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Which Headache Features May Help Identify Subarachnoid Hemorrhage?

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Prospective data refine the understanding of thunderclap headaches that may accompany subarachnoid hemorrhage.

Headaches that reach peak intensity in less than one second of onset are significantly more common in patients with subarachnoid hemorrhage (SAH) than in patients who present to a hospital with headaches caused by other conditions, according to a prospective, observational study published in the March issue of Headache. Other headache characteristics, including occipital location and a stabbing quality, also are more likely in patients with SAH.

“Our study suggests a number of features of the clinical history that may aid in identifying those patients presenting with headache at high likelihood of having an SAH,” said Brian Mac Grory, MB, BCh, BAO, Assistant Professor of Neurology at Warren Alpert Medical School of Brown University in Providence, Rhode Island, and colleagues. “This points to the possibility that we may be able to more accurately triage patients in the acute setting based on readily obtainable clinical metrics, which has the potential to reduce the number of expensive and invasive diagnostic tests performed, as well as the number of missed diagnoses.”

SAH is a life-threatening emergency. Patients most commonly present with a severe headache, but the presentation of SAH varies and is often subtle, the researchers said.

To characterize the headache associated with SAH, Dr. Mac Grory and colleagues performed a prospective, observational study examining the clinical features of the presenting headache in people with and without SAH in the emergency department and in the neurosciences intensive care unit of a tertiary referral center. They sought to assess whether any easily obtainable features of the clinical history might allow clinicians to predict whether a person has an SAH in the acute setting. The investigators documented clinical features of the headache, including the time to peak intensity, location, associated symptoms, and activities that caused worsening.

The researchers enrolled 158 subjects, of whom 20 had SAH. Distinguishing features included occipital location (55% in the SAH group vs 22% in the non-SAH group), stabbing quality (35% in the SAH group vs 5% in the non-SAH group), presence of prior headache (50% in the SAH group vs 83% in the non-SAH group), associated meningismus (80% in the SAH group vs 42% in the non-SAH group), and headache that reached peak intensity within 1 second (65% in the SAH group vs 10% in the non-SAH group).

—Jake Remaly

Natalizumab May Be Associated With Increased Disease Activity During Pregnancy

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The treatment appears not to increase the risk of spontaneous abortion or congenital anomalies.

Women with relapsing-remitting multiple sclerosis (MS) who discontinue natalizumab treatment before pregnancy may have increased disease activity, according to a study published March 6 in Neurology. In addition, taking natalizumab during the first trimester of pregnancy increases the risk of miscarriage, although the risk remains similar to that of the general population, according to an accompanying study.

An Analysis of Pregnancy Data

Emilio Portaccio, MD, of the Don Carlo Gnocchi Foundation in Florence, Italy, and colleagues analyzed data for all pregnancies between 2009 and 2015 in patients with MS who presented to 19 Italian sites. They compared data for 83 patients receiving natalizumab with those for 350 control patients who were receiving injectable immunomodulatory agents or no treatment. The investigators followed up with the women every six months, at each relapse, and at one year after birth.

The patients receiving natalizumab had 92 pregnancies. Approximately 37% of women receiving natalizumab had at least one relapse during pregnancy, compared with 10% of controls. Relapse rate during pregnancy was higher among patients whose last infusion occurred before the last menstrual period (55.9%) than among patients whose last infusion occurred after the last menstrual period (20%) or controls (10%). Receiving the last natalizumab infusion before the last menstrual period was the only predictor of relapse during pregnancy. In the first trimester after delivery, the rate of relapse was 21.7% in natalizumab-treated patients and 13.7% in controls.

Twelve patients had disability worsening at the end of the one-year follow-up. In 11 of these patients, disability accumulation resulted from relapses during pregnancy or after delivery. Disease progression was reduced in patients for whom medication was reintroduced earlier after delivery.

About 75% of pregnancies in women receiving natalizumab had treatment exposure, and the mean duration of exposure was 1.2 weeks. The odds ratio of spontaneous abortion was 3.9 among patients receiving natalizumab, compared with controls. The rate of spontaneous abortion among natalizumab-treated patients (17.4%) was similar to that observed for the general Italian population (14%), however. The rate of major congenital anomalies was 3.7% in patients exposed to natalizumab, 1.3% in patients exposed to interferon beta, and 0.9% in untreated patients. The differences between groups were not significant. Exposure to natalizumab and exposure to interferon beta were associated with a lower length of the newborn.

Relapse Severity Was Not Measured

One limitation of the studies is that the women treated with natalizumab may have been different from women not treated with natalizumab in ways that the investigators did not measure. In addition, the researchers did not measure relapse severity.

“Our findings suggest that if women who take natalizumab for MS want to become pregnant, it may be best to continue treatment up until a pregnancy test is positive and then at that point discontinue use,” said Dr. Portaccio. “While there is still a risk of increased disease activity, this course of action may lower that risk.”

—Erik Greb

Haloperidol May Not Prevent Delirium in Patients in ICUs

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Compared with placebo, prophylactic haloperidol did not improve survival or reduce the incidence of delirium among critically ill patients in a clinical trial.

Prophylactic haloperidol did not prevent delirium or improve survival in a placebo-controlled trial of 1,789 critically ill adults at 21 ICUs in the Netherlands, according to research published in the February 20 issue of JAMA.

“These findings do not support the use of prophylactic haloperidol in critically ill adults,” said Mark van den Boogaard, PhD, Assistant Professor of Intensive Care Medicine at Radboud University Medical Center in Nijmegen, the Netherlands.

Haloperidol is used routinely in ICUs to treat and prevent delirium, which affects as many as half of ICU patients and is associated with prolonged mechanical ventilation, longer ICU and hospital stays, and increased mortality. Results of past studies of haloperidol in the ICU have been mixed.

For this study, eligible participants were expected to be in the ICU for at least two days and were not delirious at baseline. Patients were randomized to receive 1 mg of haloperidol (n = 350), 2 mg of haloperidol (n = 732), or placebo (n = 707) three times daily. The 1-mg haloperidol arm was stopped early because of futility. The ICUs also used nonpharmacologic interventions to prevent delirium, including early mobilization and noise reduction.

Patients had a mean age of 66.6; 61.4% were men. Most of the ICU admissions were urgent and for medical or surgical reasons. There was no statistically significant difference in survival at 28 days following entrance into the study, which was the study’s primary end point. At that point, 83.3% of the patients who received 2-mg doses of haloperidol and 82.7% of the subjects who received placebo had survived.

Prophylactic haloperidol had no effect on reducing the incidence of delirium, which was diagnosed in 33.3% of patients who received haloperidol and 33.0% of patients who received placebo. Likewise, there were no significant differences between the groups in the number of delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay.

“The study population included severely ill ICU adults whose brains may have been too seriously affected for haloperidol to exert a prophylactic effect, since in non-ICU adults, prophylactic haloperidol may have beneficial effects. But the subgroup of patients with a low severity of illness score also demonstrated no beneficial effects,” the investigators said.

—M. Alexander Otto

Excessive Daytime Sleepiness Is Associated With an Alzheimer’s Disease Biomarker

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Among elderly individuals without dementia, excessive daytime sleepiness is associated with increased accumulation of beta-amyloid.

Elderly individuals who have excessive daytime sleepiness may be more susceptible to accumulation of an Alzheimer’s disease biomarker, according to a study published online ahead of print March 12 in JAMA Neurology.

Excessive daytime sleepiness (EDS) was associated with increased accumulation of beta-amyloid, an important biomarker of Alzheimer’s disease that manifests in early preclinical stages, said Diego Z. Carvalho, MD, a senior neurology resident at the Mayo Clinic in Rochester, Minnesota, and colleagues.

This finding corroborates previous studies showing that EDS is a risk factor for dementia or cognitive decline, the authors noted.

“It remains unclear whether EDS is a result of greater sleep instability, synaptic or network overload, or neurodegeneration of wakefulness-promoting centers,” said Dr. Carvalho and colleagues. “However, participants with EDS were more vulnerable to Alzheimer’s disease pathologic processes.”

The researchers conducted a prospective, longitudinal cohort analysis that included 283 participants age 70 or older without a diagnosis of dementia who filled out a sleepiness assessment survey and underwent baseline and follow-up imaging studies as part of the Mayo Clinic Study of Aging. All participants included in the analysis underwent at least two consecutive carbon 11–labeled Pittsburgh compound B PET (PiB-PET) scans.

EDS, defined as a score of at least 10 on the Epworth Sleepiness Scale (ESS), was observed in 63 participants (22.3%). At baseline, EDS was significantly associated with increased beta-amyloid accumulation in the anterior cingulate, posterior cingulate-precuneus, and parietal regions. The association between EDS and longitudinal beta-amyloid accumulation was most pronounced in participants who had global PiB positivity at baseline in anterior cingulate and cingulate-precuneus regions. Findings of the study are consistent with a previous investigation of middle-aged participants without dementia, said Dr. Carvalho and colleagues. In that study, increased daytime somnolence was associated with increased beta-amyloid burden in regions including the precuneus and anterior cingulate. Daytime sleepiness in that study was measured using the Sleep Scale.

Further investigation of the link between EDS and beta-amyloid accumulation is warranted. In particular, the researchers suggested that future studies might evaluate whether amyloid accumulation can be avoided through early recognition of EDS and subsequent treatment of underlying sleep disorders.

Poor Sleep Quality May Be an Early Warning Sign of Alzheimer’s Disease

The study advances the understanding of sleep disturbance as a risk factor for Alzheimer’s disease, said Joseph R. Winer, of the Department of Psychology at the University of California, Berkeley, and Bryce A. Mander, PhD, Assistant Professor of Psychiatry and Human Behavior at the University of California, Irvine School of Medicine, in an accompanying editorial.

Findings from the study suggest that poor sleep quality may be an early warning sign of Alzheimer’s disease-related processes. The results should be interpreted with caution, however, because daytime sleepiness was assessed subjectively using the Epworth Sleepiness Scale (ESS), they said. ESS score may reflect declining sleep quality, but it is not necessarily a warning sign for impending amyloidosis because of the low specificity of subjective sleepiness and the many underlying causes that could contribute to ESS scores.

The results suggest that in the future sleep dysfunction might be managed with sleep-based interventions at the optimal time to intervene in the beta-amyloid cascade, Mr. Winer and Dr. Mander said.

Future studies would ideally include other markers of Alzheimer’s disease progression, such as cortical atrophy, tau deposition, or cardiovascular changes, and better explain a physiologic link between subjective daytime sleepiness and longitudinal change in beta-amyloid, said Mr. Winer and Dr. Mander.

—Andrew D. Bowser

Are Complementary and Alternative Treatments Effective for MS?

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CAMs with the strongest evidence supporting them were cannabis extract, physical activity, and cognitive behavioral therapy.

Cannabis extract, physical activity, and cognitive behavioral therapy are complementary and alternative medicines (CAMs) with the strongest evidence of efficacy for multiple sclerosis (MS), according to a systematic review published in the January issue of Journal of Neurology, Neurosurgery and Psychiatry. However, there is little class I and class II evidence to support the effect of CAMs.

“We found little evidence for CAM treatments of MS, and class I evidence was almost universally lacking,” said Suzi B. Claflin, PhD, a postdoctoral research fellow at Menzies Institute for Medical Research at the University of Tasmania in Hobart, Australia, and colleagues. Some CAM treatments were evaluated in a single study, and when treatments were evaluated in more than one study, the studies “had different designs and methodologies, and in some cases, contradictory results.”

A Systematic Review

There is an in interest in CAM treatments among the MS community, possibly due to perceived and actual shortcomings of available pharmacologic treatments, said the researchers. Cross-sectional studies have found that 37% to 100% of patients with MS have used CAMs at some point in their lives, and up to 51.8% of these patients have used CAMs in the past year. Despite the common use of CAMs, there is a lack of understanding of their efficacy, the authors noted.

The World Health Organization has defined CAM as “a broad set of health care practices that are not part of [a] country’s own tradition and are not integrated into the dominant health care system.” For the present review, however, the researchers defined CAM broadly as a noninvasive therapy used in addition to or in lieu of the standard pharmacologic treatment of MS.

To provide an overview of the modern evidence for CAM use in patients with MS and to highlight future directions for research, Dr. Claflin and colleagues conducted a systematic review of full research articles published between January 1, 2001, and January 18, 2017, that were written in English, had only human participants, and tested the effect of a CAM treatment on health outcomes in patients with MS only. The researchers included in their review studies with at least 50 participants that provided class I or class II evidence of efficacy. In all, they included 38 studies and divided them into the following five CAM types: cannabis, diet, exercise, psychologic approaches, and other.

Best-Supported Evidence

Five studies found significant beneficial effects of cannabis extract for incontinence, pain, spasticity, and muscle stiffness, whereas two studies found no effect of cannabis extract on primary outcomes. A single study found a positive effect of tetrahydrocannabinol extract on incontinence, and one study found no effect for this treatment on spasticity.

Psychologic approaches such as cognitive behavioral therapy (CBT) appear to be effective in treating MS-related psychologic symptoms. Seven class II studies found that CBT significantly improved depression, fatigue, distress, and general health. In one study, there was no effect of CBT on functional impairment. In a single study, there was no effect of cognitive rehabilitation on function. In another study, mindfulness significantly improved health-related quality of life, depression, and fatigue.

Among exercise treatments, some balance and gait training techniques significantly improved fatigue, balance, walking, and endurance, while other techniques did not. Exercise generally was found to improve muscle strength and mobility-related health outcomes in several studies, and may have some effect on psychologic symptoms. In several studies, however, primary outcomes were not significantly affected. In a single study, yoga had no effect on attention and alertness. In another study, group yoga was not effective in improving MS Impact Scale scores, but some effects on secondary outcomes were observed.

Least-Supported Evidence

Among dietary treatments, biotin had a significant effect on disability progression in one study. In another single study, there was no effect of gingko biloba on cognitive function. Two studies of polyunsaturated fatty acid supplementation for disability had contradictory results: one study found that the treatment reduced relapse rate, and another study found no effect on gadolinium-enhancing lesions. In addition, three studies found no effect of vitamin D supplementation after MS onset on primary outcomes, but one of the studies found some suggestion of benefit of vitamin D as an add-on treatment.

Among other CAMs, acupressure significantly reduced fatigue in a single study. In another single study, amphetamine salts improved processing speed. Two studies found contradictory results for the efficacy of reflexology for pain. Finally, one study found a positive effect of relaxation on stress and depression, and one study found a positive effect of relaxation on pain.

“In order to improve our understanding of the effects of CAM on MS health outcomes, future work should cultivate methodological consistency by establishing standard control or comparator groups and outcome measures,” said Dr. Claflin and colleagues. “This field would also be well served by establishing outcomes of interest, which would allow for greater replication and the accrual of a depth of evidence about an outcome.”

—Erica Tricarico

Closure of High-Risk PFOs Reduces Risk of Recurrent Stroke

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Selecting patients based on PFO morphology may maximize the benefits of PFO closure.

Closure of a patent foramen ovale (PFO) with an atrial septal aneurysm, hypermobility, or size of 2 mm or greater reduces the risk of stroke recurrence in patients with cryptogenic stroke, according to research published online ahead of print March 12 in the Journal of the American College of Cardiology.

“Considering the high prevalence of PFO in the general population and cryptogenic stroke patients, the key to appropriate use of this medical device is determining how to select optimal candidates for the procedure,” said Jae-Kwan Song, MD, PhD, a Professor in the Department of Medicine at Asan Medical Center, University of Ulsan College of Medicine, in Seoul, South Korea. “With our study and other recent trials, the criteria for selecting patients for the procedure are becoming clearer; in particular, the results suggest that closure is beneficial for those with high-risk PFO.”

A Multisite Superiority Trial

Previous research has not offered a definitive answer to the question of whether physicians can determine the potential benefit of PFO closure according to the PFO’s morphologic characteristics. In an earlier study, Dr. Song and colleagues found that high-risk PFO, as defined by transesophageal echocardiography (TEE), helped to predict stroke recurrence. The investigators then initiated the DEFENSE-PFO trial to evaluate whether restricting treatment to patients with cryptogenic stroke and PFO morphology associated with a higher rate of recurrent stroke would enhance the benefits of PFO closure.

Dr. Song and colleagues conducted DEFENSE-PFO, an open-label superiority trial, at two sites in South Korea from June 2011 through October 2017. Eligible patients had an ischemic stroke within the previous six months with no identifiable cause other than a high-risk PFO with left-to-right shunting. The researchers performed a standardized evaluation to rule out other identifiable mechanisms of stroke. The exclusion criteria were at least 50% stenosis of a major vessel, occlusion of a major vessel, and stroke resulting from small-vessel occlusive disease. Dr. Song and colleagues performed Holter monitoring or prolonged monitoring of cardiac rhythm to rule out paroxysmal atrial fibrillation.

A high-risk PFO was defined as one with an atrial septal aneurysm (ie, protrusion of the dilated segment of the septum at least 15 mm beyond the level surface of the atrial septum), hypermobility (ie, phasic septal excursion of 10 mm or more into either atrium), or size (ie, maximum separation of the septum primum from the secundum during the Valsalva maneuver) of 2 mm or greater on TEE.

Patients were randomized in equal groups to transcatheter PFO closure with the Amplatzer PFO Occluder plus medical therapy or medical therapy alone. All participants received antiplatelet therapy or anticoagulation chosen by the local investigator. During follow-up visits at one, three, six, 12, and 24 months, investigators recorded clinical data.

The primary end point was a composite of stroke, vascular death, or Thrombolysis in Myocardial Infarction (TIMI)-defined major bleeding during two years of follow-up. The secondary end point was asymptomatic ischemic stroke on follow-up MRI.

No End-Point Events After PFO Closure

Dr. Song and colleagues identified 450 patients with cryptogenic stoke and PFO, of whom 175 had high-risk PFO. They randomized 60 patients to each study arm. Participants’ mean age was 51.8. The groups were well balanced in terms of age, sex, medical history, qualifying event, modified Rankin scale score at discharge, and the anatomic characteristics of the PFO and atrial septum.

Seven patients randomized to PFO closure declined the treatment. Dual antiplatelet therapy was the most common medication in both groups at 30 days after randomization. This trend continued for as long as 12 months in the medication-only group, but single antiplatelet therapy became the most common strategy after six months in the PFO-closure group. About 17% of patients in the PFO-closure group stopped medication after the intervention. The median duration of follow-up was 2.8 years.

In the intention-to-treat analysis, no patient in the PFO-closure group had a primary end point event, compared with six patients in the medication-only group. Events recorded in the latter group included five ischemic strokes, one cerebral hemorrhage, two TIMI-defined major bleeding events, and one transient ischemic attack. The Kaplan-Meier two-year cumulative estimate of the probability of stroke was 10.5% in the medication-only group. The number of patients needed to treat with PFO closure to avoid one stroke at two years thus was 10.

Implications for Selection Criteria

The DEFENSE-PFO study differs from two previous trials that found benefits of PFO closure, but did not consider the anatomic features of the atrial septum or PFO. “The only trial with stringent entry criteria similar to ours is the CLOSE trial, which required that patients have a large interatrial right-to-left shunt (more than 30 microbubbles in the left atrium within three cardiac cycles after opacification of the right atrium) or an atrial septal aneurysm (a septum primum excursion greater than 10 mm),” said Dr. Song and colleagues. “Both the CLOSE trial and our trial showed no occurrence of stroke in patients who underwent PFO closure, suggesting that the beneficial effect of percutaneous device closure of PFO can be maximized by adding the morphologic characteristics of PFO, as evaluated by TEE, to the selection criteria for the procedure.”

Because the DEFENSE-PFO study was terminated early for patient safety, it was underpowered to provide a hazard ratio for its primary end point. In addition, selection bias may have affected the study, since it was conducted at a small number of centers.

—Erik Greb

Congenital Heart Disease Is Associated With a Higher Risk of Dementia

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The risk of dementia is higher in patients born with heart defects who develop other heart disease risk factors later in life.

Congenital heart disease (CHD) is associated with an increased risk of dementia, especially early onset dementia, according to research published online ahead of print February 12 in Circulation. A particularly increased risk of dementia was observed among middle-aged adults with CHD and signs of early onset dementia, the authors noted.

“These results support the importance of understanding the risk of adverse long-term neurologic outcomes in the growing and aging population with CHD,” said Carina N. Bagge, a medical student at Aarhus University Hospital in Aarhus, Denmark, and colleagues.

Examining Dementia Risk in Patients With CHD

CHD occurs in six to 10 per 1,000 live births and represents the most common group of congenital defects. Dementia is the sixth most common cause of death in the United States. Although neurodevelopmental deficits among infants and children with CHD are well studied, research on long-term neurologic outcomes in adults with CHD is limited. Based on the increased incidence of neurodevelopmental impairments and associated risk factors for dementia among patients with CHD, Ms. Bagge and colleagues hypothesized that the risk of dementia is higher in adults with CHD than in the general population.

To test this hypothesis, the authors performed a nationwide, population-based cohort study in Denmark using linked medical registries that included data from all Danish hospitals. They identified all adults who received a diagnosis of CHD between 1963 and 1974 (before age 15) and between 1977 and 2012 (at any age). For each patient with CHD, 10 individuals from the general population were matched by sex and birth year, using the Civil Registration System. The authors defined CHD as an abnormally structured heart or greater intrathoracic vessels at birth, said Ms. Bagge. Participants were followed from January 1, 1981, age 30, or the date of their first CHD registration until hospital diagnosis of dementia, death, emigration, or December 31, 2012. To examine potential variation in dementia risk, the investigators categorized patients according to cyanotic potential.

The primary outcome was a first-time hospital diagnosis of all-cause dementia in the inpatient or outpatient clinic setting. Investigators categorized dementia diagnoses as Alzheimer’s disease, vascular dementia, or other dementias.

CHD Severity Correlated With Increased Risk of Dementia

The investigators identified 10,632 adults with CHD and 103,403 adults from the general population;46% were male in both cohorts. The cumulative incidence of dementia was 4% at age 80 in both cohorts. The overall hazard ratio (HR) of dementia was 1.6 among adults with CHD, compared with the general population. The HR of dementia was 1.4 among patients with CHD without extracardiac defects, 1.5 among patients with mild-to-moderate CHD, and 2.0 for patients with severe CHD, including univentricular hearts. Finally, the HR for early-onset dementia (ie, onset younger than age 65) was 2.6, and the HR for late-onset dementia was 1.3 among patients with CHD.

“These results cannot be directly applied to young adults diagnosed with CHD in the present eras. However, it is important to recognize healthcare needs and risk factors affecting the larger number of middle-aged and older adults currently living with CHD,” said Ms. Bagge and colleagues.

—Erica Tricarico

Migraine Often Results in Emergency Department Revisits

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Many of the more than one million visits to the ED for migraine are by patients who are returning for the same problem.

More than one-quarter of initial emergency department (ED) visits for migraine are followed by headache revisits in fewer than six months, according to a retrospective study of New York City hospitals. Reporting in the March issue of Headache, Mia T. Minen, MD, MPH, and colleagues found that among patients discharged from the ED with a diagnosis of migraine, 12.5% revisit the same ED for headache more than once within six months. “Targeted interventions might … decrease the frequency of headache revisits,” said Dr. Minen and colleagues. Dr. Minen is Director of Headache Services at NYU Langone Headache Center in New York City.

Migraine causes more than 1.2 million visits to US EDs annually. Many of these visits are revisits among patients who have already been treated in an ED for migraine. Dr. Minen and colleagues sought to determine the frequency of these headache revisits and the sociodemographic factors associated with them.

A Study of New York City EDs

Using the New York City Department of Health and Mental Hygiene Syndromic Surveillance database, Dr. Minen and colleagues conducted a retrospective nested cohort study. They analyzed visits from 18 New York City EDs with discharge diagnoses in the first six months of 2015. They then conducted descriptive analyses to determine the frequency of headache revisits within six months of an index ED visit for migraine and the elapsed time to revisit. Using multivariable logistic regression, the researchers assessed associations between age, sex, poverty, and revisit.

Of 1,052 ED visits with a discharge diagnosis of migraine during the first six months of 2015, 277 (26.3%) had a headache revisit within six months of their initial migraine visit, and 131 (12.5%) had two or more revisits at the same hospital. Of the revisits for headache, 9% occurred within 72 hours, and 46% occurred within 90 days of the initial migraine visit. Sex, age, and poverty were not associated with an ED revisit.

Noting that the revisit rate in New York City EDs was similar to the 30.3% revisit rate in a prior study in Maine EDs, the researchers said that frequent revisits for headache are not surprising. “Migraine is a recurrent headache disorder, and 80% of headache patients in the ED do not visit a clinic, primary care physician, or specialist before visiting the ED. In one urban ED, nearly 60% of ED patients were not instructed to follow-up with a physician, and approximately 40% were not prescribed medications.”

Potentially Preventable

Several approaches could decrease headache revisits, the researchers said. “Within the ED, the use of evidence-based algorithms can aid in the standardization of headache diagnosis and treatment. These should include the use of dexamethasone, an evidence-based intervention to decrease the frequency of moderate or severe headache within 48 hours of ED discharge.” On discharge from the ED, patients should be advised about local headache treatment facilities. “Because ED patients with migraine and psychiatric comorbidities have higher health care utilization rates than migraine patients without psychiatric comorbidities, migraine patients with comorbid psychiatric disorders could be referred to an ED case manager to ensure further intervention.” Finally, “ED revisits for headache could be mitigated by increasing the availability and access to urgent care appointments or walk-in outpatient appointments, especially during off-hour nights and weekends,” they said.

—Glenn S. Williams

Levetiracetam May Be Superior to Phenobarbital for Infantile Epilepsy

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Missing data may have influenced the analysis, and further research is needed.

Levetiracetam may be a superior initial treatment for infants with nonsyndromic epilepsy, according to a multicenter, prospective, observational study published online ahead of print February 12 in JAMA Pediatrics.

“Our findings suggest that levetiracetam has superior effectiveness, compared with phenobarbital, as initial monotherapy for nonsyndromic epilepsy in infants,” said Zachary Grinspan, MD, Director of the Pediatric Epilepsy Program at Cornell University, New York, and colleagues. “We estimate that for every 100 infants with epilepsy treated with levetiracetam instead of phenobarbital, 44 infants would be free from monotherapy failure instead of 16.”

To evaluate the effectiveness of levetiracetam vs phenobarbital, the researchers conducted the Early Life Epilepsy Study, which included 155 children with nonsyndromic epilepsy. Patient information was obtained from medical records and collected from March 1, 2012, through April 30, 2015. All participants were observed during their first three years of life.

In all, 117 children were treated with levetiracetam, and 38 with phenobarbital. Children treated with levetiracetam were, on average, two months older at seizure onset than were those in the phenobarbital group (5.2 months vs 3.0 months). Infants treated with levetiracetam also tended to begin treatment further from the time of their first seizure and exhibited less developmental delay at the time of epilepsy diagnosis.

Freedom from monotherapy failure was more common in the levetiracetam group than the phenobarbital group (40.2% vs 15.8%).

Outcome information was missing for more infants treated with levetiracetam than those treated with phenobarbital, which could have influenced the analyses, said Dr. Grinspan. The genetic interactions that influence nonsyndromic epilepsy make the latter difficult to study.

Although this study provides information that could benefit patients with infantile epilepsy, more work must be done on the topic, said the investigators. “A prospective clinical trial is needed. Levetiracetam and phenobarbital are both commonly used for infantile-onset epilepsy, indicating community equipoise regarding their relative effectiveness,” they said. “However, the effect size in our analysis was surprisingly large (number needed to treat, 3.5), suggesting that a change in practice could meaningfully improve outcomes.”

—Ian Lacy

Migraine May Be an Important Risk Factor for Cardiovascular Diseases

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In a population-based study, migraine was associated with venous thromboembolism, atrial fibrillation, myocardial infarction, and stroke.

Migraine is associated with increased risk of myocardial infarction, ischemic stroke, hemorrhagic stroke, venous thromboembolism, and atrial fibrillation or atrial flutter, according to a study published online ahead of print January 31 in BMJ. The results suggest that “migraine should be considered a potent and persistent risk factor for most cardiovascular diseases in both men and women,” the researchers said.

Prior studies have found that migraine is associated with ischemic stroke and ischemic heart disease, especially among women and patients with migraine with aura. Convincing epidemiologic evidence of an association between migraine and other cardiovascular events has been lacking, however, said Kasper Adelborg, MD, PhD, of the Department of Clinical Epidemiology at Aarhus University Hospital in Denmark, and colleagues.

To study cardiovascular morbidity associated with migraine, Dr. Adelborg and colleagues conducted a nationwide, population-based cohort study. The study included patients from all Danish hospitals and hospital outpatient clinics between 1995 and 2013. The researchers used Cox regression analysis to assess comorbidity-adjusted hazard ratios of cardiovascular outcomes.

Their analysis included 51,032 patients with migraine and 510,320 people from the general population matched on age, sex, and calendar year. Median age at migraine diagnosis was 35, and 71% of the participants were women.

Incidence per 1,000 People

Patients with incident migraine had greater absolute risk of most cardiovascular outcomes, compared with the general population, across most follow-up periods. After 19 years of follow-up, the cumulative incidences per 1,000 people were greater among migraineurs, compared with the general population, for myocardial infarction (25 vs 17), ischemic stroke (45 vs 25), hemorrhagic stroke (11 vs 6), peripheral artery disease (13 vs 11), venous thromboembolism (27 vs 18), atrial fibrillation or atrial flutter (47 vs 34), and heart failure (19 vs 18).

Migraine was associated with myocardial infarction (adjusted hazard ratio [HR], 1.49), ischemic stroke (adjusted HR, 2.26), and hemorrhagic stroke (adjusted HR, 1.94), as well as venous thromboembolism (adjusted HR, 1.59) and atrial fibrillation or atrial flutter (adjusted HR, 1.25). Migraine was not meaningfully associated with peripheral artery disease or heart failure. “The associations, particularly for stroke outcomes, were stronger during the short term (0–1 years) after diagnosis than the long term (up to 19 years),” the researchers said. In addition, associations were stronger in migraine with aura than in migraine without aura, and in women than in men. In a subcohort of patients with additional data, the associations persisted after additional adjustments for BMI and smoking.

The absolute risk of cardiovascular outcomes was low, which was expected, given the young age of the study population, the researchers noted. Although the investigators adjusted for a range of potential confounders, other unknown or residual confounding (eg, by physical activity) is possible.

Multifactorial mechanisms may explain the observed increased risk of cardiovascular disease in migraine, and different mechanisms may be involved in specific cardiovascular outcomes. Migraine and cardiovascular diseases may share genetic, inflammatory, vascular, endothelial, electrical or depolarizing, or coagulable factors, the researchers said. In addition, migraineurs often use NSAIDs, which are associated with increased risk of cardiovascular events. It is also possible that immobilization due to migraine attacks may increase the risk of venous thromboembolism.

Reducing Risk

“Although the magnitude of the increased cardiovascular risk associated with migraine was fairly small at the individual level, it translates into a substantial increase in risk at the population level, because migraine is a common disease,” Dr. Adelborg and colleagues said. Migraine increasingly is recognized as an important cardiovascular risk factor to consider in clinical practice, and the recently developed QRISK3 algorithm, which predicts 10-year risk of cardiovascular disease in men and women ages 25 to 84, is the first cardiovascular risk-stratification tool to incorporate migraine.

“Ultimately, it will be important to determine whether prevention strategies in patients with migraine can reduce the burden of cardiovascular disease in patients with this common disorder,” the researchers said. “Current migraine guidelines do not recommend use of aspirin and clopidogrel in the prophylaxis of migraine, but clinicians should consider whether patients at particularly high risk of cardiovascular diseases would benefit from anticoagulant treatment.”

The present study and prior research provide “plenty of evidence that migraine should be taken seriously as a strong cardiovascular risk marker,” and data indicate that migraine is associated with “a measurable risk of cardiovascular death,” said Tobias Kurth, MD, Professor of Public Health and Epidemiology and Director of the Institute of Public Health at the Charité-Universitätsmedizin Berlin, and colleagues, in an accompanying editorial. Strategies to reduce the risk of cardiovascular disease in patients with migraine are urgently needed and long overdue, they said.

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