oral magnesium can be considered. Feverfew and butterbur should be avoided because of concerns about fetal malformation and preterm labor.⁵⁸

Older adults. Choosing appropriate migraine therapy for older adults requires special consideration because of changes in drug metabolism and risks associated with drug adverse effects. Additionally, few studies of migraine drugs have included large populations of adults older than 65 years; medications should therefore be prescribed cautiously in this population, with particular attention to drug–drug interactions.

Continue to: Just as for younger adults...

Just as for younger adults, mild symptoms can be managed effectively with acetaminophen. NSAIDs may be used as well, but carry increased risks of gastric bleeding and elevation in blood pressure.⁵⁹ The use of triptans is acceptable for the appropriate patient, but should be avoided in patients with known vascular disease.⁶⁰ Antiemetics present an increased risk of extrapyramidal adverse effects in the elderly and should be used with caution at the lowest effective dosage.⁵⁹ Novel mechanisms of action make some of the newer agents potentially safer for use in older adults when treating acute migraine.

Stress is one of the most common migraine triggers in children.

For migraine prevention in older adults, particular attention should be paid to reducing triggers and minimizing polypharmacy.

More and more, successful treatment is within reach

With many clinical trials evaluating novel drugs underway, and additional studies contributing to our understanding of nonpharmacotherapeutic approaches to migraine treatment, improved headache control may become increasingly common over the next few years.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Thomas Jefferson University, 1015 Walnut St, Philadelphia PA 19107; [email protected].

LAS VEGAS – Deep brain stimulation (DBS) provides motor and nonmotor benefits at 6 months, 1 year, and 2 years after implantation in patients with Parkinson’s disease, according to a large-scale collection of outcome data. The treatment improves motor function and quality of life and has an acceptable safety profile. The analysis was presented at the annual meeting of the North American Neuromodulation Society.

Research by Okun et al. in 2012 and Schuepbach et al. in 2013 demonstrated that DBS effectively reduces the motor complications of Parkinson’s disease. To monitor the treatment’s efficacy and safety on a large scale, investigators established a prospective registry of patients with levodopa-responsive Parkinson’s disease who underwent DBS implantation. An aim of the registry is to improve understanding of the clinical use and outcomes of DBS in this population. As many as 1,000 patients have been implanted with Vercise DBS systems at 70 international sites. These systems enable multiple independent current source control.

Participants presented for clinical visits at 3 months, 6 months, 1 year, 2 years, and 3 years after surgery. Jan Vesper, MD, PhD, professor of neurosurgery at Heinrich Heine University in Düsseldorf, Germany, and his colleagues analyzed patient outcomes, including the Parkinson’s Disease Questionnaire (PDQ-39), Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Clinical Global Impression of Change (as assessed by the patient, caregiver, and clinician), and the Schwab and England (SE) scale. The researchers also reported adverse events.

As of November 2018, 403 participants had been enrolled in the registry, and 359 had undergone DBS implantation. At baseline, mean age was 59.6 years, and approximately 70% of participants were male. Mean disease duration was 10.4 years. Without medication, mean MDS-UPDRS III score was 44.8, and mean PDQ-39 Summary Index score was 28.8.

At 1 year, participants’ mean off-medication MDS-UPDRS III score was 29.7. This result represented a significant 34% improvement in motor performance.

PDQ-39 Summary Index score was improved by 6.7 points at 6 months, 4.7 points at 1 year, and 3.0 points at 2 years, which represented a sustained benefit for participants’ quality of life. Improvements in activities of daily living were sustained throughout the 2-year period. Cognition was improved at 6 months, but not at subsequent visits. Mobility, stigma, and bodily discomfort were improved at 6 months and 1 year, but not at 2 years. Furthermore, more than 80% of patients, caregivers, and clinicians observed improvements in Parkinson’s disease symptoms at all time points.

The investigators did not find any unanticipated adverse events. In all, 217 serious adverse events occurred in 121 participants. Of these events, 60 were related to stimulation. No lead fractures or breakages occurred.

“This registry represents the first large-scale collection of outcomes using a DBS system capable of multiple independent current source control,” said Dr. Vesper and colleagues.

The investigators did not report any conflicts of interest.
 

[email protected]

LAS VEGAS – Deep brain stimulation (DBS) provides motor and nonmotor benefits at 6 months, 1 year, and 2 years after implantation in patients with Parkinson’s disease, according to a large-scale collection of outcome data. The treatment improves motor function and quality of life and has an acceptable safety profile. The analysis was presented at the annual meeting of the North American Neuromodulation Society.

Research by Okun et al. in 2012 and Schuepbach et al. in 2013 demonstrated that DBS effectively reduces the motor complications of Parkinson’s disease. To monitor the treatment’s efficacy and safety on a large scale, investigators established a prospective registry of patients with levodopa-responsive Parkinson’s disease who underwent DBS implantation. An aim of the registry is to improve understanding of the clinical use and outcomes of DBS in this population. As many as 1,000 patients have been implanted with Vercise DBS systems at 70 international sites. These systems enable multiple independent current source control.

Participants presented for clinical visits at 3 months, 6 months, 1 year, 2 years, and 3 years after surgery. Jan Vesper, MD, PhD, professor of neurosurgery at Heinrich Heine University in Düsseldorf, Germany, and his colleagues analyzed patient outcomes, including the Parkinson’s Disease Questionnaire (PDQ-39), Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Clinical Global Impression of Change (as assessed by the patient, caregiver, and clinician), and the Schwab and England (SE) scale. The researchers also reported adverse events.

As of November 2018, 403 participants had been enrolled in the registry, and 359 had undergone DBS implantation. At baseline, mean age was 59.6 years, and approximately 70% of participants were male. Mean disease duration was 10.4 years. Without medication, mean MDS-UPDRS III score was 44.8, and mean PDQ-39 Summary Index score was 28.8.

At 1 year, participants’ mean off-medication MDS-UPDRS III score was 29.7. This result represented a significant 34% improvement in motor performance.

PDQ-39 Summary Index score was improved by 6.7 points at 6 months, 4.7 points at 1 year, and 3.0 points at 2 years, which represented a sustained benefit for participants’ quality of life. Improvements in activities of daily living were sustained throughout the 2-year period. Cognition was improved at 6 months, but not at subsequent visits. Mobility, stigma, and bodily discomfort were improved at 6 months and 1 year, but not at 2 years. Furthermore, more than 80% of patients, caregivers, and clinicians observed improvements in Parkinson’s disease symptoms at all time points.

The investigators did not find any unanticipated adverse events. In all, 217 serious adverse events occurred in 121 participants. Of these events, 60 were related to stimulation. No lead fractures or breakages occurred.

“This registry represents the first large-scale collection of outcomes using a DBS system capable of multiple independent current source control,” said Dr. Vesper and colleagues.

The investigators did not report any conflicts of interest.
 

[email protected]

LAS VEGAS – Deep brain stimulation (DBS) provides motor and nonmotor benefits at 6 months, 1 year, and 2 years after implantation in patients with Parkinson’s disease, according to a large-scale collection of outcome data. The treatment improves motor function and quality of life and has an acceptable safety profile. The analysis was presented at the annual meeting of the North American Neuromodulation Society.

Research by Okun et al. in 2012 and Schuepbach et al. in 2013 demonstrated that DBS effectively reduces the motor complications of Parkinson’s disease. To monitor the treatment’s efficacy and safety on a large scale, investigators established a prospective registry of patients with levodopa-responsive Parkinson’s disease who underwent DBS implantation. An aim of the registry is to improve understanding of the clinical use and outcomes of DBS in this population. As many as 1,000 patients have been implanted with Vercise DBS systems at 70 international sites. These systems enable multiple independent current source control.

Participants presented for clinical visits at 3 months, 6 months, 1 year, 2 years, and 3 years after surgery. Jan Vesper, MD, PhD, professor of neurosurgery at Heinrich Heine University in Düsseldorf, Germany, and his colleagues analyzed patient outcomes, including the Parkinson’s Disease Questionnaire (PDQ-39), Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Clinical Global Impression of Change (as assessed by the patient, caregiver, and clinician), and the Schwab and England (SE) scale. The researchers also reported adverse events.

As of November 2018, 403 participants had been enrolled in the registry, and 359 had undergone DBS implantation. At baseline, mean age was 59.6 years, and approximately 70% of participants were male. Mean disease duration was 10.4 years. Without medication, mean MDS-UPDRS III score was 44.8, and mean PDQ-39 Summary Index score was 28.8.

At 1 year, participants’ mean off-medication MDS-UPDRS III score was 29.7. This result represented a significant 34% improvement in motor performance.

PDQ-39 Summary Index score was improved by 6.7 points at 6 months, 4.7 points at 1 year, and 3.0 points at 2 years, which represented a sustained benefit for participants’ quality of life. Improvements in activities of daily living were sustained throughout the 2-year period. Cognition was improved at 6 months, but not at subsequent visits. Mobility, stigma, and bodily discomfort were improved at 6 months and 1 year, but not at 2 years. Furthermore, more than 80% of patients, caregivers, and clinicians observed improvements in Parkinson’s disease symptoms at all time points.

The investigators did not find any unanticipated adverse events. In all, 217 serious adverse events occurred in 121 participants. Of these events, 60 were related to stimulation. No lead fractures or breakages occurred.

“This registry represents the first large-scale collection of outcomes using a DBS system capable of multiple independent current source control,” said Dr. Vesper and colleagues.

The investigators did not report any conflicts of interest.
 

[email protected]

The age at which a patient develops migraine with aura may be an important factor in assessing stroke risk, according to a prospective cohort study published in Headache.

DKart/iStockphoto

Patients who had onset of migraine with visual aura after age 50 years had an increased risk of ischemic stroke, compared with patients with no headache, the researchers found. Patients with longer exposure to migraine with visual aura – that is, onset before age 50 years – did not have significantly increased ischemic stroke risk, said X. Michelle Androulakis, MD, of the department of neurology at the University of South Carolina in Columbia, and her colleagues.

“Migraine, especially migraine with aura, is associated with increased risk of ischemic stroke,” but whether age of migraine onset affects the risk of cardiovascular disease has been unclear, the researchers said.

To examine the risk of ischemic stroke in migraineurs with and without aura with onset before and after age 50 years, the investigators conducted a post hoc analysis of data from the ongoing Atherosclerosis Risk in Communities (ARIC) study. The researchers adjusted for potential confounders, including diabetes, body mass index, hypertension, and hyperlipidemia.

In ARIC, participants completed a questionnaire about their migraine history at their third study visit (1993-1995) and were followed for ischemic stroke incidence over 20 years.

Of the 11,592 ARIC participants included in the analysis (mean age, 61 years; 76.5% white; and 55.3% female), 447 had migraine with aura, and 1,128 had migraine without aura. Onset of migraine with aura at age 50 years or older (average duration, 4.75 years) was associated with more than twofold greater risk of ischemic stroke, compared with no headache (multivariable adjusted hazard ratio = 2.17). Onset of migraine with aura before age 50 years (average duration, 28.17 years) was not significantly associated with stroke. A logistic regression model yielded consistent results.

In addition, patients with migraine without aura did not have an increased risk of stroke, regardless of the age of onset. The absolute risk for stroke in migraine with aura was 8.27%, and the absolute risk in migraine without aura was 4.25%.

“We found unexpected results suggesting that the onset of migraine with aura before age 50 is not associated with ischemic stroke. ... These results are specific to first-time ischemic stroke incidents that occurred in mid- to late life; therefore, it cannot be generalized to stroke in younger patients,” the authors wrote.

It could be that migraine with aura symptoms that start at a later age are a red flag for paradoxical emboli from a patent foramen ovale or microemboli, Dr. Androulakis and her colleagues noted. It also is possible that the degree of cortical spreading depression required to induce migraine with aura symptoms is different later in life versus earlier in life.

“This study underscores the importance of MA symptoms onset in evaluation of ischemic stroke risk in late life,” the researchers concluded.

The authors had no relevant conflicts of interest. ARIC has been funded by the National Heart, Lung, and Blood Institute.

[email protected]

SOURCE: Androulakis XM et al. Headache. 2019 Jan 21. doi: 10.1111/head.13468.

The age at which a patient develops migraine with aura may be an important factor in assessing stroke risk, according to a prospective cohort study published in Headache.

DKart/iStockphoto

Patients who had onset of migraine with visual aura after age 50 years had an increased risk of ischemic stroke, compared with patients with no headache, the researchers found. Patients with longer exposure to migraine with visual aura – that is, onset before age 50 years – did not have significantly increased ischemic stroke risk, said X. Michelle Androulakis, MD, of the department of neurology at the University of South Carolina in Columbia, and her colleagues.

“Migraine, especially migraine with aura, is associated with increased risk of ischemic stroke,” but whether age of migraine onset affects the risk of cardiovascular disease has been unclear, the researchers said.

To examine the risk of ischemic stroke in migraineurs with and without aura with onset before and after age 50 years, the investigators conducted a post hoc analysis of data from the ongoing Atherosclerosis Risk in Communities (ARIC) study. The researchers adjusted for potential confounders, including diabetes, body mass index, hypertension, and hyperlipidemia.

In ARIC, participants completed a questionnaire about their migraine history at their third study visit (1993-1995) and were followed for ischemic stroke incidence over 20 years.

Of the 11,592 ARIC participants included in the analysis (mean age, 61 years; 76.5% white; and 55.3% female), 447 had migraine with aura, and 1,128 had migraine without aura. Onset of migraine with aura at age 50 years or older (average duration, 4.75 years) was associated with more than twofold greater risk of ischemic stroke, compared with no headache (multivariable adjusted hazard ratio = 2.17). Onset of migraine with aura before age 50 years (average duration, 28.17 years) was not significantly associated with stroke. A logistic regression model yielded consistent results.

In addition, patients with migraine without aura did not have an increased risk of stroke, regardless of the age of onset. The absolute risk for stroke in migraine with aura was 8.27%, and the absolute risk in migraine without aura was 4.25%.

“We found unexpected results suggesting that the onset of migraine with aura before age 50 is not associated with ischemic stroke. ... These results are specific to first-time ischemic stroke incidents that occurred in mid- to late life; therefore, it cannot be generalized to stroke in younger patients,” the authors wrote.

It could be that migraine with aura symptoms that start at a later age are a red flag for paradoxical emboli from a patent foramen ovale or microemboli, Dr. Androulakis and her colleagues noted. It also is possible that the degree of cortical spreading depression required to induce migraine with aura symptoms is different later in life versus earlier in life.

“This study underscores the importance of MA symptoms onset in evaluation of ischemic stroke risk in late life,” the researchers concluded.

The authors had no relevant conflicts of interest. ARIC has been funded by the National Heart, Lung, and Blood Institute.

[email protected]

SOURCE: Androulakis XM et al. Headache. 2019 Jan 21. doi: 10.1111/head.13468.

The age at which a patient develops migraine with aura may be an important factor in assessing stroke risk, according to a prospective cohort study published in Headache.

DKart/iStockphoto

Patients who had onset of migraine with visual aura after age 50 years had an increased risk of ischemic stroke, compared with patients with no headache, the researchers found. Patients with longer exposure to migraine with visual aura – that is, onset before age 50 years – did not have significantly increased ischemic stroke risk, said X. Michelle Androulakis, MD, of the department of neurology at the University of South Carolina in Columbia, and her colleagues.

“Migraine, especially migraine with aura, is associated with increased risk of ischemic stroke,” but whether age of migraine onset affects the risk of cardiovascular disease has been unclear, the researchers said.

To examine the risk of ischemic stroke in migraineurs with and without aura with onset before and after age 50 years, the investigators conducted a post hoc analysis of data from the ongoing Atherosclerosis Risk in Communities (ARIC) study. The researchers adjusted for potential confounders, including diabetes, body mass index, hypertension, and hyperlipidemia.

In ARIC, participants completed a questionnaire about their migraine history at their third study visit (1993-1995) and were followed for ischemic stroke incidence over 20 years.

Of the 11,592 ARIC participants included in the analysis (mean age, 61 years; 76.5% white; and 55.3% female), 447 had migraine with aura, and 1,128 had migraine without aura. Onset of migraine with aura at age 50 years or older (average duration, 4.75 years) was associated with more than twofold greater risk of ischemic stroke, compared with no headache (multivariable adjusted hazard ratio = 2.17). Onset of migraine with aura before age 50 years (average duration, 28.17 years) was not significantly associated with stroke. A logistic regression model yielded consistent results.

In addition, patients with migraine without aura did not have an increased risk of stroke, regardless of the age of onset. The absolute risk for stroke in migraine with aura was 8.27%, and the absolute risk in migraine without aura was 4.25%.

“We found unexpected results suggesting that the onset of migraine with aura before age 50 is not associated with ischemic stroke. ... These results are specific to first-time ischemic stroke incidents that occurred in mid- to late life; therefore, it cannot be generalized to stroke in younger patients,” the authors wrote.

It could be that migraine with aura symptoms that start at a later age are a red flag for paradoxical emboli from a patent foramen ovale or microemboli, Dr. Androulakis and her colleagues noted. It also is possible that the degree of cortical spreading depression required to induce migraine with aura symptoms is different later in life versus earlier in life.

“This study underscores the importance of MA symptoms onset in evaluation of ischemic stroke risk in late life,” the researchers concluded.

The authors had no relevant conflicts of interest. ARIC has been funded by the National Heart, Lung, and Blood Institute.

[email protected]

SOURCE: Androulakis XM et al. Headache. 2019 Jan 21. doi: 10.1111/head.13468.

Levodopa did not significantly alter the course of Parkinson’s disease in a randomized, 80-week, delayed-start, clinical trial, investigators reported. The disease course was not significantly different for patients who had a full 80 weeks of levodopa/carbodopa therapy, compared with that seen with those who started treatment after a 40-week delay, according to the investigators.

“These findings imply that levodopa had no disease-modifying effect on Parkinson’s disease over the period of the trial,” wrote investigator Rob M. A. de Bie, MD, PhD, professor of movement disorders at the University of Amsterdam, and his colleagues in the New England Journal of Medicine.

By contrast, results of an earlier randomized, placebo-controlled trial suggested that levodopa had disease-modifying effects, though the findings of that study were inconclusive, according to authors of an editorial (see Views on the News).

In the current multicenter trial, known as LEAP (Levodopa in Early Parkinson’s Disease) a total of 445 patients with early Parkinson’s disease were randomized to either 80 weeks of levodopa and carbodopa or to 40 weeks of placebo followed by 40 weeks of levodopa/carbodopa.

Levodopa was dosed at 100 mg three times per day, and carbodopa at 25 mg three times per day, according to the report.

There was no significant difference between the early and delayed treatment groups for primary outcome of the trial, which was change in the Unified Parkinson’s Disease Rating Scale (UPDRS) from baseline to week 80.

The mean change in UPDRS was –1.0 in the group of patients who had the full 80 weeks of levodopa/carbodopa and –2.0 for those who had delayed therapy, for a difference of 1 point (P = .44). Higher scores on the UPDRS signify worse disease.

At week 40, there was a change in UPDRS favoring the early-initiation strategy, which reflected the effects of levodopa on disease symptoms, investigators added.

Nausea was more common in the early-start group during the first 40 weeks of the trial. However, there were no differences between groups in other adverse events of particular interest, including dyskinesias and motor fluctuations related to levodopa, Dr. de Bie and his colleagues reported.

Taken together, these results suggest no beneficial or detrimental disease-modifying effect for an early treatment strategy, although further trials are warranted to evaluate other strategies, such as higher levodopa doses, longer administration, or starting the drug at later stages of disease, they wrote.

Dr. de Bie reported grants from ZonMw, Parkinson Vereniging, and Stichting Parkinsonfonds during the conduct of the study, as well as grants from GE Health and Medtronic outside the submitted work. Study authors provided disclosures related to Netherlands Organization for Scientific Research, Michael J. Fox Foundation, UCB, AbbVie, Boston Scientific, Biogen, Merck, and others.

[email protected]

SOURCE: Verschuur CVM et al. N Engl J Med. 2019;380:315-24.

Levodopa did not significantly alter the course of Parkinson’s disease in a randomized, 80-week, delayed-start, clinical trial, investigators reported. The disease course was not significantly different for patients who had a full 80 weeks of levodopa/carbodopa therapy, compared with that seen with those who started treatment after a 40-week delay, according to the investigators.

“These findings imply that levodopa had no disease-modifying effect on Parkinson’s disease over the period of the trial,” wrote investigator Rob M. A. de Bie, MD, PhD, professor of movement disorders at the University of Amsterdam, and his colleagues in the New England Journal of Medicine.

By contrast, results of an earlier randomized, placebo-controlled trial suggested that levodopa had disease-modifying effects, though the findings of that study were inconclusive, according to authors of an editorial (see Views on the News).

In the current multicenter trial, known as LEAP (Levodopa in Early Parkinson’s Disease) a total of 445 patients with early Parkinson’s disease were randomized to either 80 weeks of levodopa and carbodopa or to 40 weeks of placebo followed by 40 weeks of levodopa/carbodopa.

Levodopa was dosed at 100 mg three times per day, and carbodopa at 25 mg three times per day, according to the report.

There was no significant difference between the early and delayed treatment groups for primary outcome of the trial, which was change in the Unified Parkinson’s Disease Rating Scale (UPDRS) from baseline to week 80.

The mean change in UPDRS was –1.0 in the group of patients who had the full 80 weeks of levodopa/carbodopa and –2.0 for those who had delayed therapy, for a difference of 1 point (P = .44). Higher scores on the UPDRS signify worse disease.

At week 40, there was a change in UPDRS favoring the early-initiation strategy, which reflected the effects of levodopa on disease symptoms, investigators added.

Nausea was more common in the early-start group during the first 40 weeks of the trial. However, there were no differences between groups in other adverse events of particular interest, including dyskinesias and motor fluctuations related to levodopa, Dr. de Bie and his colleagues reported.

Taken together, these results suggest no beneficial or detrimental disease-modifying effect for an early treatment strategy, although further trials are warranted to evaluate other strategies, such as higher levodopa doses, longer administration, or starting the drug at later stages of disease, they wrote.

Dr. de Bie reported grants from ZonMw, Parkinson Vereniging, and Stichting Parkinsonfonds during the conduct of the study, as well as grants from GE Health and Medtronic outside the submitted work. Study authors provided disclosures related to Netherlands Organization for Scientific Research, Michael J. Fox Foundation, UCB, AbbVie, Boston Scientific, Biogen, Merck, and others.

[email protected]

SOURCE: Verschuur CVM et al. N Engl J Med. 2019;380:315-24.

Levodopa did not significantly alter the course of Parkinson’s disease in a randomized, 80-week, delayed-start, clinical trial, investigators reported. The disease course was not significantly different for patients who had a full 80 weeks of levodopa/carbodopa therapy, compared with that seen with those who started treatment after a 40-week delay, according to the investigators.

“These findings imply that levodopa had no disease-modifying effect on Parkinson’s disease over the period of the trial,” wrote investigator Rob M. A. de Bie, MD, PhD, professor of movement disorders at the University of Amsterdam, and his colleagues in the New England Journal of Medicine.

By contrast, results of an earlier randomized, placebo-controlled trial suggested that levodopa had disease-modifying effects, though the findings of that study were inconclusive, according to authors of an editorial (see Views on the News).

In the current multicenter trial, known as LEAP (Levodopa in Early Parkinson’s Disease) a total of 445 patients with early Parkinson’s disease were randomized to either 80 weeks of levodopa and carbodopa or to 40 weeks of placebo followed by 40 weeks of levodopa/carbodopa.

Levodopa was dosed at 100 mg three times per day, and carbodopa at 25 mg three times per day, according to the report.

There was no significant difference between the early and delayed treatment groups for primary outcome of the trial, which was change in the Unified Parkinson’s Disease Rating Scale (UPDRS) from baseline to week 80.

The mean change in UPDRS was –1.0 in the group of patients who had the full 80 weeks of levodopa/carbodopa and –2.0 for those who had delayed therapy, for a difference of 1 point (P = .44). Higher scores on the UPDRS signify worse disease.

At week 40, there was a change in UPDRS favoring the early-initiation strategy, which reflected the effects of levodopa on disease symptoms, investigators added.

Nausea was more common in the early-start group during the first 40 weeks of the trial. However, there were no differences between groups in other adverse events of particular interest, including dyskinesias and motor fluctuations related to levodopa, Dr. de Bie and his colleagues reported.

Taken together, these results suggest no beneficial or detrimental disease-modifying effect for an early treatment strategy, although further trials are warranted to evaluate other strategies, such as higher levodopa doses, longer administration, or starting the drug at later stages of disease, they wrote.

Dr. de Bie reported grants from ZonMw, Parkinson Vereniging, and Stichting Parkinsonfonds during the conduct of the study, as well as grants from GE Health and Medtronic outside the submitted work. Study authors provided disclosures related to Netherlands Organization for Scientific Research, Michael J. Fox Foundation, UCB, AbbVie, Boston Scientific, Biogen, Merck, and others.

[email protected]

SOURCE: Verschuur CVM et al. N Engl J Med. 2019;380:315-24.

As a treatment for small fiber neuropathy (SFN), lacosamide decreased pain and had a positive effect on sleep quality with minimal adverse events in patients with mutations in the gene SCN9A that encodes the voltage-gated sodium channel Na_v1.7, according to a randomized, placebo-controlled, double-blind, crossover-design study published in Brain.

“This is the first study that investigated the efficacy of lacosamide [Vimpat] in patients with SFN,” wrote lead author Bianca T.A. de Greef, MD, of Maastricht University Medical Center, the Netherlands, and her coauthors. “Compared with placebo, lacosamide appeared to be safe to use and well tolerated in this cohort of patients.”

Lacosamide, which is approved in the United States to treat partial-onset seizures in people aged 4 years and older, has been shown to bind to and inhibit Na_v1.7.

The investigators randomized 25 Dutch patients with Na_v1.7-related SFN into the Lacosamide-Efficacy-’N’-Safety in SFN (LENSS) study to receive lacosamide followed by placebo, or vice versa. The patients were recruited between November 2014 and July 2016; 1 patient dropped out before treatment and another after the first treatment period, leaving 24 patients who received lacosamide and 23 patients who received placebo. They went through a 3-week titration period, an 8-week treatment period, a 2-week tapering period, and a washout period of at least 2 weeks, after which they switched to the other treatment arm and repeated the same schedule.

Through the daily pain intensity numerical rating scale and the daily sleep interference scale (DSIS), among other questionnaires, the investigators sought to determine if lacosamide reduced pain and thereby improved sleep quality. Lacosamide treatment led to a decrease in mean average pain by at least 1 point in 50.0% of patients, compared with 21.7% in the placebo group (odds ratio, 4.45; 95% confidence interval, 1.38-14.36; P = .0213). In addition, 25.0% of the lacosamide group reported at least a 2-point decrease in mean average pain versus 8.7% in the placebo group. There was also a notable difference in pain’s impact on sleep quality between the two, with the lacosamide period seeing a DSIS median value of 5.3, compared with 5.7 for the placebo period.

According to the patients’ global impression of change questionnaire, 33.3% felt better while using lacosamide versus 4.3% who felt better while using placebo (P = .0156). Six serious adverse events occurred during the study, though only two occurred during the lacosamide period. The most common adverse events for patients taking lacosamide included dizziness, headache, and nausea, all of which were comparable with adverse events in patients taking placebo.

Dr. de Greef and her colleagues noted the study’s potential limitations, including a carryover effect that could have confounded direct treatment effects (which they attempted to mitigate via a lengthier washout period) and a small cohort that was limited to very specific patients. However, the authors chose this particular cohort because “our aim was to demonstrate proof of-concept, which can be used for future studies involving larger groups of patients diagnosed with SFN.” They observed that their response rates were slightly lower than expected, but they noted that “lacosamide appears to be as effective as currently available neuropathic pain treatment.”

The study was funded by the Prinses Beatrix Spierfonds. Some of the authors reported receiving grants, personal fees, funding for research, and/or honoraria from foundations, pharmaceutical companies, life sciences companies, and the European Commission.

SOURCE: de Greef BTA et al. Brain. 2019 Jan 14. doi: 10.1093/brain/awy329.

As a treatment for small fiber neuropathy (SFN), lacosamide decreased pain and had a positive effect on sleep quality with minimal adverse events in patients with mutations in the gene SCN9A that encodes the voltage-gated sodium channel Na_v1.7, according to a randomized, placebo-controlled, double-blind, crossover-design study published in Brain.

“This is the first study that investigated the efficacy of lacosamide [Vimpat] in patients with SFN,” wrote lead author Bianca T.A. de Greef, MD, of Maastricht University Medical Center, the Netherlands, and her coauthors. “Compared with placebo, lacosamide appeared to be safe to use and well tolerated in this cohort of patients.”

Lacosamide, which is approved in the United States to treat partial-onset seizures in people aged 4 years and older, has been shown to bind to and inhibit Na_v1.7.

The investigators randomized 25 Dutch patients with Na_v1.7-related SFN into the Lacosamide-Efficacy-’N’-Safety in SFN (LENSS) study to receive lacosamide followed by placebo, or vice versa. The patients were recruited between November 2014 and July 2016; 1 patient dropped out before treatment and another after the first treatment period, leaving 24 patients who received lacosamide and 23 patients who received placebo. They went through a 3-week titration period, an 8-week treatment period, a 2-week tapering period, and a washout period of at least 2 weeks, after which they switched to the other treatment arm and repeated the same schedule.

Through the daily pain intensity numerical rating scale and the daily sleep interference scale (DSIS), among other questionnaires, the investigators sought to determine if lacosamide reduced pain and thereby improved sleep quality. Lacosamide treatment led to a decrease in mean average pain by at least 1 point in 50.0% of patients, compared with 21.7% in the placebo group (odds ratio, 4.45; 95% confidence interval, 1.38-14.36; P = .0213). In addition, 25.0% of the lacosamide group reported at least a 2-point decrease in mean average pain versus 8.7% in the placebo group. There was also a notable difference in pain’s impact on sleep quality between the two, with the lacosamide period seeing a DSIS median value of 5.3, compared with 5.7 for the placebo period.

According to the patients’ global impression of change questionnaire, 33.3% felt better while using lacosamide versus 4.3% who felt better while using placebo (P = .0156). Six serious adverse events occurred during the study, though only two occurred during the lacosamide period. The most common adverse events for patients taking lacosamide included dizziness, headache, and nausea, all of which were comparable with adverse events in patients taking placebo.

Dr. de Greef and her colleagues noted the study’s potential limitations, including a carryover effect that could have confounded direct treatment effects (which they attempted to mitigate via a lengthier washout period) and a small cohort that was limited to very specific patients. However, the authors chose this particular cohort because “our aim was to demonstrate proof of-concept, which can be used for future studies involving larger groups of patients diagnosed with SFN.” They observed that their response rates were slightly lower than expected, but they noted that “lacosamide appears to be as effective as currently available neuropathic pain treatment.”

The study was funded by the Prinses Beatrix Spierfonds. Some of the authors reported receiving grants, personal fees, funding for research, and/or honoraria from foundations, pharmaceutical companies, life sciences companies, and the European Commission.

SOURCE: de Greef BTA et al. Brain. 2019 Jan 14. doi: 10.1093/brain/awy329.

As a treatment for small fiber neuropathy (SFN), lacosamide decreased pain and had a positive effect on sleep quality with minimal adverse events in patients with mutations in the gene SCN9A that encodes the voltage-gated sodium channel Na_v1.7, according to a randomized, placebo-controlled, double-blind, crossover-design study published in Brain.

“This is the first study that investigated the efficacy of lacosamide [Vimpat] in patients with SFN,” wrote lead author Bianca T.A. de Greef, MD, of Maastricht University Medical Center, the Netherlands, and her coauthors. “Compared with placebo, lacosamide appeared to be safe to use and well tolerated in this cohort of patients.”

Lacosamide, which is approved in the United States to treat partial-onset seizures in people aged 4 years and older, has been shown to bind to and inhibit Na_v1.7.

The investigators randomized 25 Dutch patients with Na_v1.7-related SFN into the Lacosamide-Efficacy-’N’-Safety in SFN (LENSS) study to receive lacosamide followed by placebo, or vice versa. The patients were recruited between November 2014 and July 2016; 1 patient dropped out before treatment and another after the first treatment period, leaving 24 patients who received lacosamide and 23 patients who received placebo. They went through a 3-week titration period, an 8-week treatment period, a 2-week tapering period, and a washout period of at least 2 weeks, after which they switched to the other treatment arm and repeated the same schedule.

Through the daily pain intensity numerical rating scale and the daily sleep interference scale (DSIS), among other questionnaires, the investigators sought to determine if lacosamide reduced pain and thereby improved sleep quality. Lacosamide treatment led to a decrease in mean average pain by at least 1 point in 50.0% of patients, compared with 21.7% in the placebo group (odds ratio, 4.45; 95% confidence interval, 1.38-14.36; P = .0213). In addition, 25.0% of the lacosamide group reported at least a 2-point decrease in mean average pain versus 8.7% in the placebo group. There was also a notable difference in pain’s impact on sleep quality between the two, with the lacosamide period seeing a DSIS median value of 5.3, compared with 5.7 for the placebo period.

According to the patients’ global impression of change questionnaire, 33.3% felt better while using lacosamide versus 4.3% who felt better while using placebo (P = .0156). Six serious adverse events occurred during the study, though only two occurred during the lacosamide period. The most common adverse events for patients taking lacosamide included dizziness, headache, and nausea, all of which were comparable with adverse events in patients taking placebo.

Dr. de Greef and her colleagues noted the study’s potential limitations, including a carryover effect that could have confounded direct treatment effects (which they attempted to mitigate via a lengthier washout period) and a small cohort that was limited to very specific patients. However, the authors chose this particular cohort because “our aim was to demonstrate proof of-concept, which can be used for future studies involving larger groups of patients diagnosed with SFN.” They observed that their response rates were slightly lower than expected, but they noted that “lacosamide appears to be as effective as currently available neuropathic pain treatment.”

The study was funded by the Prinses Beatrix Spierfonds. Some of the authors reported receiving grants, personal fees, funding for research, and/or honoraria from foundations, pharmaceutical companies, life sciences companies, and the European Commission.

SOURCE: de Greef BTA et al. Brain. 2019 Jan 14. doi: 10.1093/brain/awy329.