Migraine ICYMI

ASHEVILLE, NC—The 30 days after surgery are a period of exceptionally high risk for ischemic stroke, and the risk is greater for patients with migraine, compared with patients without migraine, according to a lecture at the Eighth Annual Scientific Meeting of the Southern Headache Society.

“When we send individuals with migraine to surgery who do not have classical risk factors [for stroke], they may, in fact, still be at risk for stroke during the perioperative period,” said Timothy T. Houle, PhD, Associate Professor of Anesthesia at Massachusetts General Hospital and Harvard Medical School in Boston.

Dr. Houle described a hospital-based registry study that he and his colleagues published in BMJ. They found that the rate of ischemic stroke within 30 days of surgery was about 240 strokes per 100,000 patients without migraine, whereas among migraineurs, the rate was 430 strokes per 100,000 patients. Among patients with migraine without aura, the rate was 390 strokes per 100,000 patients, and among patients with migraine with aura, the rate was 630 strokes per 100,000 patients. “If you have migraine with aura, your risk of having a stroke is appreciably elevated and not trivial,” Dr. Houle said. “This is something to take seriously.”

The Migraine–Stroke Connection

Researchers consistently have found that migraine is associated with an increased risk of ischemic stroke in the general population, but the relationship has been challenging to study.

Possible mechanisms underlying the relationship between migraine and stroke include comorbidities (eg, higher BMI and increased cardiovascular risk factors) and medication use. In addition, research suggests that cortical spreading depression might make migraineurs’ brains more susceptible to stroke, Dr. Houle said. Patent foramen ovale, arterial dissection, coagulation dysfunction, endothelial dysfunction, or a genotype that increases the risk of migraine and stroke are other potential pathways.

Spector et al conducted a meta-analysis of 21 studies and concluded that migraine appears to be independently associated with a twofold increased risk of ischemic stroke. A meta-analysis by Schürks et al found that the relative risk of stroke was about 1.73 for patients with migraine and 2.16 for patients with migraine with aura. Migraine without aura was associated with a relative risk of 1.23, but this result was not statistically significant.

Dr. Houle and colleagues hypothesized that focusing on the perioperative period, when stroke is more prevalent, “could yield unique insights into the migraine–stroke connection,” he said.

Ischemic stroke in the perioperative period occurs at a rate of about 100 strokes per 100,000 individuals for the lowest-risk surgeries. After major cardiac and vascular surgery, the risk may be between 600 and 7,400 strokes per 100,000 individuals. “We have … a risk period that is intensely elevated for patients about to receive surgical insult,” Dr. Houle said. The increased risk may result from the indication for the surgery, as well as factors related to surgery itself, such as surgical stress, inflammatory responses, and intraoperative hypotension.

A Retrospective Cohort Study

Based on the increased risk of stroke in the general population, the investigators hypothesized that individuals with migraine also would have an elevated risk of stroke in the 30 days after surgery. They analyzed data from 124,558 patients (mean age, 52.6; 54.5% women) who underwent surgery between 2007 and 2014 at Massachusetts General Hospital and two satellite campuses. They included patients who had surgery under general anesthesia with mechanical ventilation and were successfully extubated. They used ICD-9 codes to identify patients with migraine. The primary outcome was ischemic stroke within 30 days. They identified strokes using ICD-9 codes and confirmed strokes by reviewing brain scans and medical records.

The investigators adjusted for confounders, including sex, age, BMI, emergent versus nonemergent surgery, prescriptions of antiplatelet drugs or beta blockers within four weeks before surgery, minutes of intraoperative hypotension, diabetes, hypertension, atrial fibrillation, Charleston Comorbidity Index, and work relative value units (ie, a surrogate for surgical complexity).

The cohort included 10,179 individuals with migraine (8.2%). Of the patients with migraine, 12.6% had migraine with aura.

Patients with migraine generally were younger, had higher BMI, and were more likely to be women. They were less likely to have diabetes or hypertension and to be taking antiplatelet drugs or beta blockers. Patients with migraine “were a little healthier” than the patients without migraine, Dr. Houle said.

In all, 771 patients had perioperative stroke, of whom 89 (11.5%) had migraine. About 0.6% of patients without migraine had perioperative stroke versus 0.9% of patients with migraine. The unadjusted odds ratio for stroke among migraineurs was 1.47, and the adjusted odds ratio was 1.75. “Individuals in this sample who had any migraine were at greater risk for stroke during the period after surgery, just like in the regular population,” said Dr. Houle. Although migraine without aura was not a statistically significant risk factor for stroke in the general population, it was after surgery.

Prediction Models

In one sensitivity analysis, the researchers determined each patient’s stroke risk based on known risk factors excluding migraine, such as age and cardiovascular disorders, and grouped patients by low, intermediate, and high levels of risk. Among patients in the low-risk group, the relative risk of stroke for patients with migraine versus patients without migraine was 3.5-fold higher. “These are people you would not have identified as having risk,” said Dr. Houle.

Future studies should try to identify the mechanisms involved in this relationship and assess interventions to mitigate the risk of stroke in patients with migraine who undergo surgery, Dr. Houle said.

Dr. Houle and colleagues have created a stroke prediction model that includes migraine and will “give surgeons a risk model to predict the risk of stroke for their patients,” he said. The model will “realize the risks that we uncovered in this study.”

—Jake Remaly

Suggested Reading

Schürks M, Rist PM, Bigal ME, et al. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ. 2009;339:b3914.

Spector JT, Kahn SR, Jones MR, et al. Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med. 2010;123(7):612-624.

Timm FP, Houle TT, Grabitz SD, et al. Migraine and risk of perioperative ischemic stroke and hospital readmission: hospital based registry study. BMJ. 2017;356:i6635.

ASHEVILLE, NC—The 30 days after surgery are a period of exceptionally high risk for ischemic stroke, and the risk is greater for patients with migraine, compared with patients without migraine, according to a lecture at the Eighth Annual Scientific Meeting of the Southern Headache Society.

“When we send individuals with migraine to surgery who do not have classical risk factors [for stroke], they may, in fact, still be at risk for stroke during the perioperative period,” said Timothy T. Houle, PhD, Associate Professor of Anesthesia at Massachusetts General Hospital and Harvard Medical School in Boston.

Dr. Houle described a hospital-based registry study that he and his colleagues published in BMJ. They found that the rate of ischemic stroke within 30 days of surgery was about 240 strokes per 100,000 patients without migraine, whereas among migraineurs, the rate was 430 strokes per 100,000 patients. Among patients with migraine without aura, the rate was 390 strokes per 100,000 patients, and among patients with migraine with aura, the rate was 630 strokes per 100,000 patients. “If you have migraine with aura, your risk of having a stroke is appreciably elevated and not trivial,” Dr. Houle said. “This is something to take seriously.”

The Migraine–Stroke Connection

Researchers consistently have found that migraine is associated with an increased risk of ischemic stroke in the general population, but the relationship has been challenging to study.

Possible mechanisms underlying the relationship between migraine and stroke include comorbidities (eg, higher BMI and increased cardiovascular risk factors) and medication use. In addition, research suggests that cortical spreading depression might make migraineurs’ brains more susceptible to stroke, Dr. Houle said. Patent foramen ovale, arterial dissection, coagulation dysfunction, endothelial dysfunction, or a genotype that increases the risk of migraine and stroke are other potential pathways.

Spector et al conducted a meta-analysis of 21 studies and concluded that migraine appears to be independently associated with a twofold increased risk of ischemic stroke. A meta-analysis by Schürks et al found that the relative risk of stroke was about 1.73 for patients with migraine and 2.16 for patients with migraine with aura. Migraine without aura was associated with a relative risk of 1.23, but this result was not statistically significant.

Dr. Houle and colleagues hypothesized that focusing on the perioperative period, when stroke is more prevalent, “could yield unique insights into the migraine–stroke connection,” he said.

Ischemic stroke in the perioperative period occurs at a rate of about 100 strokes per 100,000 individuals for the lowest-risk surgeries. After major cardiac and vascular surgery, the risk may be between 600 and 7,400 strokes per 100,000 individuals. “We have … a risk period that is intensely elevated for patients about to receive surgical insult,” Dr. Houle said. The increased risk may result from the indication for the surgery, as well as factors related to surgery itself, such as surgical stress, inflammatory responses, and intraoperative hypotension.

A Retrospective Cohort Study

Based on the increased risk of stroke in the general population, the investigators hypothesized that individuals with migraine also would have an elevated risk of stroke in the 30 days after surgery. They analyzed data from 124,558 patients (mean age, 52.6; 54.5% women) who underwent surgery between 2007 and 2014 at Massachusetts General Hospital and two satellite campuses. They included patients who had surgery under general anesthesia with mechanical ventilation and were successfully extubated. They used ICD-9 codes to identify patients with migraine. The primary outcome was ischemic stroke within 30 days. They identified strokes using ICD-9 codes and confirmed strokes by reviewing brain scans and medical records.

The investigators adjusted for confounders, including sex, age, BMI, emergent versus nonemergent surgery, prescriptions of antiplatelet drugs or beta blockers within four weeks before surgery, minutes of intraoperative hypotension, diabetes, hypertension, atrial fibrillation, Charleston Comorbidity Index, and work relative value units (ie, a surrogate for surgical complexity).

The cohort included 10,179 individuals with migraine (8.2%). Of the patients with migraine, 12.6% had migraine with aura.

Patients with migraine generally were younger, had higher BMI, and were more likely to be women. They were less likely to have diabetes or hypertension and to be taking antiplatelet drugs or beta blockers. Patients with migraine “were a little healthier” than the patients without migraine, Dr. Houle said.

In all, 771 patients had perioperative stroke, of whom 89 (11.5%) had migraine. About 0.6% of patients without migraine had perioperative stroke versus 0.9% of patients with migraine. The unadjusted odds ratio for stroke among migraineurs was 1.47, and the adjusted odds ratio was 1.75. “Individuals in this sample who had any migraine were at greater risk for stroke during the period after surgery, just like in the regular population,” said Dr. Houle. Although migraine without aura was not a statistically significant risk factor for stroke in the general population, it was after surgery.

Prediction Models

In one sensitivity analysis, the researchers determined each patient’s stroke risk based on known risk factors excluding migraine, such as age and cardiovascular disorders, and grouped patients by low, intermediate, and high levels of risk. Among patients in the low-risk group, the relative risk of stroke for patients with migraine versus patients without migraine was 3.5-fold higher. “These are people you would not have identified as having risk,” said Dr. Houle.

Future studies should try to identify the mechanisms involved in this relationship and assess interventions to mitigate the risk of stroke in patients with migraine who undergo surgery, Dr. Houle said.

Dr. Houle and colleagues have created a stroke prediction model that includes migraine and will “give surgeons a risk model to predict the risk of stroke for their patients,” he said. The model will “realize the risks that we uncovered in this study.”

—Jake Remaly

Suggested Reading

Schürks M, Rist PM, Bigal ME, et al. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ. 2009;339:b3914.

Spector JT, Kahn SR, Jones MR, et al. Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med. 2010;123(7):612-624.

Timm FP, Houle TT, Grabitz SD, et al. Migraine and risk of perioperative ischemic stroke and hospital readmission: hospital based registry study. BMJ. 2017;356:i6635.

ASHEVILLE, NC—The 30 days after surgery are a period of exceptionally high risk for ischemic stroke, and the risk is greater for patients with migraine, compared with patients without migraine, according to a lecture at the Eighth Annual Scientific Meeting of the Southern Headache Society.

“When we send individuals with migraine to surgery who do not have classical risk factors [for stroke], they may, in fact, still be at risk for stroke during the perioperative period,” said Timothy T. Houle, PhD, Associate Professor of Anesthesia at Massachusetts General Hospital and Harvard Medical School in Boston.

Dr. Houle described a hospital-based registry study that he and his colleagues published in BMJ. They found that the rate of ischemic stroke within 30 days of surgery was about 240 strokes per 100,000 patients without migraine, whereas among migraineurs, the rate was 430 strokes per 100,000 patients. Among patients with migraine without aura, the rate was 390 strokes per 100,000 patients, and among patients with migraine with aura, the rate was 630 strokes per 100,000 patients. “If you have migraine with aura, your risk of having a stroke is appreciably elevated and not trivial,” Dr. Houle said. “This is something to take seriously.”

The Migraine–Stroke Connection

Researchers consistently have found that migraine is associated with an increased risk of ischemic stroke in the general population, but the relationship has been challenging to study.

Possible mechanisms underlying the relationship between migraine and stroke include comorbidities (eg, higher BMI and increased cardiovascular risk factors) and medication use. In addition, research suggests that cortical spreading depression might make migraineurs’ brains more susceptible to stroke, Dr. Houle said. Patent foramen ovale, arterial dissection, coagulation dysfunction, endothelial dysfunction, or a genotype that increases the risk of migraine and stroke are other potential pathways.

Spector et al conducted a meta-analysis of 21 studies and concluded that migraine appears to be independently associated with a twofold increased risk of ischemic stroke. A meta-analysis by Schürks et al found that the relative risk of stroke was about 1.73 for patients with migraine and 2.16 for patients with migraine with aura. Migraine without aura was associated with a relative risk of 1.23, but this result was not statistically significant.

Dr. Houle and colleagues hypothesized that focusing on the perioperative period, when stroke is more prevalent, “could yield unique insights into the migraine–stroke connection,” he said.

Ischemic stroke in the perioperative period occurs at a rate of about 100 strokes per 100,000 individuals for the lowest-risk surgeries. After major cardiac and vascular surgery, the risk may be between 600 and 7,400 strokes per 100,000 individuals. “We have … a risk period that is intensely elevated for patients about to receive surgical insult,” Dr. Houle said. The increased risk may result from the indication for the surgery, as well as factors related to surgery itself, such as surgical stress, inflammatory responses, and intraoperative hypotension.

A Retrospective Cohort Study

Based on the increased risk of stroke in the general population, the investigators hypothesized that individuals with migraine also would have an elevated risk of stroke in the 30 days after surgery. They analyzed data from 124,558 patients (mean age, 52.6; 54.5% women) who underwent surgery between 2007 and 2014 at Massachusetts General Hospital and two satellite campuses. They included patients who had surgery under general anesthesia with mechanical ventilation and were successfully extubated. They used ICD-9 codes to identify patients with migraine. The primary outcome was ischemic stroke within 30 days. They identified strokes using ICD-9 codes and confirmed strokes by reviewing brain scans and medical records.

The investigators adjusted for confounders, including sex, age, BMI, emergent versus nonemergent surgery, prescriptions of antiplatelet drugs or beta blockers within four weeks before surgery, minutes of intraoperative hypotension, diabetes, hypertension, atrial fibrillation, Charleston Comorbidity Index, and work relative value units (ie, a surrogate for surgical complexity).

The cohort included 10,179 individuals with migraine (8.2%). Of the patients with migraine, 12.6% had migraine with aura.

Patients with migraine generally were younger, had higher BMI, and were more likely to be women. They were less likely to have diabetes or hypertension and to be taking antiplatelet drugs or beta blockers. Patients with migraine “were a little healthier” than the patients without migraine, Dr. Houle said.

In all, 771 patients had perioperative stroke, of whom 89 (11.5%) had migraine. About 0.6% of patients without migraine had perioperative stroke versus 0.9% of patients with migraine. The unadjusted odds ratio for stroke among migraineurs was 1.47, and the adjusted odds ratio was 1.75. “Individuals in this sample who had any migraine were at greater risk for stroke during the period after surgery, just like in the regular population,” said Dr. Houle. Although migraine without aura was not a statistically significant risk factor for stroke in the general population, it was after surgery.

Prediction Models

In one sensitivity analysis, the researchers determined each patient’s stroke risk based on known risk factors excluding migraine, such as age and cardiovascular disorders, and grouped patients by low, intermediate, and high levels of risk. Among patients in the low-risk group, the relative risk of stroke for patients with migraine versus patients without migraine was 3.5-fold higher. “These are people you would not have identified as having risk,” said Dr. Houle.

Future studies should try to identify the mechanisms involved in this relationship and assess interventions to mitigate the risk of stroke in patients with migraine who undergo surgery, Dr. Houle said.

Dr. Houle and colleagues have created a stroke prediction model that includes migraine and will “give surgeons a risk model to predict the risk of stroke for their patients,” he said. The model will “realize the risks that we uncovered in this study.”

—Jake Remaly

Suggested Reading

Schürks M, Rist PM, Bigal ME, et al. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ. 2009;339:b3914.

Spector JT, Kahn SR, Jones MR, et al. Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med. 2010;123(7):612-624.

Timm FP, Houle TT, Grabitz SD, et al. Migraine and risk of perioperative ischemic stroke and hospital readmission: hospital based registry study. BMJ. 2017;356:i6635.

ASHEVILLE, NC—Patients with intractable cluster headache present an urgent challenge to neurologists. The disorder is associated with “the worst pain you can experience,” and most patients have suicidal ideation, said Todd Rozen, MD, a neurologist at Mayo Clinic in Jacksonville, Florida. To help these patients, it is necessary to confirm the diagnosis, conduct proper evaluations for secondary mimics, and choose the most appropriate and effective treatments, he said at the Eighth Annual Scientific Meeting of the Southern Headache Society.

Making the Diagnosis

The current diagnostic criteria for cluster headache include severe unilateral orbital, supraorbital, or temporal pain that lasts for 15 minutes to 180 minutes when untreated. Patients may have conjunctival injection, lacrimation, rhinorrhea, or a sense of restlessness. Most patients have between one and three attacks per day, and the average attack lasts from 60 minutes to 75 minutes, said Dr. Rozen. Migrainous features such as photophobia, phonophobia, and nausea are common in cluster headache, but should not affect the diagnosis. If the duration and frequency of attacks are consistent with cluster headache, then that is the correct diagnosis, said Dr. Rozen.

Like migraine, cluster headache may be episodic or chronic. Episodic cluster headache is more likely to remit than chronic cluster headache, but the former may transition to the latter.

The European Headache Fed­er­ation has defined treatment-refractory cluster headache as cluster headache that fails to respond to more than three typical preventive medicines. Regardless of whether the disorder is episodic or chronic for a given patient, it may become intractable, said Dr. Rozen.

Reasons for Intractability

One potential reason for intractability is an incorrect diagnosis. Cluster headache is a trigeminal autonomic cephalalgia (TAC), and a person with a diagnosis of intractable cluster headache may in fact have a different TAC. The TACs form a spectrum, and a patient’s disorder may change from cluster headache to paroxysmal hemicrania, for example, said Dr. Rozen. “Always think of [attack] duration and frequency to make your diagnosis.”

Another potential reason for intractability is that the headache is secondary to a lesion. The secondary headache disorders often mimic the primary headache disorders, but do not respond to typical medications. The three most common causes of secondary cluster headache are secretory pituitary tumors, carotid dissections, and cavernous sinus lesions. “Every cluster patient … deserves a brain MRI with or without the pituitary cuts, an MR angiogram (both head and neck with dissection protocol), and pituitary hormones,” said Dr. Rozen.

Established and Emerging Acute Treatments

The most common acute treatments for cluster headache are sumatriptan injection or nasal spray and high-flow oxygen. Most patients respond to these treatments, but for those who do not, neurologists may consider options such as dihydroergotamine (DHE) injection, ergotamines, intranasal lidocaine, olanzapine, chlorpromazine suppository, and indomethacin suppository. Data from the US Cluster Headache Survey, however, indicate that less than 45% of patients respond to these treatments.

Most patients with cluster headache do not respond to oral acute medications because they have slow onsets of action. An exception is zolmitriptan, which is administered in a 10-mg dose, as opposed to the traditional 5-mg oral dose. Another acute nonmedicinal therapy is a suboccipital nerve block, which often terminates a headache within a minute, said Dr. Rozen.

In addition, new acute treatments for cluster headache have emerged. One is the delivery of oxygen by demand valve, which provides oxygen according to the user’s respiration rate and tidal volume. Unlike previous delivery methods, which deliver a small amount of ambient air, the demand valve delivers 100% pure oxygen. The demand valve also allows hyperventilation, which may be crucial for effective treatment, said Dr. Rozen. Several studies have suggested that demand-valve oxygen may be more effective than the typically prescribed continuous-flow oxygen administered through a nonrebreather face mask.

In 2017, the FDA cleared gamma­Core, a noninvasive vagus nerve stimulation (VNS) device, for the acute treatment of episodic cluster headache. Patients can use the device to deliver two-minute doses of stimulation through a conductive gel applied to the neck. The treatment may be considered for patients who have not responded to other acute medications, said Dr. Rozen.

In a study by Schoenen and colleagues, 67% of patients with chronic cluster headache who were treated with on-demand sphenopalatine ganglion stimulation achieved pain relief. In comparison, 7% of patients who received sham treatment achieved pain relief. Sphenopalatine ganglion stimulation is not approved in the United States, however.

Preventive Treatment Is Essential

“It is absolutely key to treat cluster headaches with preventives unless [the patients] have two- to three-week cycles [of attacks],” said Dr. Rozen. Verapamil, lithium, valproic acid, daily corticosteroids, topiramate, melatonin, and methylergonovine can be used for the prevention of cluster headache attacks. Daily corticosteroids are appropriate if the patient’s cycles last for two to three weeks, said Dr. Rozen. Topiramate appears to be more effective in women with cluster headache than men.

Until a patient has failed to respond to all of these preventive treatments, it may be inappropriate to describe his or her disorder as refractory, said Dr. Rozen. If a patient partially responds to one preventive therapy, another can be added. Combination therapy for cluster headache is common, and as many as three medications can be administered concomitantly, said Dr. Rozen. Unlike for other headache disorders, doses for cluster headache can be raised to high levels.

Data from the US Cluster Headache Survey, though, show that less than half of patients respond to preventive treatments. In addition, more than 70% of respondents had never received any preventive treatment, “which is quite scary for such a horrible disorder,” said Dr. Rozen.

Other Treatments May Be Effective

The literature provides a small amount of evidence to support additional treatments for cluster headache. Three studies have indicated a benefit of daily treatment with triptans, particularly frovatriptan, said Dr. Rozen. Data also support transdermal clonidine, indomethacin, and intranasal civamide. “Gabapentin is a wonderful add-on therapy. It is not good as a primary therapy,” said Dr. Rozen. Neurologists also may choose baclofen or mycophenolate mofetil.

Reports indicate that sodium oxybate can alleviate episodic and chronic cluster headache, especially if the patient has multiple nocturnal headaches, said Dr. Rozen. Three trials have examined hyperbaric oxygen, and a placebo-controlled trial found a benefit of warfarin. Rozen, and later Nobre et al, reported that clomiphene was effective and could change the pattern of cluster headache attacks.

Between 40% and 50% of patients respond to a single suboccipital nerve block as preventive therapy. Dr. Rozen has reported on high-volume suboccipital nerve blocks that administer 9 cm3 of 1% lidocaine and a small amount of corticosteroid. This treatment has “an excellent preventive effect in chronic refractory cluster headache,” he added. “Most of these patients have failed eight to 10 preventive [treatments]…. If you fail block one, you will most likely not respond to blocks.” Many patients who respond to this block could respond well to greater occipital nerve stimulation, but it is not easy to get insurance coverage for this treatment, said Dr. Rozen.

Finally, a new class of medications may be approved for cluster headache prevention. The monoclonal calcitonin gene-related peptide antibodies, which have been approved for migraine prevention, appear to be effective for episodic cluster headache in clinical trials. These treatments may not show efficacy for chronic cluster headache, however.

—Erik Greb

Suggested Reading

Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA. 2009;302(22):2451-2457.

Nobre ME, Peres MFP, Moreira PF Filho, Leal AJ. Clomiphene treatment may be effective in refractory episodic and chronic cluster headache. Arq Neuropsiquiatr. 2017;75(9):620-624.

Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012;52(1):99-113.

Rozen TD, Fishman RS. Demand valve oxygen: a promising new oxygen delivery system for the acute treatment of cluster headache. Pain Med. 2013;14(4):455-459.

Schoenen J, Jensen RH, Lantéri-Minet M, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013;33(10):816-830.

ASHEVILLE, NC—Patients with intractable cluster headache present an urgent challenge to neurologists. The disorder is associated with “the worst pain you can experience,” and most patients have suicidal ideation, said Todd Rozen, MD, a neurologist at Mayo Clinic in Jacksonville, Florida. To help these patients, it is necessary to confirm the diagnosis, conduct proper evaluations for secondary mimics, and choose the most appropriate and effective treatments, he said at the Eighth Annual Scientific Meeting of the Southern Headache Society.

Making the Diagnosis

The current diagnostic criteria for cluster headache include severe unilateral orbital, supraorbital, or temporal pain that lasts for 15 minutes to 180 minutes when untreated. Patients may have conjunctival injection, lacrimation, rhinorrhea, or a sense of restlessness. Most patients have between one and three attacks per day, and the average attack lasts from 60 minutes to 75 minutes, said Dr. Rozen. Migrainous features such as photophobia, phonophobia, and nausea are common in cluster headache, but should not affect the diagnosis. If the duration and frequency of attacks are consistent with cluster headache, then that is the correct diagnosis, said Dr. Rozen.

Like migraine, cluster headache may be episodic or chronic. Episodic cluster headache is more likely to remit than chronic cluster headache, but the former may transition to the latter.

The European Headache Fed­er­ation has defined treatment-refractory cluster headache as cluster headache that fails to respond to more than three typical preventive medicines. Regardless of whether the disorder is episodic or chronic for a given patient, it may become intractable, said Dr. Rozen.

Reasons for Intractability

One potential reason for intractability is an incorrect diagnosis. Cluster headache is a trigeminal autonomic cephalalgia (TAC), and a person with a diagnosis of intractable cluster headache may in fact have a different TAC. The TACs form a spectrum, and a patient’s disorder may change from cluster headache to paroxysmal hemicrania, for example, said Dr. Rozen. “Always think of [attack] duration and frequency to make your diagnosis.”

Another potential reason for intractability is that the headache is secondary to a lesion. The secondary headache disorders often mimic the primary headache disorders, but do not respond to typical medications. The three most common causes of secondary cluster headache are secretory pituitary tumors, carotid dissections, and cavernous sinus lesions. “Every cluster patient … deserves a brain MRI with or without the pituitary cuts, an MR angiogram (both head and neck with dissection protocol), and pituitary hormones,” said Dr. Rozen.

Established and Emerging Acute Treatments

The most common acute treatments for cluster headache are sumatriptan injection or nasal spray and high-flow oxygen. Most patients respond to these treatments, but for those who do not, neurologists may consider options such as dihydroergotamine (DHE) injection, ergotamines, intranasal lidocaine, olanzapine, chlorpromazine suppository, and indomethacin suppository. Data from the US Cluster Headache Survey, however, indicate that less than 45% of patients respond to these treatments.

Most patients with cluster headache do not respond to oral acute medications because they have slow onsets of action. An exception is zolmitriptan, which is administered in a 10-mg dose, as opposed to the traditional 5-mg oral dose. Another acute nonmedicinal therapy is a suboccipital nerve block, which often terminates a headache within a minute, said Dr. Rozen.

In addition, new acute treatments for cluster headache have emerged. One is the delivery of oxygen by demand valve, which provides oxygen according to the user’s respiration rate and tidal volume. Unlike previous delivery methods, which deliver a small amount of ambient air, the demand valve delivers 100% pure oxygen. The demand valve also allows hyperventilation, which may be crucial for effective treatment, said Dr. Rozen. Several studies have suggested that demand-valve oxygen may be more effective than the typically prescribed continuous-flow oxygen administered through a nonrebreather face mask.

In 2017, the FDA cleared gamma­Core, a noninvasive vagus nerve stimulation (VNS) device, for the acute treatment of episodic cluster headache. Patients can use the device to deliver two-minute doses of stimulation through a conductive gel applied to the neck. The treatment may be considered for patients who have not responded to other acute medications, said Dr. Rozen.

In a study by Schoenen and colleagues, 67% of patients with chronic cluster headache who were treated with on-demand sphenopalatine ganglion stimulation achieved pain relief. In comparison, 7% of patients who received sham treatment achieved pain relief. Sphenopalatine ganglion stimulation is not approved in the United States, however.

Preventive Treatment Is Essential

“It is absolutely key to treat cluster headaches with preventives unless [the patients] have two- to three-week cycles [of attacks],” said Dr. Rozen. Verapamil, lithium, valproic acid, daily corticosteroids, topiramate, melatonin, and methylergonovine can be used for the prevention of cluster headache attacks. Daily corticosteroids are appropriate if the patient’s cycles last for two to three weeks, said Dr. Rozen. Topiramate appears to be more effective in women with cluster headache than men.

Until a patient has failed to respond to all of these preventive treatments, it may be inappropriate to describe his or her disorder as refractory, said Dr. Rozen. If a patient partially responds to one preventive therapy, another can be added. Combination therapy for cluster headache is common, and as many as three medications can be administered concomitantly, said Dr. Rozen. Unlike for other headache disorders, doses for cluster headache can be raised to high levels.

Data from the US Cluster Headache Survey, though, show that less than half of patients respond to preventive treatments. In addition, more than 70% of respondents had never received any preventive treatment, “which is quite scary for such a horrible disorder,” said Dr. Rozen.

Other Treatments May Be Effective

The literature provides a small amount of evidence to support additional treatments for cluster headache. Three studies have indicated a benefit of daily treatment with triptans, particularly frovatriptan, said Dr. Rozen. Data also support transdermal clonidine, indomethacin, and intranasal civamide. “Gabapentin is a wonderful add-on therapy. It is not good as a primary therapy,” said Dr. Rozen. Neurologists also may choose baclofen or mycophenolate mofetil.

Reports indicate that sodium oxybate can alleviate episodic and chronic cluster headache, especially if the patient has multiple nocturnal headaches, said Dr. Rozen. Three trials have examined hyperbaric oxygen, and a placebo-controlled trial found a benefit of warfarin. Rozen, and later Nobre et al, reported that clomiphene was effective and could change the pattern of cluster headache attacks.

Between 40% and 50% of patients respond to a single suboccipital nerve block as preventive therapy. Dr. Rozen has reported on high-volume suboccipital nerve blocks that administer 9 cm3 of 1% lidocaine and a small amount of corticosteroid. This treatment has “an excellent preventive effect in chronic refractory cluster headache,” he added. “Most of these patients have failed eight to 10 preventive [treatments]…. If you fail block one, you will most likely not respond to blocks.” Many patients who respond to this block could respond well to greater occipital nerve stimulation, but it is not easy to get insurance coverage for this treatment, said Dr. Rozen.

Finally, a new class of medications may be approved for cluster headache prevention. The monoclonal calcitonin gene-related peptide antibodies, which have been approved for migraine prevention, appear to be effective for episodic cluster headache in clinical trials. These treatments may not show efficacy for chronic cluster headache, however.

—Erik Greb

Suggested Reading

Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA. 2009;302(22):2451-2457.

Nobre ME, Peres MFP, Moreira PF Filho, Leal AJ. Clomiphene treatment may be effective in refractory episodic and chronic cluster headache. Arq Neuropsiquiatr. 2017;75(9):620-624.

Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012;52(1):99-113.

Rozen TD, Fishman RS. Demand valve oxygen: a promising new oxygen delivery system for the acute treatment of cluster headache. Pain Med. 2013;14(4):455-459.

Schoenen J, Jensen RH, Lantéri-Minet M, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013;33(10):816-830.

ASHEVILLE, NC—Patients with intractable cluster headache present an urgent challenge to neurologists. The disorder is associated with “the worst pain you can experience,” and most patients have suicidal ideation, said Todd Rozen, MD, a neurologist at Mayo Clinic in Jacksonville, Florida. To help these patients, it is necessary to confirm the diagnosis, conduct proper evaluations for secondary mimics, and choose the most appropriate and effective treatments, he said at the Eighth Annual Scientific Meeting of the Southern Headache Society.

Making the Diagnosis

The current diagnostic criteria for cluster headache include severe unilateral orbital, supraorbital, or temporal pain that lasts for 15 minutes to 180 minutes when untreated. Patients may have conjunctival injection, lacrimation, rhinorrhea, or a sense of restlessness. Most patients have between one and three attacks per day, and the average attack lasts from 60 minutes to 75 minutes, said Dr. Rozen. Migrainous features such as photophobia, phonophobia, and nausea are common in cluster headache, but should not affect the diagnosis. If the duration and frequency of attacks are consistent with cluster headache, then that is the correct diagnosis, said Dr. Rozen.

Like migraine, cluster headache may be episodic or chronic. Episodic cluster headache is more likely to remit than chronic cluster headache, but the former may transition to the latter.

The European Headache Fed­er­ation has defined treatment-refractory cluster headache as cluster headache that fails to respond to more than three typical preventive medicines. Regardless of whether the disorder is episodic or chronic for a given patient, it may become intractable, said Dr. Rozen.

Reasons for Intractability

One potential reason for intractability is an incorrect diagnosis. Cluster headache is a trigeminal autonomic cephalalgia (TAC), and a person with a diagnosis of intractable cluster headache may in fact have a different TAC. The TACs form a spectrum, and a patient’s disorder may change from cluster headache to paroxysmal hemicrania, for example, said Dr. Rozen. “Always think of [attack] duration and frequency to make your diagnosis.”

Another potential reason for intractability is that the headache is secondary to a lesion. The secondary headache disorders often mimic the primary headache disorders, but do not respond to typical medications. The three most common causes of secondary cluster headache are secretory pituitary tumors, carotid dissections, and cavernous sinus lesions. “Every cluster patient … deserves a brain MRI with or without the pituitary cuts, an MR angiogram (both head and neck with dissection protocol), and pituitary hormones,” said Dr. Rozen.

Established and Emerging Acute Treatments

The most common acute treatments for cluster headache are sumatriptan injection or nasal spray and high-flow oxygen. Most patients respond to these treatments, but for those who do not, neurologists may consider options such as dihydroergotamine (DHE) injection, ergotamines, intranasal lidocaine, olanzapine, chlorpromazine suppository, and indomethacin suppository. Data from the US Cluster Headache Survey, however, indicate that less than 45% of patients respond to these treatments.

Most patients with cluster headache do not respond to oral acute medications because they have slow onsets of action. An exception is zolmitriptan, which is administered in a 10-mg dose, as opposed to the traditional 5-mg oral dose. Another acute nonmedicinal therapy is a suboccipital nerve block, which often terminates a headache within a minute, said Dr. Rozen.

In addition, new acute treatments for cluster headache have emerged. One is the delivery of oxygen by demand valve, which provides oxygen according to the user’s respiration rate and tidal volume. Unlike previous delivery methods, which deliver a small amount of ambient air, the demand valve delivers 100% pure oxygen. The demand valve also allows hyperventilation, which may be crucial for effective treatment, said Dr. Rozen. Several studies have suggested that demand-valve oxygen may be more effective than the typically prescribed continuous-flow oxygen administered through a nonrebreather face mask.

In 2017, the FDA cleared gamma­Core, a noninvasive vagus nerve stimulation (VNS) device, for the acute treatment of episodic cluster headache. Patients can use the device to deliver two-minute doses of stimulation through a conductive gel applied to the neck. The treatment may be considered for patients who have not responded to other acute medications, said Dr. Rozen.

In a study by Schoenen and colleagues, 67% of patients with chronic cluster headache who were treated with on-demand sphenopalatine ganglion stimulation achieved pain relief. In comparison, 7% of patients who received sham treatment achieved pain relief. Sphenopalatine ganglion stimulation is not approved in the United States, however.

Preventive Treatment Is Essential

“It is absolutely key to treat cluster headaches with preventives unless [the patients] have two- to three-week cycles [of attacks],” said Dr. Rozen. Verapamil, lithium, valproic acid, daily corticosteroids, topiramate, melatonin, and methylergonovine can be used for the prevention of cluster headache attacks. Daily corticosteroids are appropriate if the patient’s cycles last for two to three weeks, said Dr. Rozen. Topiramate appears to be more effective in women with cluster headache than men.

Until a patient has failed to respond to all of these preventive treatments, it may be inappropriate to describe his or her disorder as refractory, said Dr. Rozen. If a patient partially responds to one preventive therapy, another can be added. Combination therapy for cluster headache is common, and as many as three medications can be administered concomitantly, said Dr. Rozen. Unlike for other headache disorders, doses for cluster headache can be raised to high levels.

Data from the US Cluster Headache Survey, though, show that less than half of patients respond to preventive treatments. In addition, more than 70% of respondents had never received any preventive treatment, “which is quite scary for such a horrible disorder,” said Dr. Rozen.

Other Treatments May Be Effective

The literature provides a small amount of evidence to support additional treatments for cluster headache. Three studies have indicated a benefit of daily treatment with triptans, particularly frovatriptan, said Dr. Rozen. Data also support transdermal clonidine, indomethacin, and intranasal civamide. “Gabapentin is a wonderful add-on therapy. It is not good as a primary therapy,” said Dr. Rozen. Neurologists also may choose baclofen or mycophenolate mofetil.

Reports indicate that sodium oxybate can alleviate episodic and chronic cluster headache, especially if the patient has multiple nocturnal headaches, said Dr. Rozen. Three trials have examined hyperbaric oxygen, and a placebo-controlled trial found a benefit of warfarin. Rozen, and later Nobre et al, reported that clomiphene was effective and could change the pattern of cluster headache attacks.

Between 40% and 50% of patients respond to a single suboccipital nerve block as preventive therapy. Dr. Rozen has reported on high-volume suboccipital nerve blocks that administer 9 cm3 of 1% lidocaine and a small amount of corticosteroid. This treatment has “an excellent preventive effect in chronic refractory cluster headache,” he added. “Most of these patients have failed eight to 10 preventive [treatments]…. If you fail block one, you will most likely not respond to blocks.” Many patients who respond to this block could respond well to greater occipital nerve stimulation, but it is not easy to get insurance coverage for this treatment, said Dr. Rozen.

Finally, a new class of medications may be approved for cluster headache prevention. The monoclonal calcitonin gene-related peptide antibodies, which have been approved for migraine prevention, appear to be effective for episodic cluster headache in clinical trials. These treatments may not show efficacy for chronic cluster headache, however.

—Erik Greb

Suggested Reading

Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA. 2009;302(22):2451-2457.

Nobre ME, Peres MFP, Moreira PF Filho, Leal AJ. Clomiphene treatment may be effective in refractory episodic and chronic cluster headache. Arq Neuropsiquiatr. 2017;75(9):620-624.

Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012;52(1):99-113.

Rozen TD, Fishman RS. Demand valve oxygen: a promising new oxygen delivery system for the acute treatment of cluster headache. Pain Med. 2013;14(4):455-459.

Schoenen J, Jensen RH, Lantéri-Minet M, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013;33(10):816-830.

Researchers did not find any difference in number of self-reported premenstrual syndrome (PMS) symptoms between migraineurs with and without menstrual migraine (MM), according to a recent study. A total of 237 women from the general population who self-reported migraine in at least 50% of their menstrual periods were invited to a clinical interview and diagnosed by a neurologist. All women were asked to complete a self-administered form containing 11 questions about PMS symptoms adapted from the Diagnostic and Statistical Manual of Mental Disorders. In addition, each participant completed the Headache Impact test (HIT-6) and Migraine Disability Assessment Score (MIDAS). They found:

• 193 women returned a complete PMS questionnaire, of which 67 women were excluded from the analyses due to current use of hormonal contraception (n=61) or because they did not fulfill the ICHD-criteria for migraine (n=6).
• Among the remaining 126 migraineurs, 78 had MM and 48 had non-menstrually related migraine.
• PMS symptoms were equally frequent in migraineurs with and without MM (5.4 vs 5.9).
• Women with MM reported more migraine days/month, longer lasting migraine attacks, and higher HIT-6 scores than those without MM, but MIDAS scores were similar.

Vetvik KG, MacGregor EA, Lundqyist C, Russell MB. Symptoms of premenstrual syndrome in female migraineurs with and without menstrual migraine. [Published online ahead of print October 17, 2018]. J Headache Pain. doi:10.1186/s10194-018-0931-6.

Researchers did not find any difference in number of self-reported premenstrual syndrome (PMS) symptoms between migraineurs with and without menstrual migraine (MM), according to a recent study. A total of 237 women from the general population who self-reported migraine in at least 50% of their menstrual periods were invited to a clinical interview and diagnosed by a neurologist. All women were asked to complete a self-administered form containing 11 questions about PMS symptoms adapted from the Diagnostic and Statistical Manual of Mental Disorders. In addition, each participant completed the Headache Impact test (HIT-6) and Migraine Disability Assessment Score (MIDAS). They found:

• 193 women returned a complete PMS questionnaire, of which 67 women were excluded from the analyses due to current use of hormonal contraception (n=61) or because they did not fulfill the ICHD-criteria for migraine (n=6).
• Among the remaining 126 migraineurs, 78 had MM and 48 had non-menstrually related migraine.
• PMS symptoms were equally frequent in migraineurs with and without MM (5.4 vs 5.9).
• Women with MM reported more migraine days/month, longer lasting migraine attacks, and higher HIT-6 scores than those without MM, but MIDAS scores were similar.

Vetvik KG, MacGregor EA, Lundqyist C, Russell MB. Symptoms of premenstrual syndrome in female migraineurs with and without menstrual migraine. [Published online ahead of print October 17, 2018]. J Headache Pain. doi:10.1186/s10194-018-0931-6.

Researchers did not find any difference in number of self-reported premenstrual syndrome (PMS) symptoms between migraineurs with and without menstrual migraine (MM), according to a recent study. A total of 237 women from the general population who self-reported migraine in at least 50% of their menstrual periods were invited to a clinical interview and diagnosed by a neurologist. All women were asked to complete a self-administered form containing 11 questions about PMS symptoms adapted from the Diagnostic and Statistical Manual of Mental Disorders. In addition, each participant completed the Headache Impact test (HIT-6) and Migraine Disability Assessment Score (MIDAS). They found:

• 193 women returned a complete PMS questionnaire, of which 67 women were excluded from the analyses due to current use of hormonal contraception (n=61) or because they did not fulfill the ICHD-criteria for migraine (n=6).
• Among the remaining 126 migraineurs, 78 had MM and 48 had non-menstrually related migraine.
• PMS symptoms were equally frequent in migraineurs with and without MM (5.4 vs 5.9).
• Women with MM reported more migraine days/month, longer lasting migraine attacks, and higher HIT-6 scores than those without MM, but MIDAS scores were similar.

Vetvik KG, MacGregor EA, Lundqyist C, Russell MB. Symptoms of premenstrual syndrome in female migraineurs with and without menstrual migraine. [Published online ahead of print October 17, 2018]. J Headache Pain. doi:10.1186/s10194-018-0931-6.

Typical aura without headache, a rare subtype of migraine, occurs exclusively in 4% patients with migraine, and may take place at some point in 38% of patients with migraine with aura, according to recent study. Furthermore, typical aura without headache, also known as migraine aura without headache or acephalgic migraine, commonly presents with visual aura without headache, brainstem aura without headache, and can also develop later in life, known as late-onset migraine accompaniment. Its pathophysiology is suggested to be similar to classic migraines, with cortical spreading depression leading to aura formation but without an associated headache. Presently, no clinical trials have been performed to evaluate treatment options, but case reports suggest that most patients will respond to the traditional treatments for migraine with aura.

Shah DR, Dilwali S, Friedman DI. Migraine aura without headache. Curr Pain Headache Rep. 2018;22:77. doi:10.1007/s11916-018-0725-1.

Typical aura without headache, a rare subtype of migraine, occurs exclusively in 4% patients with migraine, and may take place at some point in 38% of patients with migraine with aura, according to recent study. Furthermore, typical aura without headache, also known as migraine aura without headache or acephalgic migraine, commonly presents with visual aura without headache, brainstem aura without headache, and can also develop later in life, known as late-onset migraine accompaniment. Its pathophysiology is suggested to be similar to classic migraines, with cortical spreading depression leading to aura formation but without an associated headache. Presently, no clinical trials have been performed to evaluate treatment options, but case reports suggest that most patients will respond to the traditional treatments for migraine with aura.

Shah DR, Dilwali S, Friedman DI. Migraine aura without headache. Curr Pain Headache Rep. 2018;22:77. doi:10.1007/s11916-018-0725-1.

Typical aura without headache, a rare subtype of migraine, occurs exclusively in 4% patients with migraine, and may take place at some point in 38% of patients with migraine with aura, according to recent study. Furthermore, typical aura without headache, also known as migraine aura without headache or acephalgic migraine, commonly presents with visual aura without headache, brainstem aura without headache, and can also develop later in life, known as late-onset migraine accompaniment. Its pathophysiology is suggested to be similar to classic migraines, with cortical spreading depression leading to aura formation but without an associated headache. Presently, no clinical trials have been performed to evaluate treatment options, but case reports suggest that most patients will respond to the traditional treatments for migraine with aura.

Shah DR, Dilwali S, Friedman DI. Migraine aura without headache. Curr Pain Headache Rep. 2018;22:77. doi:10.1007/s11916-018-0725-1.

Patients with migraines and patients classified as Caucasian had higher odds of being diagnosed with transient global amnesia (TGA), according to a recent study. All minority populations, however, showed a lower rate of diagnosis that fell short of statistical significance.  Data were obtained from the Nationwide Inpatient Sample using ICD-9 and procedure codes. Descriptive and survey logistic regression analyses were conducted and adjusted for influence of comorbidities, demographic characteristics, and hospitalization-related factors. Researchers found:

• Patients with migraines were 5.98 times more likely to also have a diagnosis of TGA compared with patients without migraines.
• Similarly, patients with TGA were more likely to have hypertension, precerebral disease, and hyperlipidemia.
• The odds of being diagnosed with TGA was lower among African Americans and Hispanics as well as among patients classified as Asian/other, compared with Caucasians.
• TGA was associated with lower hospital charges ($14,242 vs $21,319), shorter hospital stays (mean days: 2.49 [SE=0.036] vs 4.72 [SE=0.025]), and routine hospital discharges (91.4% vs 74.5%).

Yi M, Sherzai AZ, Ani C, et al. Strong association between migraine and transient global amnesia: A National Inpatient Sample analysis. [Published online ahead of print October 11, 2018]. J Neuropsychiatry Clin Neurosci. doi:10.1176/appi.neuropsych.17120353.

Patients with migraines and patients classified as Caucasian had higher odds of being diagnosed with transient global amnesia (TGA), according to a recent study. All minority populations, however, showed a lower rate of diagnosis that fell short of statistical significance.  Data were obtained from the Nationwide Inpatient Sample using ICD-9 and procedure codes. Descriptive and survey logistic regression analyses were conducted and adjusted for influence of comorbidities, demographic characteristics, and hospitalization-related factors. Researchers found:

• Patients with migraines were 5.98 times more likely to also have a diagnosis of TGA compared with patients without migraines.
• Similarly, patients with TGA were more likely to have hypertension, precerebral disease, and hyperlipidemia.
• The odds of being diagnosed with TGA was lower among African Americans and Hispanics as well as among patients classified as Asian/other, compared with Caucasians.
• TGA was associated with lower hospital charges ($14,242 vs $21,319), shorter hospital stays (mean days: 2.49 [SE=0.036] vs 4.72 [SE=0.025]), and routine hospital discharges (91.4% vs 74.5%).

Yi M, Sherzai AZ, Ani C, et al. Strong association between migraine and transient global amnesia: A National Inpatient Sample analysis. [Published online ahead of print October 11, 2018]. J Neuropsychiatry Clin Neurosci. doi:10.1176/appi.neuropsych.17120353.

Patients with migraines and patients classified as Caucasian had higher odds of being diagnosed with transient global amnesia (TGA), according to a recent study. All minority populations, however, showed a lower rate of diagnosis that fell short of statistical significance.  Data were obtained from the Nationwide Inpatient Sample using ICD-9 and procedure codes. Descriptive and survey logistic regression analyses were conducted and adjusted for influence of comorbidities, demographic characteristics, and hospitalization-related factors. Researchers found:

• Patients with migraines were 5.98 times more likely to also have a diagnosis of TGA compared with patients without migraines.
• Similarly, patients with TGA were more likely to have hypertension, precerebral disease, and hyperlipidemia.
• The odds of being diagnosed with TGA was lower among African Americans and Hispanics as well as among patients classified as Asian/other, compared with Caucasians.
• TGA was associated with lower hospital charges ($14,242 vs $21,319), shorter hospital stays (mean days: 2.49 [SE=0.036] vs 4.72 [SE=0.025]), and routine hospital discharges (91.4% vs 74.5%).

Yi M, Sherzai AZ, Ani C, et al. Strong association between migraine and transient global amnesia: A National Inpatient Sample analysis. [Published online ahead of print October 11, 2018]. J Neuropsychiatry Clin Neurosci. doi:10.1176/appi.neuropsych.17120353.

CHICAGO—Among children with pediatric stroke, older age at stroke onset, unilateral infarct location, and stroke etiologies of arterio­pathy and chronic illness are associated with the development of poststroke headache, according to a retrospective study presented at the 47th Annual Meeting of the Child Neurology Society.

Poststroke headache is a common morbidity among patients with pediatric stroke, said Ana B. Chelse, MD, of Ann & Robert H. Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine in Chicago, and colleagues. In addition, poststroke headache in children may increase health care utilization, including neuroimaging and hospital admission, the investigators said.

Research indicates that about 20% of children with stroke have headache one year after the stroke, but data about poststroke headache in children are limited.

To assess the prevalence of novel headache after pediatric stroke, the characteristics of patients with poststroke headache, and the association between poststroke headache and stroke recurrence, Dr. Chelse and colleagues conducted a single-center, retrospective study of children 30 days to 18 years old with stroke. The researchers used an internal database to identify patients with a radiographically confirmed stroke at Lurie Children’s Hospital between January 1, 2008, and December 31, 2016.

Patients with ischemic stroke with secondary hemorrhage were included in the study, but patients with primary intracerebral hemorrhage were not. The researchers obtained patients’ demographic characteristics, infarct location, headache history, emergency department visits, neuroimaging, hospital admissions, and headache treatment from medical records. They defined stroke recurrence as an acute neurologic deficit with evidence of new radiologically confirmed ischemia.

The investigators analyzed the data using chi-squared and Fisher’s exact tests. They also performed exploratory multiple logistic regression analyses that included predictors deemed significant in univariate analyses.

Of 183 patients, 45 (24.5%) had poststroke headache. Headache developed at an average of 11.7 months after stroke. In multiple logistic regression analysis, older age and unilateral infarct location were associated with poststroke headache, as were stroke etiologies of arteriopathy (odds ratio [OR], 7.28) or chronic illness (OR, 1.90). Twenty-one patients (11.4%) had a recurrent stroke during the study period. Poststroke headache was associated with stroke recurrence in a univariate analysis, but the association did not reach statistical significance after multiple logistic regression. This association is “uncertain but potentially important,” Dr. Chelse and colleagues said.

CHICAGO—Among children with pediatric stroke, older age at stroke onset, unilateral infarct location, and stroke etiologies of arterio­pathy and chronic illness are associated with the development of poststroke headache, according to a retrospective study presented at the 47th Annual Meeting of the Child Neurology Society.

Poststroke headache is a common morbidity among patients with pediatric stroke, said Ana B. Chelse, MD, of Ann & Robert H. Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine in Chicago, and colleagues. In addition, poststroke headache in children may increase health care utilization, including neuroimaging and hospital admission, the investigators said.

Research indicates that about 20% of children with stroke have headache one year after the stroke, but data about poststroke headache in children are limited.

To assess the prevalence of novel headache after pediatric stroke, the characteristics of patients with poststroke headache, and the association between poststroke headache and stroke recurrence, Dr. Chelse and colleagues conducted a single-center, retrospective study of children 30 days to 18 years old with stroke. The researchers used an internal database to identify patients with a radiographically confirmed stroke at Lurie Children’s Hospital between January 1, 2008, and December 31, 2016.

Patients with ischemic stroke with secondary hemorrhage were included in the study, but patients with primary intracerebral hemorrhage were not. The researchers obtained patients’ demographic characteristics, infarct location, headache history, emergency department visits, neuroimaging, hospital admissions, and headache treatment from medical records. They defined stroke recurrence as an acute neurologic deficit with evidence of new radiologically confirmed ischemia.

The investigators analyzed the data using chi-squared and Fisher’s exact tests. They also performed exploratory multiple logistic regression analyses that included predictors deemed significant in univariate analyses.

Of 183 patients, 45 (24.5%) had poststroke headache. Headache developed at an average of 11.7 months after stroke. In multiple logistic regression analysis, older age and unilateral infarct location were associated with poststroke headache, as were stroke etiologies of arteriopathy (odds ratio [OR], 7.28) or chronic illness (OR, 1.90). Twenty-one patients (11.4%) had a recurrent stroke during the study period. Poststroke headache was associated with stroke recurrence in a univariate analysis, but the association did not reach statistical significance after multiple logistic regression. This association is “uncertain but potentially important,” Dr. Chelse and colleagues said.

CHICAGO—Among children with pediatric stroke, older age at stroke onset, unilateral infarct location, and stroke etiologies of arterio­pathy and chronic illness are associated with the development of poststroke headache, according to a retrospective study presented at the 47th Annual Meeting of the Child Neurology Society.

Poststroke headache is a common morbidity among patients with pediatric stroke, said Ana B. Chelse, MD, of Ann & Robert H. Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine in Chicago, and colleagues. In addition, poststroke headache in children may increase health care utilization, including neuroimaging and hospital admission, the investigators said.

Research indicates that about 20% of children with stroke have headache one year after the stroke, but data about poststroke headache in children are limited.

To assess the prevalence of novel headache after pediatric stroke, the characteristics of patients with poststroke headache, and the association between poststroke headache and stroke recurrence, Dr. Chelse and colleagues conducted a single-center, retrospective study of children 30 days to 18 years old with stroke. The researchers used an internal database to identify patients with a radiographically confirmed stroke at Lurie Children’s Hospital between January 1, 2008, and December 31, 2016.

Patients with ischemic stroke with secondary hemorrhage were included in the study, but patients with primary intracerebral hemorrhage were not. The researchers obtained patients’ demographic characteristics, infarct location, headache history, emergency department visits, neuroimaging, hospital admissions, and headache treatment from medical records. They defined stroke recurrence as an acute neurologic deficit with evidence of new radiologically confirmed ischemia.

The investigators analyzed the data using chi-squared and Fisher’s exact tests. They also performed exploratory multiple logistic regression analyses that included predictors deemed significant in univariate analyses.

Of 183 patients, 45 (24.5%) had poststroke headache. Headache developed at an average of 11.7 months after stroke. In multiple logistic regression analysis, older age and unilateral infarct location were associated with poststroke headache, as were stroke etiologies of arteriopathy (odds ratio [OR], 7.28) or chronic illness (OR, 1.90). Twenty-one patients (11.4%) had a recurrent stroke during the study period. Poststroke headache was associated with stroke recurrence in a univariate analysis, but the association did not reach statistical significance after multiple logistic regression. This association is “uncertain but potentially important,” Dr. Chelse and colleagues said.

ASHEVILLE, NC—New daily persistent headache is rare and difficult to treat. Although neurologists may be tempted to try a series of treatments until the patient improves, therapeutic success is more likely if the neurologist can identify a triggering event, said Todd Rozen, MD, a neurologist at Mayo Clinic in Jacksonville, Florida. Elements of the patient’s history or clinical examination also can guide treatment, he added at the Eighth Annual Scientific Meeting of the Southern Headache Society.

Patients Remember the Onset

New daily persistent headache was first described in 1986, and few researchers have studied it. It is a persistent headache with a clearly remembered onset. “Most [patients] can name the date it began or at least the month,” said Dr. Rozen. The headache becomes unremitting within 24 hours and must be present for longer than three months, according to the current diagnostic criteria. Patients may have a remitting form, a relapsing-remitting form, or a refractory form of the headache. The age of onset “can be as early as in the mid to late teens or early 20s, especially in the female population,” said Dr. Rozen. Age of onset also depends on the triggering event.

The pain typically is bilateral and moderate to severe. Although many patients may present with a tension-type headache, more than 60% have migrainous symptoms such as nausea, photophobia, or phonophobia, said Dr. Rozen.

The disorder is more common among women than among men. Between 10% and 13% of patients who present to headache clinics have new daily persistent headache, said Dr. Rozen. “It is either becoming more prevalent in the office, or we are better at recognizing it.”

Comparing Effects on the Genders

For a study published in 2016, Dr. Rozen examined 97 patients (65 women) with new daily persistent headache. Approximately 53% of patients could not identify a triggering event for their headache, which makes treatment “much more difficult,” said Dr. Rozen. Although the mean age of onset was younger in women (32.4) than men (35.8), the age of onset was the same between genders when Dr. Rozen examined for individual triggers.

The frequency of individual triggering events also was the same between genders, and these results suggest that each trigger may be associated with a discrete pathogenesis. Triggers included infection or flulike illness (22%), stressful life event (9%), surgery (9%), and other (7%). All patients who had identified surgery as a trigger had been intubated, and Dr. Rozen hypothesized that their headaches were cervicogenic. The younger patients who had undergone surgery were hypermobile, and the older patients had neck arthritis as predisposing risk factors for neck irritation with intubation.

A Somatoform Disorder?

The stubbornly refractory nature of this disorder has aroused the suspicion that it may be somatoform. In 2017, Uniyal and colleagues found that somatization, generalized anxiety disorder, depression, and catastrophization were more common in patients with new daily persistent headache, compared with patients with chronic low back pain and healthy controls.

Interpreting these data is difficult, said Dr. Rozen. They may indicate that these psychiatric comorbidities are risk factors for new daily persistent headache. An equally plausible interpretation is that these patients have a different disorder (eg, Ehlers-Danlos syndrome) that encompasses these common traits. Finally, symptoms such as depression and catastrophization may be sequelae of, rather than risk factors for, new daily persistent headache.

Researchers have found imaging abnormalities to be rare in patients with new daily persistent headache. About two-thirds of patients in a 2002 study had normal MRI or CT results, and the rest had nonspecific findings unrelated to the headache. Dr. Rozen found that white matter lesions were uncommon in patients with this disorder, except for those with a history of migraine or cardiovascular or cerebrovascular risk factors. CSF likewise generally is normal in patients with new daily persistent headache.

Triggers Suggest Treatments

Goadsby proposed in 2011 that new daily persistent headache is a syndrome rather than a single disorder. “I’m completely in agreement,” said Dr. Rozen. “However, I do believe that individuals who have the same triggering event have the same pathogenesis.” Identifying the triggering event and understanding the temporal profile of the first headache can enable the choice of appropriate therapy, he added.

A patient whose persistent headache begins with a thunderclap onset likely has a prolonged cerebral artery vasospasm. Dr. Rozen treated a patient whose initial headache was a thunderclap; imaging ultimately revealed that she had a vasospasm. Her headache responded to nimodipine within days. Nimodipine generally provides relief within three to five days, said Dr. Rozen. If it worsens the headache, then the patient does not have vasospasm, he added.

Many patients with new daily persistent headache have a physical presentation that suggests Marfan syndrome. This observation led Dr. Rozen to hypothesize that cervical hypermobility is a risk factor for new daily persistent headache. Hypermobile patients may put significant stress on the C1, C2, and C3 joints, which are “where the trigeminal–cervical complex comes together,” said Dr. Rozen. A long plane ride or appointment with the dentist could trigger new daily persistent headache. Treatment with onabotulinumtoxinA often helps these patients. High cervical blocks also can bring relief, said Dr. Rozen.

He and his colleagues recently identified a new subset of patients with new daily persistent headache. They were older female patients with a mean age of 57 who suddenly developed the disorder. Most of them reported that the pain was worst before they got out of bed in the morning. Within seconds of assuming the Trendelenburg position, these patients had intensified pain and nausea, suggesting CSF hypertension. The patients all responded to acetazolamide or spironolactone, which lowered CSF pressure. “I think these individuals developed cerebral vein insufficiency because of estrogen withdrawal based on their age. Plus, the majority were overweight, which can also raise baseline CSF pressure.”

Examination Should Incorporate Imaging

All patients with new daily persistent headache should undergo imaging, including a brain MRI with and without gadolinium, plus an MR venogram, which can identify CSF leaks and a cerebral vein thrombosis, which are leading secondary causes of the disorder. Neurologists could examine patients’ viral titers in addition if the history suggests a post infectious trigger. A lumbar puncture and measurement of opening CSF pressure are appropriate for patients who have not responded to medication.

Evidence From the Literature

The literature possibly supports the efficacy of several treatments in new daily persistent headache, but includes no placebo-controlled trials for them. Dr. Rozen found doxycycline to be helpful for several patients with elevated CSF tumor necrosis factor alpha.

Marmura and colleagues found that mexiletine reduced the severity of pain in patients with refractory new daily persistent headache. The treatment did not reduce headache frequency, however, and side effects were common.

In a retrospective study, Prakash et al followed 63 patients with new daily persistent headache for five years. They found that patients who received IV methyl prednisolone and sodium valproate had a better response than patients who received other therapies. They called for prospective and controlled studies to confirm this observation.

In general, aggressive initial therapy is warranted, “especially if you meet an individual within one year of headache onset,” said Dr. Rozen. The likelihood of response to therapy appears to decline with the duration of the headache. “Infusion therapy or inpatient therapy with IV medications, even with standard migraine protocols, may help break the cycle,” Dr. Rozen concluded.

—Erik Greb

Suggested Reading

Goadsby PJ. New daily persistent headache: a syndrome, not a discrete disorder. Headache. 2011;51(4):650-653.

Marmura MJ, Passero FC Jr, Young WB. Mexiletine for refractory chronic daily headache: a report of nine cases. Headache. 2008;48(10):1506-1510.

Prakash S, Saini S, Rana KR, Mahato P. Refining clinical features and therapeutic options of new daily persistent headache: a retrospective study of 63 patients in India. J Headache Pain. 2012;13(6):477-485.

Rozen TD. A new subtype of chronic daily headache presenting in older women. J Womens Health (Larchmt). 2018;27(2):203-208.

Rozen TD. Triggering events and new daily persistent headache: age and gender differences and insights on pathogenesis-a clinic-based study. Headache. 2016;56(1):164-173.

Uniyal R, Paliwal VK, Tripathi A. Psychiatric comorbidity in new daily persistent headache: a cross-sectional study. Eur J Pain. 2017;21(6):1031-1038.

ASHEVILLE, NC—New daily persistent headache is rare and difficult to treat. Although neurologists may be tempted to try a series of treatments until the patient improves, therapeutic success is more likely if the neurologist can identify a triggering event, said Todd Rozen, MD, a neurologist at Mayo Clinic in Jacksonville, Florida. Elements of the patient’s history or clinical examination also can guide treatment, he added at the Eighth Annual Scientific Meeting of the Southern Headache Society.

Patients Remember the Onset

New daily persistent headache was first described in 1986, and few researchers have studied it. It is a persistent headache with a clearly remembered onset. “Most [patients] can name the date it began or at least the month,” said Dr. Rozen. The headache becomes unremitting within 24 hours and must be present for longer than three months, according to the current diagnostic criteria. Patients may have a remitting form, a relapsing-remitting form, or a refractory form of the headache. The age of onset “can be as early as in the mid to late teens or early 20s, especially in the female population,” said Dr. Rozen. Age of onset also depends on the triggering event.

The pain typically is bilateral and moderate to severe. Although many patients may present with a tension-type headache, more than 60% have migrainous symptoms such as nausea, photophobia, or phonophobia, said Dr. Rozen.

The disorder is more common among women than among men. Between 10% and 13% of patients who present to headache clinics have new daily persistent headache, said Dr. Rozen. “It is either becoming more prevalent in the office, or we are better at recognizing it.”

Comparing Effects on the Genders

For a study published in 2016, Dr. Rozen examined 97 patients (65 women) with new daily persistent headache. Approximately 53% of patients could not identify a triggering event for their headache, which makes treatment “much more difficult,” said Dr. Rozen. Although the mean age of onset was younger in women (32.4) than men (35.8), the age of onset was the same between genders when Dr. Rozen examined for individual triggers.

The frequency of individual triggering events also was the same between genders, and these results suggest that each trigger may be associated with a discrete pathogenesis. Triggers included infection or flulike illness (22%), stressful life event (9%), surgery (9%), and other (7%). All patients who had identified surgery as a trigger had been intubated, and Dr. Rozen hypothesized that their headaches were cervicogenic. The younger patients who had undergone surgery were hypermobile, and the older patients had neck arthritis as predisposing risk factors for neck irritation with intubation.

A Somatoform Disorder?

The stubbornly refractory nature of this disorder has aroused the suspicion that it may be somatoform. In 2017, Uniyal and colleagues found that somatization, generalized anxiety disorder, depression, and catastrophization were more common in patients with new daily persistent headache, compared with patients with chronic low back pain and healthy controls.

Interpreting these data is difficult, said Dr. Rozen. They may indicate that these psychiatric comorbidities are risk factors for new daily persistent headache. An equally plausible interpretation is that these patients have a different disorder (eg, Ehlers-Danlos syndrome) that encompasses these common traits. Finally, symptoms such as depression and catastrophization may be sequelae of, rather than risk factors for, new daily persistent headache.

Researchers have found imaging abnormalities to be rare in patients with new daily persistent headache. About two-thirds of patients in a 2002 study had normal MRI or CT results, and the rest had nonspecific findings unrelated to the headache. Dr. Rozen found that white matter lesions were uncommon in patients with this disorder, except for those with a history of migraine or cardiovascular or cerebrovascular risk factors. CSF likewise generally is normal in patients with new daily persistent headache.

Triggers Suggest Treatments

Goadsby proposed in 2011 that new daily persistent headache is a syndrome rather than a single disorder. “I’m completely in agreement,” said Dr. Rozen. “However, I do believe that individuals who have the same triggering event have the same pathogenesis.” Identifying the triggering event and understanding the temporal profile of the first headache can enable the choice of appropriate therapy, he added.

A patient whose persistent headache begins with a thunderclap onset likely has a prolonged cerebral artery vasospasm. Dr. Rozen treated a patient whose initial headache was a thunderclap; imaging ultimately revealed that she had a vasospasm. Her headache responded to nimodipine within days. Nimodipine generally provides relief within three to five days, said Dr. Rozen. If it worsens the headache, then the patient does not have vasospasm, he added.

Many patients with new daily persistent headache have a physical presentation that suggests Marfan syndrome. This observation led Dr. Rozen to hypothesize that cervical hypermobility is a risk factor for new daily persistent headache. Hypermobile patients may put significant stress on the C1, C2, and C3 joints, which are “where the trigeminal–cervical complex comes together,” said Dr. Rozen. A long plane ride or appointment with the dentist could trigger new daily persistent headache. Treatment with onabotulinumtoxinA often helps these patients. High cervical blocks also can bring relief, said Dr. Rozen.

He and his colleagues recently identified a new subset of patients with new daily persistent headache. They were older female patients with a mean age of 57 who suddenly developed the disorder. Most of them reported that the pain was worst before they got out of bed in the morning. Within seconds of assuming the Trendelenburg position, these patients had intensified pain and nausea, suggesting CSF hypertension. The patients all responded to acetazolamide or spironolactone, which lowered CSF pressure. “I think these individuals developed cerebral vein insufficiency because of estrogen withdrawal based on their age. Plus, the majority were overweight, which can also raise baseline CSF pressure.”

Examination Should Incorporate Imaging

All patients with new daily persistent headache should undergo imaging, including a brain MRI with and without gadolinium, plus an MR venogram, which can identify CSF leaks and a cerebral vein thrombosis, which are leading secondary causes of the disorder. Neurologists could examine patients’ viral titers in addition if the history suggests a post infectious trigger. A lumbar puncture and measurement of opening CSF pressure are appropriate for patients who have not responded to medication.

Evidence From the Literature

The literature possibly supports the efficacy of several treatments in new daily persistent headache, but includes no placebo-controlled trials for them. Dr. Rozen found doxycycline to be helpful for several patients with elevated CSF tumor necrosis factor alpha.

Marmura and colleagues found that mexiletine reduced the severity of pain in patients with refractory new daily persistent headache. The treatment did not reduce headache frequency, however, and side effects were common.

In a retrospective study, Prakash et al followed 63 patients with new daily persistent headache for five years. They found that patients who received IV methyl prednisolone and sodium valproate had a better response than patients who received other therapies. They called for prospective and controlled studies to confirm this observation.

In general, aggressive initial therapy is warranted, “especially if you meet an individual within one year of headache onset,” said Dr. Rozen. The likelihood of response to therapy appears to decline with the duration of the headache. “Infusion therapy or inpatient therapy with IV medications, even with standard migraine protocols, may help break the cycle,” Dr. Rozen concluded.

—Erik Greb

Suggested Reading

Goadsby PJ. New daily persistent headache: a syndrome, not a discrete disorder. Headache. 2011;51(4):650-653.

Marmura MJ, Passero FC Jr, Young WB. Mexiletine for refractory chronic daily headache: a report of nine cases. Headache. 2008;48(10):1506-1510.

Prakash S, Saini S, Rana KR, Mahato P. Refining clinical features and therapeutic options of new daily persistent headache: a retrospective study of 63 patients in India. J Headache Pain. 2012;13(6):477-485.

Rozen TD. A new subtype of chronic daily headache presenting in older women. J Womens Health (Larchmt). 2018;27(2):203-208.

Rozen TD. Triggering events and new daily persistent headache: age and gender differences and insights on pathogenesis-a clinic-based study. Headache. 2016;56(1):164-173.

Uniyal R, Paliwal VK, Tripathi A. Psychiatric comorbidity in new daily persistent headache: a cross-sectional study. Eur J Pain. 2017;21(6):1031-1038.

ASHEVILLE, NC—New daily persistent headache is rare and difficult to treat. Although neurologists may be tempted to try a series of treatments until the patient improves, therapeutic success is more likely if the neurologist can identify a triggering event, said Todd Rozen, MD, a neurologist at Mayo Clinic in Jacksonville, Florida. Elements of the patient’s history or clinical examination also can guide treatment, he added at the Eighth Annual Scientific Meeting of the Southern Headache Society.

Patients Remember the Onset

New daily persistent headache was first described in 1986, and few researchers have studied it. It is a persistent headache with a clearly remembered onset. “Most [patients] can name the date it began or at least the month,” said Dr. Rozen. The headache becomes unremitting within 24 hours and must be present for longer than three months, according to the current diagnostic criteria. Patients may have a remitting form, a relapsing-remitting form, or a refractory form of the headache. The age of onset “can be as early as in the mid to late teens or early 20s, especially in the female population,” said Dr. Rozen. Age of onset also depends on the triggering event.

The pain typically is bilateral and moderate to severe. Although many patients may present with a tension-type headache, more than 60% have migrainous symptoms such as nausea, photophobia, or phonophobia, said Dr. Rozen.

The disorder is more common among women than among men. Between 10% and 13% of patients who present to headache clinics have new daily persistent headache, said Dr. Rozen. “It is either becoming more prevalent in the office, or we are better at recognizing it.”

Comparing Effects on the Genders

For a study published in 2016, Dr. Rozen examined 97 patients (65 women) with new daily persistent headache. Approximately 53% of patients could not identify a triggering event for their headache, which makes treatment “much more difficult,” said Dr. Rozen. Although the mean age of onset was younger in women (32.4) than men (35.8), the age of onset was the same between genders when Dr. Rozen examined for individual triggers.

The frequency of individual triggering events also was the same between genders, and these results suggest that each trigger may be associated with a discrete pathogenesis. Triggers included infection or flulike illness (22%), stressful life event (9%), surgery (9%), and other (7%). All patients who had identified surgery as a trigger had been intubated, and Dr. Rozen hypothesized that their headaches were cervicogenic. The younger patients who had undergone surgery were hypermobile, and the older patients had neck arthritis as predisposing risk factors for neck irritation with intubation.

A Somatoform Disorder?

The stubbornly refractory nature of this disorder has aroused the suspicion that it may be somatoform. In 2017, Uniyal and colleagues found that somatization, generalized anxiety disorder, depression, and catastrophization were more common in patients with new daily persistent headache, compared with patients with chronic low back pain and healthy controls.

Interpreting these data is difficult, said Dr. Rozen. They may indicate that these psychiatric comorbidities are risk factors for new daily persistent headache. An equally plausible interpretation is that these patients have a different disorder (eg, Ehlers-Danlos syndrome) that encompasses these common traits. Finally, symptoms such as depression and catastrophization may be sequelae of, rather than risk factors for, new daily persistent headache.

Researchers have found imaging abnormalities to be rare in patients with new daily persistent headache. About two-thirds of patients in a 2002 study had normal MRI or CT results, and the rest had nonspecific findings unrelated to the headache. Dr. Rozen found that white matter lesions were uncommon in patients with this disorder, except for those with a history of migraine or cardiovascular or cerebrovascular risk factors. CSF likewise generally is normal in patients with new daily persistent headache.

Triggers Suggest Treatments

Goadsby proposed in 2011 that new daily persistent headache is a syndrome rather than a single disorder. “I’m completely in agreement,” said Dr. Rozen. “However, I do believe that individuals who have the same triggering event have the same pathogenesis.” Identifying the triggering event and understanding the temporal profile of the first headache can enable the choice of appropriate therapy, he added.

A patient whose persistent headache begins with a thunderclap onset likely has a prolonged cerebral artery vasospasm. Dr. Rozen treated a patient whose initial headache was a thunderclap; imaging ultimately revealed that she had a vasospasm. Her headache responded to nimodipine within days. Nimodipine generally provides relief within three to five days, said Dr. Rozen. If it worsens the headache, then the patient does not have vasospasm, he added.

Many patients with new daily persistent headache have a physical presentation that suggests Marfan syndrome. This observation led Dr. Rozen to hypothesize that cervical hypermobility is a risk factor for new daily persistent headache. Hypermobile patients may put significant stress on the C1, C2, and C3 joints, which are “where the trigeminal–cervical complex comes together,” said Dr. Rozen. A long plane ride or appointment with the dentist could trigger new daily persistent headache. Treatment with onabotulinumtoxinA often helps these patients. High cervical blocks also can bring relief, said Dr. Rozen.

He and his colleagues recently identified a new subset of patients with new daily persistent headache. They were older female patients with a mean age of 57 who suddenly developed the disorder. Most of them reported that the pain was worst before they got out of bed in the morning. Within seconds of assuming the Trendelenburg position, these patients had intensified pain and nausea, suggesting CSF hypertension. The patients all responded to acetazolamide or spironolactone, which lowered CSF pressure. “I think these individuals developed cerebral vein insufficiency because of estrogen withdrawal based on their age. Plus, the majority were overweight, which can also raise baseline CSF pressure.”

Examination Should Incorporate Imaging

All patients with new daily persistent headache should undergo imaging, including a brain MRI with and without gadolinium, plus an MR venogram, which can identify CSF leaks and a cerebral vein thrombosis, which are leading secondary causes of the disorder. Neurologists could examine patients’ viral titers in addition if the history suggests a post infectious trigger. A lumbar puncture and measurement of opening CSF pressure are appropriate for patients who have not responded to medication.

Evidence From the Literature

The literature possibly supports the efficacy of several treatments in new daily persistent headache, but includes no placebo-controlled trials for them. Dr. Rozen found doxycycline to be helpful for several patients with elevated CSF tumor necrosis factor alpha.

Marmura and colleagues found that mexiletine reduced the severity of pain in patients with refractory new daily persistent headache. The treatment did not reduce headache frequency, however, and side effects were common.

In a retrospective study, Prakash et al followed 63 patients with new daily persistent headache for five years. They found that patients who received IV methyl prednisolone and sodium valproate had a better response than patients who received other therapies. They called for prospective and controlled studies to confirm this observation.

In general, aggressive initial therapy is warranted, “especially if you meet an individual within one year of headache onset,” said Dr. Rozen. The likelihood of response to therapy appears to decline with the duration of the headache. “Infusion therapy or inpatient therapy with IV medications, even with standard migraine protocols, may help break the cycle,” Dr. Rozen concluded.

—Erik Greb

Suggested Reading

Goadsby PJ. New daily persistent headache: a syndrome, not a discrete disorder. Headache. 2011;51(4):650-653.

Marmura MJ, Passero FC Jr, Young WB. Mexiletine for refractory chronic daily headache: a report of nine cases. Headache. 2008;48(10):1506-1510.

Prakash S, Saini S, Rana KR, Mahato P. Refining clinical features and therapeutic options of new daily persistent headache: a retrospective study of 63 patients in India. J Headache Pain. 2012;13(6):477-485.

Rozen TD. A new subtype of chronic daily headache presenting in older women. J Womens Health (Larchmt). 2018;27(2):203-208.

Rozen TD. Triggering events and new daily persistent headache: age and gender differences and insights on pathogenesis-a clinic-based study. Headache. 2016;56(1):164-173.

Uniyal R, Paliwal VK, Tripathi A. Psychiatric comorbidity in new daily persistent headache: a cross-sectional study. Eur J Pain. 2017;21(6):1031-1038.

ASHEVILLE, NC—Menstrual-related migraine (MRM) can be particularly disabling and is difficult to treat using conventional migraine medications. To reduce the risk of MRM, a patient’s decrease in estrogen levels on the days around menses onset must be limited to 10 µg of ethinyl estradiol or less, said Anne H. Calhoun, MD, Professor of Anesthesiology and Psychiatry at the University of North Carolina and Partner and Cofounder of the Carolina Headache Institute in Durham, North Carolina.

“Most migraineurs by far are women, and as such, most migraineurs have MRM,” she said. “Nearly two-thirds of migraineurs have hormonal triggers, and it is our job to help our patients cope with them.”

Peak Times for Headache Occurrence

MRM occurrence correlates with days during a woman’s menstrual cycle, Dr. Calhoun said at the Eighth Annual Scientific Meeting of the Southern Headache Society. A study of diary data from 155 women found a 50% increased likelihood of migraine during the five days before menses, compared with all other times during the cycle.

“However, during the five days after the onset of bleeding, there was a 2.5 times increased risk of migraine,” Dr. Calhoun said. “Analysis of an even narrower time frame—two days before and after the onset of menses—shows a three to nearly five times increased migraine risk.” The pain was twice as likely to be considered severe two days before menses and more than three times as likely to be considered severe during the first three days of menstruation, she added.

Conventional migraine therapy may have limited efficacy for the treatment of MRM, Dr. Calhoun suggested. For example, one retrospective analysis examined data from two randomized trials of oral rizatriptan. In a subgroup of 335 women with MRM, 68% of women taking rizatriptan 10 mg and 70% of women taking rizatriptan 5 mg experienced pain relief, compared with 44% of women taking placebo. “However, for women who used the treatment on the day of bleeding, the response was about the same as placebo,” she said.

Hormonal Fluctuations Associated With Migraine

Fluctuations in estrogen levels are key to why migraine is more likely at certain times during a woman’s cycle, Dr. Calhoun said. She cited a study of 81 menstruating women with clinically diagnosed migraine that assessed their risk of tension-type headache and migraine with and without aura. There was a significantly elevated risk of tension-type headache and migraine without aura on the first two days of menses and a significantly higher risk of migraine without aura during the two days before menses onset. Furthermore, there was a significantly lower risk of all headache types around the time of ovulation.

“I looked at the data from this study and used the information differently,” Dr. Calhoun said. “In this same population of migraineurs, I added all their headaches together for each day and discovered that there was an increase in headache frequency when estrogen levels were low.”

When estrogen levels decrease, monoamine oxidase increases, serotonin and β-endorphin levels decrease, and serotonergic postsynaptic responsiveness and neurotransmitter uptake decrease. “In addition, there is an increase in calcitonin gene-related peptide concentrations,” Dr. Calhoun said. “This is why menstrual migraine is so much more intense than … non-MRM.”

Manipulation of Estrogen Levels

Corroborating evidence was found in a study that looked at hormone-related symptoms in 262 oral contraceptive users. Headache occurred significantly more frequently during the one-week hormone-free interval than during the three active-pill weeks, Dr. Calhoun noted. “Typical contraceptive treatment consists of a low-dose 20-µg ethinyl estradiol pill (combined with a progestin) for 21 days, followed by seven days of placebo,” she said. “A 20-µg drop in ethinyl estradiol (the estrogen in most oral contraceptives) is enough to cause a migraine, but if you limit that to a 10-µg drop, you can prevent migraine.”

Therefore, a patient on a 20-µg pill should be prescribed a 10-µg dose of ethinyl estradiol in the fourth week, Dr. Calhoun explained. If she is on a 30-µg pill, a 20-µg dose of ethinyl estradiol would be needed in the fourth week. “Continual hormonal combined contraceptives (with no placebo days) are also a good solution, so long as she does not have breakthrough bleeding,” she added.

Dr. Calhoun and colleagues examined the patient records of 229 consecutive women who were prescribed hormonal prophylaxis for MRM. Three hormonal preventive strategies were used: low-dose oral contraceptive with supplemental estrogen during the menstrual week; extended-cycle oral contraception with supplemental estrogen in the menstrual week; or a natural menstrual cycle with perimenstrual application of an estradiol patch two days beforethe expected onset of bleeding and continued for a week. In all, 168 women had resolution of MRM, 40 had persistence of MRM, and 21 refused or discontinued hormonal prophylaxis. Resolution of MRM was associated with a reversion to episodic migraine, resolution of medication overuse, and an overall decreased consumption of triptans, opioids, acute agents, and migraine preventive medication.

—Adriene Marshall

Suggested Reading

Calhoun A, Ford S. Elimination of menstrual-related migraine beneficially impacts chronification and medication overuse. Headache. 2008;48(8):1186-1193.

MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology. 2004;63(2):351-353.

Silberstein SD, Massiou H, Le Jeunne C, et al. Rizatriptan in the treatment of menstrual migraine. Obstet Gynecol. 2000;96(2):237-242.Stewart WF, Lipton RB, Chee E, et al. Menstrual cycle and headache in a population sample of migraineurs. Neurology. 2000;55(10):1517-1523.

ASHEVILLE, NC—Menstrual-related migraine (MRM) can be particularly disabling and is difficult to treat using conventional migraine medications. To reduce the risk of MRM, a patient’s decrease in estrogen levels on the days around menses onset must be limited to 10 µg of ethinyl estradiol or less, said Anne H. Calhoun, MD, Professor of Anesthesiology and Psychiatry at the University of North Carolina and Partner and Cofounder of the Carolina Headache Institute in Durham, North Carolina.

“Most migraineurs by far are women, and as such, most migraineurs have MRM,” she said. “Nearly two-thirds of migraineurs have hormonal triggers, and it is our job to help our patients cope with them.”

Peak Times for Headache Occurrence

MRM occurrence correlates with days during a woman’s menstrual cycle, Dr. Calhoun said at the Eighth Annual Scientific Meeting of the Southern Headache Society. A study of diary data from 155 women found a 50% increased likelihood of migraine during the five days before menses, compared with all other times during the cycle.

“However, during the five days after the onset of bleeding, there was a 2.5 times increased risk of migraine,” Dr. Calhoun said. “Analysis of an even narrower time frame—two days before and after the onset of menses—shows a three to nearly five times increased migraine risk.” The pain was twice as likely to be considered severe two days before menses and more than three times as likely to be considered severe during the first three days of menstruation, she added.

Conventional migraine therapy may have limited efficacy for the treatment of MRM, Dr. Calhoun suggested. For example, one retrospective analysis examined data from two randomized trials of oral rizatriptan. In a subgroup of 335 women with MRM, 68% of women taking rizatriptan 10 mg and 70% of women taking rizatriptan 5 mg experienced pain relief, compared with 44% of women taking placebo. “However, for women who used the treatment on the day of bleeding, the response was about the same as placebo,” she said.

Hormonal Fluctuations Associated With Migraine

Fluctuations in estrogen levels are key to why migraine is more likely at certain times during a woman’s cycle, Dr. Calhoun said. She cited a study of 81 menstruating women with clinically diagnosed migraine that assessed their risk of tension-type headache and migraine with and without aura. There was a significantly elevated risk of tension-type headache and migraine without aura on the first two days of menses and a significantly higher risk of migraine without aura during the two days before menses onset. Furthermore, there was a significantly lower risk of all headache types around the time of ovulation.

“I looked at the data from this study and used the information differently,” Dr. Calhoun said. “In this same population of migraineurs, I added all their headaches together for each day and discovered that there was an increase in headache frequency when estrogen levels were low.”

When estrogen levels decrease, monoamine oxidase increases, serotonin and β-endorphin levels decrease, and serotonergic postsynaptic responsiveness and neurotransmitter uptake decrease. “In addition, there is an increase in calcitonin gene-related peptide concentrations,” Dr. Calhoun said. “This is why menstrual migraine is so much more intense than … non-MRM.”

Manipulation of Estrogen Levels

Corroborating evidence was found in a study that looked at hormone-related symptoms in 262 oral contraceptive users. Headache occurred significantly more frequently during the one-week hormone-free interval than during the three active-pill weeks, Dr. Calhoun noted. “Typical contraceptive treatment consists of a low-dose 20-µg ethinyl estradiol pill (combined with a progestin) for 21 days, followed by seven days of placebo,” she said. “A 20-µg drop in ethinyl estradiol (the estrogen in most oral contraceptives) is enough to cause a migraine, but if you limit that to a 10-µg drop, you can prevent migraine.”

Therefore, a patient on a 20-µg pill should be prescribed a 10-µg dose of ethinyl estradiol in the fourth week, Dr. Calhoun explained. If she is on a 30-µg pill, a 20-µg dose of ethinyl estradiol would be needed in the fourth week. “Continual hormonal combined contraceptives (with no placebo days) are also a good solution, so long as she does not have breakthrough bleeding,” she added.

Dr. Calhoun and colleagues examined the patient records of 229 consecutive women who were prescribed hormonal prophylaxis for MRM. Three hormonal preventive strategies were used: low-dose oral contraceptive with supplemental estrogen during the menstrual week; extended-cycle oral contraception with supplemental estrogen in the menstrual week; or a natural menstrual cycle with perimenstrual application of an estradiol patch two days beforethe expected onset of bleeding and continued for a week. In all, 168 women had resolution of MRM, 40 had persistence of MRM, and 21 refused or discontinued hormonal prophylaxis. Resolution of MRM was associated with a reversion to episodic migraine, resolution of medication overuse, and an overall decreased consumption of triptans, opioids, acute agents, and migraine preventive medication.

—Adriene Marshall

Suggested Reading

Calhoun A, Ford S. Elimination of menstrual-related migraine beneficially impacts chronification and medication overuse. Headache. 2008;48(8):1186-1193.

MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology. 2004;63(2):351-353.

Silberstein SD, Massiou H, Le Jeunne C, et al. Rizatriptan in the treatment of menstrual migraine. Obstet Gynecol. 2000;96(2):237-242.Stewart WF, Lipton RB, Chee E, et al. Menstrual cycle and headache in a population sample of migraineurs. Neurology. 2000;55(10):1517-1523.

ASHEVILLE, NC—Menstrual-related migraine (MRM) can be particularly disabling and is difficult to treat using conventional migraine medications. To reduce the risk of MRM, a patient’s decrease in estrogen levels on the days around menses onset must be limited to 10 µg of ethinyl estradiol or less, said Anne H. Calhoun, MD, Professor of Anesthesiology and Psychiatry at the University of North Carolina and Partner and Cofounder of the Carolina Headache Institute in Durham, North Carolina.

“Most migraineurs by far are women, and as such, most migraineurs have MRM,” she said. “Nearly two-thirds of migraineurs have hormonal triggers, and it is our job to help our patients cope with them.”

Peak Times for Headache Occurrence

MRM occurrence correlates with days during a woman’s menstrual cycle, Dr. Calhoun said at the Eighth Annual Scientific Meeting of the Southern Headache Society. A study of diary data from 155 women found a 50% increased likelihood of migraine during the five days before menses, compared with all other times during the cycle.

“However, during the five days after the onset of bleeding, there was a 2.5 times increased risk of migraine,” Dr. Calhoun said. “Analysis of an even narrower time frame—two days before and after the onset of menses—shows a three to nearly five times increased migraine risk.” The pain was twice as likely to be considered severe two days before menses and more than three times as likely to be considered severe during the first three days of menstruation, she added.

Conventional migraine therapy may have limited efficacy for the treatment of MRM, Dr. Calhoun suggested. For example, one retrospective analysis examined data from two randomized trials of oral rizatriptan. In a subgroup of 335 women with MRM, 68% of women taking rizatriptan 10 mg and 70% of women taking rizatriptan 5 mg experienced pain relief, compared with 44% of women taking placebo. “However, for women who used the treatment on the day of bleeding, the response was about the same as placebo,” she said.

Hormonal Fluctuations Associated With Migraine

Fluctuations in estrogen levels are key to why migraine is more likely at certain times during a woman’s cycle, Dr. Calhoun said. She cited a study of 81 menstruating women with clinically diagnosed migraine that assessed their risk of tension-type headache and migraine with and without aura. There was a significantly elevated risk of tension-type headache and migraine without aura on the first two days of menses and a significantly higher risk of migraine without aura during the two days before menses onset. Furthermore, there was a significantly lower risk of all headache types around the time of ovulation.

“I looked at the data from this study and used the information differently,” Dr. Calhoun said. “In this same population of migraineurs, I added all their headaches together for each day and discovered that there was an increase in headache frequency when estrogen levels were low.”

When estrogen levels decrease, monoamine oxidase increases, serotonin and β-endorphin levels decrease, and serotonergic postsynaptic responsiveness and neurotransmitter uptake decrease. “In addition, there is an increase in calcitonin gene-related peptide concentrations,” Dr. Calhoun said. “This is why menstrual migraine is so much more intense than … non-MRM.”

Manipulation of Estrogen Levels

Corroborating evidence was found in a study that looked at hormone-related symptoms in 262 oral contraceptive users. Headache occurred significantly more frequently during the one-week hormone-free interval than during the three active-pill weeks, Dr. Calhoun noted. “Typical contraceptive treatment consists of a low-dose 20-µg ethinyl estradiol pill (combined with a progestin) for 21 days, followed by seven days of placebo,” she said. “A 20-µg drop in ethinyl estradiol (the estrogen in most oral contraceptives) is enough to cause a migraine, but if you limit that to a 10-µg drop, you can prevent migraine.”

Therefore, a patient on a 20-µg pill should be prescribed a 10-µg dose of ethinyl estradiol in the fourth week, Dr. Calhoun explained. If she is on a 30-µg pill, a 20-µg dose of ethinyl estradiol would be needed in the fourth week. “Continual hormonal combined contraceptives (with no placebo days) are also a good solution, so long as she does not have breakthrough bleeding,” she added.

Dr. Calhoun and colleagues examined the patient records of 229 consecutive women who were prescribed hormonal prophylaxis for MRM. Three hormonal preventive strategies were used: low-dose oral contraceptive with supplemental estrogen during the menstrual week; extended-cycle oral contraception with supplemental estrogen in the menstrual week; or a natural menstrual cycle with perimenstrual application of an estradiol patch two days beforethe expected onset of bleeding and continued for a week. In all, 168 women had resolution of MRM, 40 had persistence of MRM, and 21 refused or discontinued hormonal prophylaxis. Resolution of MRM was associated with a reversion to episodic migraine, resolution of medication overuse, and an overall decreased consumption of triptans, opioids, acute agents, and migraine preventive medication.

—Adriene Marshall

Suggested Reading

Calhoun A, Ford S. Elimination of menstrual-related migraine beneficially impacts chronification and medication overuse. Headache. 2008;48(8):1186-1193.

MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology. 2004;63(2):351-353.

Silberstein SD, Massiou H, Le Jeunne C, et al. Rizatriptan in the treatment of menstrual migraine. Obstet Gynecol. 2000;96(2):237-242.Stewart WF, Lipton RB, Chee E, et al. Menstrual cycle and headache in a population sample of migraineurs. Neurology. 2000;55(10):1517-1523.

CHICAGO—Among pediatric patients who receive IV dihydroergotamine (DHE) for headache, chest pain is a common side effect and reason for early cessation of DHE, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. Chest pain may not represent a serious cardiovascular problem, and patients who continue DHE despite chest pain have better chances of acute headache resolution, compared with patients who stop DHE, said Sara Fridinger, MD, a fellow with the Division of Neurology at Children’s Hospital of Philadelphia.

IV DHE is an effective headache treatment for children, but it has many side effects, including chest pain. Chest pain in pediatric patients who receive IV DHE may result from esophageal spasms, but it raises concerns about myocardial ischemia because of the drug’s vasospastic qualities, the researchers said.

To determine the incidence and significance of chest pain among pediatric patients who received IV DHE for headache, Dr. Fridinger and Christina Szperka, MD, Director of the Pediatric Headache Program at Children’s Hospital of Philadelphia, conducted a retrospective chart review. They examined data from pediatric patients at their hospital who received IV DHE between January 2014 and July 2016. They excluded patients who received DHE for secondary headache. Data from 183 patients (median age, 15.7; 81% female) were included in their analysis, including reports of chest pain and other side effects, EKG data, and cardiac enzymes.

Chest pain occurred in 27% (n = 49) of patients who received DHE. Chest pain occurred after the first dose in 33% of patients and after the second dose in 61%. All patients received premedication before the dose that caused chest pain, and metoclopramide was used as premedication in 80% of cases. No patients with chest pain had elevated troponin. Of the 31% of patients with chest pain who had EKG abnormalities, the abnormalities were either unchanged from baseline or deemed not clinically significant. Of patients with chest pain, 39% stopped DHE due to chest pain, whereas 61% continued with the DHE protocol.

Thirty-seven percent of patients who stopped DHE due to chest pain and 50% of those who continued DHE despite chest pain achieved resolution of the acute headache.

“It is reassuring that no patients were found to have elevated cardiac enzymes and no patients had frankly abnormal EKGs,” said Drs. Fridinger and Szperka.

CHICAGO—Among pediatric patients who receive IV dihydroergotamine (DHE) for headache, chest pain is a common side effect and reason for early cessation of DHE, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. Chest pain may not represent a serious cardiovascular problem, and patients who continue DHE despite chest pain have better chances of acute headache resolution, compared with patients who stop DHE, said Sara Fridinger, MD, a fellow with the Division of Neurology at Children’s Hospital of Philadelphia.

IV DHE is an effective headache treatment for children, but it has many side effects, including chest pain. Chest pain in pediatric patients who receive IV DHE may result from esophageal spasms, but it raises concerns about myocardial ischemia because of the drug’s vasospastic qualities, the researchers said.

To determine the incidence and significance of chest pain among pediatric patients who received IV DHE for headache, Dr. Fridinger and Christina Szperka, MD, Director of the Pediatric Headache Program at Children’s Hospital of Philadelphia, conducted a retrospective chart review. They examined data from pediatric patients at their hospital who received IV DHE between January 2014 and July 2016. They excluded patients who received DHE for secondary headache. Data from 183 patients (median age, 15.7; 81% female) were included in their analysis, including reports of chest pain and other side effects, EKG data, and cardiac enzymes.

Chest pain occurred in 27% (n = 49) of patients who received DHE. Chest pain occurred after the first dose in 33% of patients and after the second dose in 61%. All patients received premedication before the dose that caused chest pain, and metoclopramide was used as premedication in 80% of cases. No patients with chest pain had elevated troponin. Of the 31% of patients with chest pain who had EKG abnormalities, the abnormalities were either unchanged from baseline or deemed not clinically significant. Of patients with chest pain, 39% stopped DHE due to chest pain, whereas 61% continued with the DHE protocol.

Thirty-seven percent of patients who stopped DHE due to chest pain and 50% of those who continued DHE despite chest pain achieved resolution of the acute headache.

“It is reassuring that no patients were found to have elevated cardiac enzymes and no patients had frankly abnormal EKGs,” said Drs. Fridinger and Szperka.

CHICAGO—Among pediatric patients who receive IV dihydroergotamine (DHE) for headache, chest pain is a common side effect and reason for early cessation of DHE, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. Chest pain may not represent a serious cardiovascular problem, and patients who continue DHE despite chest pain have better chances of acute headache resolution, compared with patients who stop DHE, said Sara Fridinger, MD, a fellow with the Division of Neurology at Children’s Hospital of Philadelphia.

IV DHE is an effective headache treatment for children, but it has many side effects, including chest pain. Chest pain in pediatric patients who receive IV DHE may result from esophageal spasms, but it raises concerns about myocardial ischemia because of the drug’s vasospastic qualities, the researchers said.

To determine the incidence and significance of chest pain among pediatric patients who received IV DHE for headache, Dr. Fridinger and Christina Szperka, MD, Director of the Pediatric Headache Program at Children’s Hospital of Philadelphia, conducted a retrospective chart review. They examined data from pediatric patients at their hospital who received IV DHE between January 2014 and July 2016. They excluded patients who received DHE for secondary headache. Data from 183 patients (median age, 15.7; 81% female) were included in their analysis, including reports of chest pain and other side effects, EKG data, and cardiac enzymes.

Chest pain occurred in 27% (n = 49) of patients who received DHE. Chest pain occurred after the first dose in 33% of patients and after the second dose in 61%. All patients received premedication before the dose that caused chest pain, and metoclopramide was used as premedication in 80% of cases. No patients with chest pain had elevated troponin. Of the 31% of patients with chest pain who had EKG abnormalities, the abnormalities were either unchanged from baseline or deemed not clinically significant. Of patients with chest pain, 39% stopped DHE due to chest pain, whereas 61% continued with the DHE protocol.

Thirty-seven percent of patients who stopped DHE due to chest pain and 50% of those who continued DHE despite chest pain achieved resolution of the acute headache.

“It is reassuring that no patients were found to have elevated cardiac enzymes and no patients had frankly abnormal EKGs,” said Drs. Fridinger and Szperka.

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California