Headache & Migraine

Biologically active pituitary adenylate cyclase-activating polypeptide (PACAP) is released by mast cells: a finding that may provide an explanation for the association between allergy and migraine. “In the investigation of the role of mast cells in migraine pathology, we found that human mast cells contain PACAP in their cytoplasmic granules. Bioactive PACAP can be released from mast cells by inducing degranulation,” said lead author Angela J. Okragly, Senior Research Scientist at Eli Lilly and Company in Indianapolis, and colleagues. “This finding provides a potential explanation linking mast cell activation to migraine through the release of PACAP.” Their study was published in the August issue of Cephalalgia.

The relationship between allergy and migraine has long been noted. Many patients with migraines have allergies, and vice versa. In 1983, researchers hypothesized that mast cells, which are effectors of allergies, play a role in the pathophysiology of migraines. To investigate the relationship between mast cell activation and known neurogenic peptides related to migraine, researchers from Eli Lilly and Company assayed cultured human mast cells for the presence of neuropeptides and their receptors at the RNA and protein levels. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. The investigators also performed mast cell degranulation assays and measured PACAP activity with bioassay.

The team of Lilly researchers found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. In addition, the researchers confirmed existing evidence that several neurogenic peptides also can induce mast cell degranulation, which results in PACAP release.

“Since it has been demonstrated that PACAP infusion can trigger migraines, we propose that [our] finding provides a potential mechanistic explanation of how mast cell degranulation could contribute to migraines,” the authors said.

Migraine remains a complex disorder with multiple causes, the researchers noted. “Recent clinical trial results demonstrate a role for the calcitonin gene-related peptide (CGRP) pathway, since its blockade resulted in a high degree of efficacy in significant groups of patients. In our study, we found no direct relationship between mast cells and CGRP, suggesting that migraines involving mast cell activation, either via classical IgE or pseudoallergic pathways, involve a different pathophysiologic mechanism,” the authors said.

—Glenn S. Williams

Suggested Reading

Okragly AJ, Morin SM, DeRosa D, et al. Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP). Cephalalgia. 2018;38(9):1564-1574.

Biologically active pituitary adenylate cyclase-activating polypeptide (PACAP) is released by mast cells: a finding that may provide an explanation for the association between allergy and migraine. “In the investigation of the role of mast cells in migraine pathology, we found that human mast cells contain PACAP in their cytoplasmic granules. Bioactive PACAP can be released from mast cells by inducing degranulation,” said lead author Angela J. Okragly, Senior Research Scientist at Eli Lilly and Company in Indianapolis, and colleagues. “This finding provides a potential explanation linking mast cell activation to migraine through the release of PACAP.” Their study was published in the August issue of Cephalalgia.

The relationship between allergy and migraine has long been noted. Many patients with migraines have allergies, and vice versa. In 1983, researchers hypothesized that mast cells, which are effectors of allergies, play a role in the pathophysiology of migraines. To investigate the relationship between mast cell activation and known neurogenic peptides related to migraine, researchers from Eli Lilly and Company assayed cultured human mast cells for the presence of neuropeptides and their receptors at the RNA and protein levels. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. The investigators also performed mast cell degranulation assays and measured PACAP activity with bioassay.

The team of Lilly researchers found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. In addition, the researchers confirmed existing evidence that several neurogenic peptides also can induce mast cell degranulation, which results in PACAP release.

“Since it has been demonstrated that PACAP infusion can trigger migraines, we propose that [our] finding provides a potential mechanistic explanation of how mast cell degranulation could contribute to migraines,” the authors said.

Migraine remains a complex disorder with multiple causes, the researchers noted. “Recent clinical trial results demonstrate a role for the calcitonin gene-related peptide (CGRP) pathway, since its blockade resulted in a high degree of efficacy in significant groups of patients. In our study, we found no direct relationship between mast cells and CGRP, suggesting that migraines involving mast cell activation, either via classical IgE or pseudoallergic pathways, involve a different pathophysiologic mechanism,” the authors said.

—Glenn S. Williams

Suggested Reading

Okragly AJ, Morin SM, DeRosa D, et al. Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP). Cephalalgia. 2018;38(9):1564-1574.

Biologically active pituitary adenylate cyclase-activating polypeptide (PACAP) is released by mast cells: a finding that may provide an explanation for the association between allergy and migraine. “In the investigation of the role of mast cells in migraine pathology, we found that human mast cells contain PACAP in their cytoplasmic granules. Bioactive PACAP can be released from mast cells by inducing degranulation,” said lead author Angela J. Okragly, Senior Research Scientist at Eli Lilly and Company in Indianapolis, and colleagues. “This finding provides a potential explanation linking mast cell activation to migraine through the release of PACAP.” Their study was published in the August issue of Cephalalgia.

The relationship between allergy and migraine has long been noted. Many patients with migraines have allergies, and vice versa. In 1983, researchers hypothesized that mast cells, which are effectors of allergies, play a role in the pathophysiology of migraines. To investigate the relationship between mast cell activation and known neurogenic peptides related to migraine, researchers from Eli Lilly and Company assayed cultured human mast cells for the presence of neuropeptides and their receptors at the RNA and protein levels. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. The investigators also performed mast cell degranulation assays and measured PACAP activity with bioassay.

The team of Lilly researchers found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. In addition, the researchers confirmed existing evidence that several neurogenic peptides also can induce mast cell degranulation, which results in PACAP release.

“Since it has been demonstrated that PACAP infusion can trigger migraines, we propose that [our] finding provides a potential mechanistic explanation of how mast cell degranulation could contribute to migraines,” the authors said.

Migraine remains a complex disorder with multiple causes, the researchers noted. “Recent clinical trial results demonstrate a role for the calcitonin gene-related peptide (CGRP) pathway, since its blockade resulted in a high degree of efficacy in significant groups of patients. In our study, we found no direct relationship between mast cells and CGRP, suggesting that migraines involving mast cell activation, either via classical IgE or pseudoallergic pathways, involve a different pathophysiologic mechanism,” the authors said.

—Glenn S. Williams

Suggested Reading

Okragly AJ, Morin SM, DeRosa D, et al. Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP). Cephalalgia. 2018;38(9):1564-1574.

Teva Pharmaceutical Industries Ltd. announced that the FDA approved Ajovy (fremanezumab-vfrm) injection for the preventive treatment of migraine in adults. Ajovy, a humanized monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor, is the first and only anti-CGRP treatment for the prevention of migraine with quarterly (675 mg) and monthly (225 mg) dosing options.

“Migraine is a disabling neurological disease that affects more than 36 million people in the United States,” said Stephen Silberstein, MD, Director of the Jefferson Headache Center at Thomas Jefferson University Hospital in Philadelphia, and lead investigator of the Phase III clinical trial program for Ajovy. “About 40% of people living with migraine may be appropriate candidates for preventive treatment, yet the majority of them are untreated. I am pleased to have another treatment option that may allow my patients to experience fewer monthly migraine days.”

Ajovy was evaluated in two Phase III, placebo-controlled clinical trials that enrolled patients with disabling migraine and was studied as both a stand-alone preventive treatment and in combination with oral preventive treatments. In these trials, patients experienced a reduction in monthly migraine days during a 12-week period. The most common adverse reactions (≥ 5% and greater than placebo) were injection site reactions.

Teva Pharmaceutical Industries Ltd. announced that the FDA approved Ajovy (fremanezumab-vfrm) injection for the preventive treatment of migraine in adults. Ajovy, a humanized monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor, is the first and only anti-CGRP treatment for the prevention of migraine with quarterly (675 mg) and monthly (225 mg) dosing options.

“Migraine is a disabling neurological disease that affects more than 36 million people in the United States,” said Stephen Silberstein, MD, Director of the Jefferson Headache Center at Thomas Jefferson University Hospital in Philadelphia, and lead investigator of the Phase III clinical trial program for Ajovy. “About 40% of people living with migraine may be appropriate candidates for preventive treatment, yet the majority of them are untreated. I am pleased to have another treatment option that may allow my patients to experience fewer monthly migraine days.”

Ajovy was evaluated in two Phase III, placebo-controlled clinical trials that enrolled patients with disabling migraine and was studied as both a stand-alone preventive treatment and in combination with oral preventive treatments. In these trials, patients experienced a reduction in monthly migraine days during a 12-week period. The most common adverse reactions (≥ 5% and greater than placebo) were injection site reactions.

Teva Pharmaceutical Industries Ltd. announced that the FDA approved Ajovy (fremanezumab-vfrm) injection for the preventive treatment of migraine in adults. Ajovy, a humanized monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor, is the first and only anti-CGRP treatment for the prevention of migraine with quarterly (675 mg) and monthly (225 mg) dosing options.

“Migraine is a disabling neurological disease that affects more than 36 million people in the United States,” said Stephen Silberstein, MD, Director of the Jefferson Headache Center at Thomas Jefferson University Hospital in Philadelphia, and lead investigator of the Phase III clinical trial program for Ajovy. “About 40% of people living with migraine may be appropriate candidates for preventive treatment, yet the majority of them are untreated. I am pleased to have another treatment option that may allow my patients to experience fewer monthly migraine days.”

Ajovy was evaluated in two Phase III, placebo-controlled clinical trials that enrolled patients with disabling migraine and was studied as both a stand-alone preventive treatment and in combination with oral preventive treatments. In these trials, patients experienced a reduction in monthly migraine days during a 12-week period. The most common adverse reactions (≥ 5% and greater than placebo) were injection site reactions.

A recent study found a 10.7% prevalence of migraines and synergism between female gender and stress on risk of migraine, suggesting health interventions targeting women under stress may be beneficial. Researchers used data from 42,282 persons aged ≥12 years who participated in a 2013–2014 community health survey. A multivariate log-binomial model was used to calculate adjusted prevalence ratios for migraines associated with individual and joint exposures of female gender and stress. They used relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S index) to measure additive interaction. They found:

• The prevalence of migraines was 10.7%.
• The adjusted prevalence ratios were 2.37 for female vs male, 1.63 for persons with high vs low levels of stress, and 3.38 for women with high stress vs men with low stress.
• The RERI estimate was 0.38, the AP estimate was 0.11, and the S index was 1.19.

Slatculescu AM, Chen Y. Synergism between female gender and high levels of daily stress associated with migraine headaches in Ontario, Canada. [Published online ahead of print August 28, 2018]. Neuroepidemiol. doi:10.1159/000492503.

A recent study found a 10.7% prevalence of migraines and synergism between female gender and stress on risk of migraine, suggesting health interventions targeting women under stress may be beneficial. Researchers used data from 42,282 persons aged ≥12 years who participated in a 2013–2014 community health survey. A multivariate log-binomial model was used to calculate adjusted prevalence ratios for migraines associated with individual and joint exposures of female gender and stress. They used relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S index) to measure additive interaction. They found:

• The prevalence of migraines was 10.7%.
• The adjusted prevalence ratios were 2.37 for female vs male, 1.63 for persons with high vs low levels of stress, and 3.38 for women with high stress vs men with low stress.
• The RERI estimate was 0.38, the AP estimate was 0.11, and the S index was 1.19.

Slatculescu AM, Chen Y. Synergism between female gender and high levels of daily stress associated with migraine headaches in Ontario, Canada. [Published online ahead of print August 28, 2018]. Neuroepidemiol. doi:10.1159/000492503.

A recent study found a 10.7% prevalence of migraines and synergism between female gender and stress on risk of migraine, suggesting health interventions targeting women under stress may be beneficial. Researchers used data from 42,282 persons aged ≥12 years who participated in a 2013–2014 community health survey. A multivariate log-binomial model was used to calculate adjusted prevalence ratios for migraines associated with individual and joint exposures of female gender and stress. They used relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S index) to measure additive interaction. They found:

• The prevalence of migraines was 10.7%.
• The adjusted prevalence ratios were 2.37 for female vs male, 1.63 for persons with high vs low levels of stress, and 3.38 for women with high stress vs men with low stress.
• The RERI estimate was 0.38, the AP estimate was 0.11, and the S index was 1.19.

Slatculescu AM, Chen Y. Synergism between female gender and high levels of daily stress associated with migraine headaches in Ontario, Canada. [Published online ahead of print August 28, 2018]. Neuroepidemiol. doi:10.1159/000492503.

For patients with migraine in the emergency department (ED), the use of IV fluids, dopamine receptor antagonists (DRA), nonsteroidal anti-Inflammatory drugs, and corticosteroids increased whereas the use of narcotics and discharge prescriptions for narcotics decreased, according to a recent study. Researchers also found that the return rates for migraines decreased and they speculate that the increased use of non-narcotic medications contributed to this decrease. In this study, they examined a multi-hospital retrospective cohort consisting of consecutive ED patients from January 1, 1999, to September 31, 2014. They examined charts at the beginning and end of the time period and found:

• Of the 2,824,710 total visits, 8046 (0.28%) were for migraine.
• 290 charts (147 in 1999–2000 and 143 in 2014) were reviewed to determine migraine treatments.
• Of the 8046 migraine patients, 624 (8%) returned within 72 hours.
• The return rate decreased from 1999–2000 to 2014 from 12% to 4% (difference = 8%).

Ruzek M, Richman P, Eskin B, Allegra JR. ED treatment of migraine patients has changed. [Published online ahead of print August 20, 2018]. Am J Emerg Med. doi:10.1016/j.ajem.2018.08.051.

For patients with migraine in the emergency department (ED), the use of IV fluids, dopamine receptor antagonists (DRA), nonsteroidal anti-Inflammatory drugs, and corticosteroids increased whereas the use of narcotics and discharge prescriptions for narcotics decreased, according to a recent study. Researchers also found that the return rates for migraines decreased and they speculate that the increased use of non-narcotic medications contributed to this decrease. In this study, they examined a multi-hospital retrospective cohort consisting of consecutive ED patients from January 1, 1999, to September 31, 2014. They examined charts at the beginning and end of the time period and found:

• Of the 2,824,710 total visits, 8046 (0.28%) were for migraine.
• 290 charts (147 in 1999–2000 and 143 in 2014) were reviewed to determine migraine treatments.
• Of the 8046 migraine patients, 624 (8%) returned within 72 hours.
• The return rate decreased from 1999–2000 to 2014 from 12% to 4% (difference = 8%).

Ruzek M, Richman P, Eskin B, Allegra JR. ED treatment of migraine patients has changed. [Published online ahead of print August 20, 2018]. Am J Emerg Med. doi:10.1016/j.ajem.2018.08.051.

For patients with migraine in the emergency department (ED), the use of IV fluids, dopamine receptor antagonists (DRA), nonsteroidal anti-Inflammatory drugs, and corticosteroids increased whereas the use of narcotics and discharge prescriptions for narcotics decreased, according to a recent study. Researchers also found that the return rates for migraines decreased and they speculate that the increased use of non-narcotic medications contributed to this decrease. In this study, they examined a multi-hospital retrospective cohort consisting of consecutive ED patients from January 1, 1999, to September 31, 2014. They examined charts at the beginning and end of the time period and found:

• Of the 2,824,710 total visits, 8046 (0.28%) were for migraine.
• 290 charts (147 in 1999–2000 and 143 in 2014) were reviewed to determine migraine treatments.
• Of the 8046 migraine patients, 624 (8%) returned within 72 hours.
• The return rate decreased from 1999–2000 to 2014 from 12% to 4% (difference = 8%).

Ruzek M, Richman P, Eskin B, Allegra JR. ED treatment of migraine patients has changed. [Published online ahead of print August 20, 2018]. Am J Emerg Med. doi:10.1016/j.ajem.2018.08.051.

Symptoms of autonomic dysfunction were greatest among those with persistent posttraumatic headaches (PPTH) compared to migraine and healthy controls (HCs), a recent study found. In addition, among individuals with PPTH, number of lifetime traumatic brain injuries (TBIs) was associated with greater symptoms of autonomic dysfunction, while greater headache burden was associated with higher vasomotor domain autonomic dysfunction subscores, potentially indicating that PPTH patients with higher disease burden have an increased risk for having autonomic dysfunction. Individuals with PPTH (n=56) (87.5% of whom had a migraine/probable migraine phenotype), migraine (n=30), and HCs (n=36) were prospectively assessed in this cross‐sectional cohort study using the COMPASS‐31 questionnaire. Total COMPASS‐31 scores and individual domain scores were compared between subject groups. Researchers found:

• COMPASS‐31 mean total weighted score was 37.22 ± 15.44 in the PPTH group, 27.15 ± 14.37 in the migraine group, and 11.67 ± 8.98 for HCs.
• COMPASS‐31 mean weighted total scores were significantly higher in those with PPTH vs migraine, for PPTH vs HCs, and for migraine vs HCs.

Howard L, Dumkrieger G, Chong CD, Ross K, Berisha V, Schwedt TJ. Symptoms of autonomic dysfunction among those with persistent posttraumatic headache attributed to mild traumatic brain injury: A comparison to migraine and healthy controls. [Published online ahead of print August 29, 2018]. Headache. doi:10.1111/head.13396.

Symptoms of autonomic dysfunction were greatest among those with persistent posttraumatic headaches (PPTH) compared to migraine and healthy controls (HCs), a recent study found. In addition, among individuals with PPTH, number of lifetime traumatic brain injuries (TBIs) was associated with greater symptoms of autonomic dysfunction, while greater headache burden was associated with higher vasomotor domain autonomic dysfunction subscores, potentially indicating that PPTH patients with higher disease burden have an increased risk for having autonomic dysfunction. Individuals with PPTH (n=56) (87.5% of whom had a migraine/probable migraine phenotype), migraine (n=30), and HCs (n=36) were prospectively assessed in this cross‐sectional cohort study using the COMPASS‐31 questionnaire. Total COMPASS‐31 scores and individual domain scores were compared between subject groups. Researchers found:

• COMPASS‐31 mean total weighted score was 37.22 ± 15.44 in the PPTH group, 27.15 ± 14.37 in the migraine group, and 11.67 ± 8.98 for HCs.
• COMPASS‐31 mean weighted total scores were significantly higher in those with PPTH vs migraine, for PPTH vs HCs, and for migraine vs HCs.

Howard L, Dumkrieger G, Chong CD, Ross K, Berisha V, Schwedt TJ. Symptoms of autonomic dysfunction among those with persistent posttraumatic headache attributed to mild traumatic brain injury: A comparison to migraine and healthy controls. [Published online ahead of print August 29, 2018]. Headache. doi:10.1111/head.13396.

Symptoms of autonomic dysfunction were greatest among those with persistent posttraumatic headaches (PPTH) compared to migraine and healthy controls (HCs), a recent study found. In addition, among individuals with PPTH, number of lifetime traumatic brain injuries (TBIs) was associated with greater symptoms of autonomic dysfunction, while greater headache burden was associated with higher vasomotor domain autonomic dysfunction subscores, potentially indicating that PPTH patients with higher disease burden have an increased risk for having autonomic dysfunction. Individuals with PPTH (n=56) (87.5% of whom had a migraine/probable migraine phenotype), migraine (n=30), and HCs (n=36) were prospectively assessed in this cross‐sectional cohort study using the COMPASS‐31 questionnaire. Total COMPASS‐31 scores and individual domain scores were compared between subject groups. Researchers found:

• COMPASS‐31 mean total weighted score was 37.22 ± 15.44 in the PPTH group, 27.15 ± 14.37 in the migraine group, and 11.67 ± 8.98 for HCs.
• COMPASS‐31 mean weighted total scores were significantly higher in those with PPTH vs migraine, for PPTH vs HCs, and for migraine vs HCs.

Howard L, Dumkrieger G, Chong CD, Ross K, Berisha V, Schwedt TJ. Symptoms of autonomic dysfunction among those with persistent posttraumatic headache attributed to mild traumatic brain injury: A comparison to migraine and healthy controls. [Published online ahead of print August 29, 2018]. Headache. doi:10.1111/head.13396.

The Food and Drug Administration has approved Ajovy (fremanezumab-vfrm) for the preventive treatment of migraines in adults.

Fremanezumab-vfrm is an injectable anti–calcitonin gene-related peptide monoclonal antibody, the first ever approved by the FDA. It can be administered at a 225-mg dose every month or at a 675-mg dose every 3 months, according to a press release from Teva, the drug’s manufacturer.

FDA approval was based on results from two, phase 3 trials in patients with disabling migraines, one of which involved fremanezumab-vfrm alone, with the other involving the injection in tandem with an oral treatment.

In both trials, patients experienced a reduction of monthly migraine days over a 12-week period. The most common adverse event in both trials was injection site reactions.

“Migraine is a disabling neurological disease that affects more than 36 million people in the United States. About 40 percent of people living with migraine may be appropriate candidates for preventive treatment, yet the majority of them are untreated. I am pleased to have another treatment option that may allow my patients to experience fewer monthly migraine days,” Stephen Silberstein, MD, director of the Jefferson Headache Center at Thomas Jefferson University Hospital in Philadelphia, said in the Teva press release.

[email protected]

The Food and Drug Administration has approved Ajovy (fremanezumab-vfrm) for the preventive treatment of migraines in adults.

Fremanezumab-vfrm is an injectable anti–calcitonin gene-related peptide monoclonal antibody, the first ever approved by the FDA. It can be administered at a 225-mg dose every month or at a 675-mg dose every 3 months, according to a press release from Teva, the drug’s manufacturer.

FDA approval was based on results from two, phase 3 trials in patients with disabling migraines, one of which involved fremanezumab-vfrm alone, with the other involving the injection in tandem with an oral treatment.

In both trials, patients experienced a reduction of monthly migraine days over a 12-week period. The most common adverse event in both trials was injection site reactions.

“Migraine is a disabling neurological disease that affects more than 36 million people in the United States. About 40 percent of people living with migraine may be appropriate candidates for preventive treatment, yet the majority of them are untreated. I am pleased to have another treatment option that may allow my patients to experience fewer monthly migraine days,” Stephen Silberstein, MD, director of the Jefferson Headache Center at Thomas Jefferson University Hospital in Philadelphia, said in the Teva press release.

[email protected]

The Food and Drug Administration has approved Ajovy (fremanezumab-vfrm) for the preventive treatment of migraines in adults.

Fremanezumab-vfrm is an injectable anti–calcitonin gene-related peptide monoclonal antibody, the first ever approved by the FDA. It can be administered at a 225-mg dose every month or at a 675-mg dose every 3 months, according to a press release from Teva, the drug’s manufacturer.

FDA approval was based on results from two, phase 3 trials in patients with disabling migraines, one of which involved fremanezumab-vfrm alone, with the other involving the injection in tandem with an oral treatment.

In both trials, patients experienced a reduction of monthly migraine days over a 12-week period. The most common adverse event in both trials was injection site reactions.

“Migraine is a disabling neurological disease that affects more than 36 million people in the United States. About 40 percent of people living with migraine may be appropriate candidates for preventive treatment, yet the majority of them are untreated. I am pleased to have another treatment option that may allow my patients to experience fewer monthly migraine days,” Stephen Silberstein, MD, director of the Jefferson Headache Center at Thomas Jefferson University Hospital in Philadelphia, said in the Teva press release.

[email protected]

Migraine headaches occurred in 5 (3.1%) of 158 patients who underwent cerebral angiography, according to a recent observational cohort study that ascertained the frequency and type of headaches following catheter‐based cerebral angiography. Consecutive patients who underwent cerebral angiography through the transfemoral (or infrequently, radial) route were included. Each patient underwent a brief neurological assessment after the procedure and more detailed assessment was performed if any patient reported occurrence of a headache. The headaches were classified as migraine if the diagnostic criteria specified by International Headache Society were met. Headache severity was classified using a visual numeric rating scale and time to reach pain free status for 2 consecutive hours was ascertained. Researchers found:

• The median severity of migraine headaches was 10/10 and time to resolution of headaches was 120 minutes (range 60–360 minutes).
• Migraine headaches occurred in 4 (18.1%) of 22 patients with a history of migraine and 4 (23.5%) of 17 patients with regular migraine headaches (≥1 episodes per month).
• Headaches occurred in 6 (3.8%) patients who did not meet the criteria for migraine headaches.

Qureshi AI, Naseem N, Saleem MA, Potluri A, Raja F, Wallery SS. Migraine and non‐migraine headaches following diagnostic catheter‐based cerebral angiography. [Published online ahead of print August 16, 2018]. Headache. doi:10.1111/head.13377.

Migraine headaches occurred in 5 (3.1%) of 158 patients who underwent cerebral angiography, according to a recent observational cohort study that ascertained the frequency and type of headaches following catheter‐based cerebral angiography. Consecutive patients who underwent cerebral angiography through the transfemoral (or infrequently, radial) route were included. Each patient underwent a brief neurological assessment after the procedure and more detailed assessment was performed if any patient reported occurrence of a headache. The headaches were classified as migraine if the diagnostic criteria specified by International Headache Society were met. Headache severity was classified using a visual numeric rating scale and time to reach pain free status for 2 consecutive hours was ascertained. Researchers found:

• The median severity of migraine headaches was 10/10 and time to resolution of headaches was 120 minutes (range 60–360 minutes).
• Migraine headaches occurred in 4 (18.1%) of 22 patients with a history of migraine and 4 (23.5%) of 17 patients with regular migraine headaches (≥1 episodes per month).
• Headaches occurred in 6 (3.8%) patients who did not meet the criteria for migraine headaches.

Qureshi AI, Naseem N, Saleem MA, Potluri A, Raja F, Wallery SS. Migraine and non‐migraine headaches following diagnostic catheter‐based cerebral angiography. [Published online ahead of print August 16, 2018]. Headache. doi:10.1111/head.13377.

Migraine headaches occurred in 5 (3.1%) of 158 patients who underwent cerebral angiography, according to a recent observational cohort study that ascertained the frequency and type of headaches following catheter‐based cerebral angiography. Consecutive patients who underwent cerebral angiography through the transfemoral (or infrequently, radial) route were included. Each patient underwent a brief neurological assessment after the procedure and more detailed assessment was performed if any patient reported occurrence of a headache. The headaches were classified as migraine if the diagnostic criteria specified by International Headache Society were met. Headache severity was classified using a visual numeric rating scale and time to reach pain free status for 2 consecutive hours was ascertained. Researchers found:

• The median severity of migraine headaches was 10/10 and time to resolution of headaches was 120 minutes (range 60–360 minutes).
• Migraine headaches occurred in 4 (18.1%) of 22 patients with a history of migraine and 4 (23.5%) of 17 patients with regular migraine headaches (≥1 episodes per month).
• Headaches occurred in 6 (3.8%) patients who did not meet the criteria for migraine headaches.

Qureshi AI, Naseem N, Saleem MA, Potluri A, Raja F, Wallery SS. Migraine and non‐migraine headaches following diagnostic catheter‐based cerebral angiography. [Published online ahead of print August 16, 2018]. Headache. doi:10.1111/head.13377.

Children with chronic headache and migraine who are severely functionally impaired demonstrated linear improvement in pain‐specific patient‐reported outcomes over time, according to a recent study that aimed to evaluate the trajectory of recovery for children undergoing intensive interdisciplinary pain rehabilitation treatment (IIPT). A retrospective analysis was conducted of patient‐reported outcomes in a clinical database of 135 children (mean age 15.2 [SD=2.2] and 74% female) admitted to an IIPT program between the years 2008 and 2014. Available data across 5 separate time points (up to 1‐year post‐discharge) were reviewed. Researchers found:

• A statistically significant improvement was noted in pain‐specific measures of functioning, including daily functioning, emotional functioning, family functioning, and school absences over a 12‐month period.
• A more general measure of quality of life improved during the program, based upon child and parent reports, although these gains did not continue to improve post‐discharge.
• As expected, although children did not report a reduction in pain during rehabilitation, they did report a significant drop in perceived pain in the 12 months following discharge from the program.

Benore E, Webster EE, Wang L, Banez G. Longitudinal analysis of patient‐reported outcomes from an interdisciplinary pediatric pain rehabilitation program for children with chronic migraine and headache. [Published online ahead of print August 23, 2018]. Headache. doi:10.1111/head.13389.

Children with chronic headache and migraine who are severely functionally impaired demonstrated linear improvement in pain‐specific patient‐reported outcomes over time, according to a recent study that aimed to evaluate the trajectory of recovery for children undergoing intensive interdisciplinary pain rehabilitation treatment (IIPT). A retrospective analysis was conducted of patient‐reported outcomes in a clinical database of 135 children (mean age 15.2 [SD=2.2] and 74% female) admitted to an IIPT program between the years 2008 and 2014. Available data across 5 separate time points (up to 1‐year post‐discharge) were reviewed. Researchers found:

• A statistically significant improvement was noted in pain‐specific measures of functioning, including daily functioning, emotional functioning, family functioning, and school absences over a 12‐month period.
• A more general measure of quality of life improved during the program, based upon child and parent reports, although these gains did not continue to improve post‐discharge.
• As expected, although children did not report a reduction in pain during rehabilitation, they did report a significant drop in perceived pain in the 12 months following discharge from the program.

Benore E, Webster EE, Wang L, Banez G. Longitudinal analysis of patient‐reported outcomes from an interdisciplinary pediatric pain rehabilitation program for children with chronic migraine and headache. [Published online ahead of print August 23, 2018]. Headache. doi:10.1111/head.13389.

Children with chronic headache and migraine who are severely functionally impaired demonstrated linear improvement in pain‐specific patient‐reported outcomes over time, according to a recent study that aimed to evaluate the trajectory of recovery for children undergoing intensive interdisciplinary pain rehabilitation treatment (IIPT). A retrospective analysis was conducted of patient‐reported outcomes in a clinical database of 135 children (mean age 15.2 [SD=2.2] and 74% female) admitted to an IIPT program between the years 2008 and 2014. Available data across 5 separate time points (up to 1‐year post‐discharge) were reviewed. Researchers found:

• A statistically significant improvement was noted in pain‐specific measures of functioning, including daily functioning, emotional functioning, family functioning, and school absences over a 12‐month period.
• A more general measure of quality of life improved during the program, based upon child and parent reports, although these gains did not continue to improve post‐discharge.
• As expected, although children did not report a reduction in pain during rehabilitation, they did report a significant drop in perceived pain in the 12 months following discharge from the program.

Benore E, Webster EE, Wang L, Banez G. Longitudinal analysis of patient‐reported outcomes from an interdisciplinary pediatric pain rehabilitation program for children with chronic migraine and headache. [Published online ahead of print August 23, 2018]. Headache. doi:10.1111/head.13389.

Preliminary data indicate that hybrid cognitive‐behavioral therapy is feasible and acceptable for youth with co‐occurring chronic migraine and insomnia, according to a recent study. Researchers conducted a single‐arm pilot trial to evaluate the feasibility and acceptability of delivering cognitive‐behavioral therapy for insomnia to 21 youth (mean age 15.5 years) with co‐occurring chronic migraine and insomnia. Adolescents completed up to 6 individual treatment sessions over 6 to 12 weeks, and 1 booster session 1 month later. Assessments included a prospective 7‐day headache and sleep diary, and self‐report measures of insomnia, sleep quality, sleep habits, and activity limitations at pre‐treatment, immediate post‐treatment, and 3‐month follow‐up. Researchers found:

• Adolescents demonstrated good treatment adherence and families rated the intervention as highly acceptable.
• Preliminary analyses indicated improvements from pre‐treatment to post‐treatment in primary outcomes of headache days (M=4.7, SD=2.1 vs M=2.8, SD=2.7) and insomnia symptoms (M=16.9, SD=5.2 vs M=9.5, SD=6.2), which were maintained at 3‐month follow‐up (M=2.7, SD=2.8; M=9.3, SD=5.0, respectively).
• Improvements were also found in secondary outcomes of pain‐related activity limitations as well as sleep quality, sleep hygiene, and sleep patterns.

Law EF, Tham SW, Aaron RV, Dudeney J, Palermo TM. Hybrid cognitive‐behavioral therapy intervention for adolescents with co‐occurring migraine and insomnia: A single‐arm pilot trial. [Published online ahead of print August 27, 2018]. Headache. doi:10.1111/head.13355.

Preliminary data indicate that hybrid cognitive‐behavioral therapy is feasible and acceptable for youth with co‐occurring chronic migraine and insomnia, according to a recent study. Researchers conducted a single‐arm pilot trial to evaluate the feasibility and acceptability of delivering cognitive‐behavioral therapy for insomnia to 21 youth (mean age 15.5 years) with co‐occurring chronic migraine and insomnia. Adolescents completed up to 6 individual treatment sessions over 6 to 12 weeks, and 1 booster session 1 month later. Assessments included a prospective 7‐day headache and sleep diary, and self‐report measures of insomnia, sleep quality, sleep habits, and activity limitations at pre‐treatment, immediate post‐treatment, and 3‐month follow‐up. Researchers found:

• Adolescents demonstrated good treatment adherence and families rated the intervention as highly acceptable.
• Preliminary analyses indicated improvements from pre‐treatment to post‐treatment in primary outcomes of headache days (M=4.7, SD=2.1 vs M=2.8, SD=2.7) and insomnia symptoms (M=16.9, SD=5.2 vs M=9.5, SD=6.2), which were maintained at 3‐month follow‐up (M=2.7, SD=2.8; M=9.3, SD=5.0, respectively).
• Improvements were also found in secondary outcomes of pain‐related activity limitations as well as sleep quality, sleep hygiene, and sleep patterns.

Law EF, Tham SW, Aaron RV, Dudeney J, Palermo TM. Hybrid cognitive‐behavioral therapy intervention for adolescents with co‐occurring migraine and insomnia: A single‐arm pilot trial. [Published online ahead of print August 27, 2018]. Headache. doi:10.1111/head.13355.

Preliminary data indicate that hybrid cognitive‐behavioral therapy is feasible and acceptable for youth with co‐occurring chronic migraine and insomnia, according to a recent study. Researchers conducted a single‐arm pilot trial to evaluate the feasibility and acceptability of delivering cognitive‐behavioral therapy for insomnia to 21 youth (mean age 15.5 years) with co‐occurring chronic migraine and insomnia. Adolescents completed up to 6 individual treatment sessions over 6 to 12 weeks, and 1 booster session 1 month later. Assessments included a prospective 7‐day headache and sleep diary, and self‐report measures of insomnia, sleep quality, sleep habits, and activity limitations at pre‐treatment, immediate post‐treatment, and 3‐month follow‐up. Researchers found:

• Adolescents demonstrated good treatment adherence and families rated the intervention as highly acceptable.
• Preliminary analyses indicated improvements from pre‐treatment to post‐treatment in primary outcomes of headache days (M=4.7, SD=2.1 vs M=2.8, SD=2.7) and insomnia symptoms (M=16.9, SD=5.2 vs M=9.5, SD=6.2), which were maintained at 3‐month follow‐up (M=2.7, SD=2.8; M=9.3, SD=5.0, respectively).
• Improvements were also found in secondary outcomes of pain‐related activity limitations as well as sleep quality, sleep hygiene, and sleep patterns.

Law EF, Tham SW, Aaron RV, Dudeney J, Palermo TM. Hybrid cognitive‐behavioral therapy intervention for adolescents with co‐occurring migraine and insomnia: A single‐arm pilot trial. [Published online ahead of print August 27, 2018]. Headache. doi:10.1111/head.13355.

BALTIMORE—Multiple dimensions of sleep may temporally precede acute risk of migraine attack among patients with episodic migraine, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies. While some aspects of sleep appear to protect against next-day headache, “these novel pilot data support the hypothesis that self-reported fragmented sleep is associated with higher risk of migraine two days later,” said Suzanne M. Bertisch, MD, MPH, and colleagues. Dr. Bertisch is an Assistant Professor of Medicine at Harvard Medical School and a Director of Behavioral Sleep Medicine at Brigham and Women’s Hospital in Boston.

Retrospective studies have indicated that nearly half of patients with migraine identify too little or too much sleep as a migraine trigger. One prospective study reported a higher incidence of headache, both migraine and tension type, after two consecutive nights of four or fewer hours of sleep, as measured by self-report. This study accounted for daily stress but not other potential triggers of migraine. “To date, there have been no prospective studies on the association between objectively assessed sleep parameters and migraine incidence while accounting for other potential triggers of migraine,” Dr. Bertisch said.

A Cohort Study of Migraine Triggers

She and her colleagues assessed the independent contribution of sleep characteristics as temporal precedents of migraine. “We were particularly interested … in sleep duration, fragmentation, and self-reported quality.” To examine these factors, they developed a cohort study of migraine triggers that they conducted from March 2016 to August 2017.

The researchers enrolled 101 adults with episodic migraine from the greater Boston area. Inclusion criteria included at least two migraines per month but fewer than 15 headache days per month, a history of migraine for at least three years, and fulfillment of ICHD-3 criteria for episodic migraine. Exclusion criteria included untreated obstructive sleep apnea, pregnancy, and current opioid use.

Data were collected for six weeks. Study participants were prompted to complete morning and evening diaries that recorded information on sleep, including the pattern, fragmentation, and sleep quality; physical activity and daily mood; medications; and headache characteristics. Patients also wore wrist actigraphs for the duration of the six-week study. Each patient had about 40 days of diary and actigraphy data.

Patients reported the onset and duration of headaches, associated symptoms, whether their pain was a headache or a migraine, maximum pain intensity, and any abortive medications used. Data on daily covariates such as alcohol and caffeine consumption, self-reported physical activity, menstrual cycle, stress, and mood prior to bedtime also were collected.

Dr. Bertisch and colleagues used self-matched case–crossover analyses. “Each person served as [his or her] own control. This approach accounts for time-invariant confounders, including sex, genetics, and usual migraine frequency. We used a conditional logistic regression model that was self-matched by day of the week, because there might be an influence of weekend versus weekday sleep patterns, as well as migraine, and we adjusted for time-dependent covariates, including daily alcohol and caffeine use.”

High WASO Protected Against Next-Day Headache

The 98 participants included in the analyses reflected the known migraine prevalence. “They were generally younger women with an average age of 35, and generally a healthy population,” Dr. Bertisch said. “About one-third reported a history of migraine with aura, and about one-quarter used daily medications to prevent migraines. About 60% reported that sleeping too little triggered their migraines.”

The researchers collected data by actigraphy and diary during approximately 4,500 nights and found that their cohort’s sleep was relatively healthy. “They slept over seven hours per night, they had few sleep problems, they had high sleep efficiency, and they had modest alcohol or caffeine consumption during the study,” Dr. Bertisch said.

In an analysis of diary data, there was no association between odds of a next-day headache and sleep duration, wake after sleep onset (WASO), sleep efficiency, or sleep quality. “However, when we looked at the actigraphy measures, we did find associations with lower sleep efficiency and higher WASO, each associated with lower risk of next-day headache,” Dr. Bertisch said.

“When we looked at odds of headache two days later, we did find that a low sleep efficiency based on self-report was associated with a higher risk of migraine. We also noted a similar trend with self-reported short sleep duration. For actigraphy data, we found a somewhat similar pattern. We also found that sleep duration greater than 8.5 hours was associated with lower risk of migraine two days later.”

In summary, sleep efficiency and high WASO may be associated with lower odds of next-day headache. For sleep two nights before the headache, low sleep efficiency was associated with higher odds of headache. Long sleep duration, as assessed by actigraphy, was associated with lower odds of headache two days later.

—Glenn S. Williams

BALTIMORE—Multiple dimensions of sleep may temporally precede acute risk of migraine attack among patients with episodic migraine, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies. While some aspects of sleep appear to protect against next-day headache, “these novel pilot data support the hypothesis that self-reported fragmented sleep is associated with higher risk of migraine two days later,” said Suzanne M. Bertisch, MD, MPH, and colleagues. Dr. Bertisch is an Assistant Professor of Medicine at Harvard Medical School and a Director of Behavioral Sleep Medicine at Brigham and Women’s Hospital in Boston.

Retrospective studies have indicated that nearly half of patients with migraine identify too little or too much sleep as a migraine trigger. One prospective study reported a higher incidence of headache, both migraine and tension type, after two consecutive nights of four or fewer hours of sleep, as measured by self-report. This study accounted for daily stress but not other potential triggers of migraine. “To date, there have been no prospective studies on the association between objectively assessed sleep parameters and migraine incidence while accounting for other potential triggers of migraine,” Dr. Bertisch said.

A Cohort Study of Migraine Triggers

She and her colleagues assessed the independent contribution of sleep characteristics as temporal precedents of migraine. “We were particularly interested … in sleep duration, fragmentation, and self-reported quality.” To examine these factors, they developed a cohort study of migraine triggers that they conducted from March 2016 to August 2017.

The researchers enrolled 101 adults with episodic migraine from the greater Boston area. Inclusion criteria included at least two migraines per month but fewer than 15 headache days per month, a history of migraine for at least three years, and fulfillment of ICHD-3 criteria for episodic migraine. Exclusion criteria included untreated obstructive sleep apnea, pregnancy, and current opioid use.

Data were collected for six weeks. Study participants were prompted to complete morning and evening diaries that recorded information on sleep, including the pattern, fragmentation, and sleep quality; physical activity and daily mood; medications; and headache characteristics. Patients also wore wrist actigraphs for the duration of the six-week study. Each patient had about 40 days of diary and actigraphy data.

Patients reported the onset and duration of headaches, associated symptoms, whether their pain was a headache or a migraine, maximum pain intensity, and any abortive medications used. Data on daily covariates such as alcohol and caffeine consumption, self-reported physical activity, menstrual cycle, stress, and mood prior to bedtime also were collected.

Dr. Bertisch and colleagues used self-matched case–crossover analyses. “Each person served as [his or her] own control. This approach accounts for time-invariant confounders, including sex, genetics, and usual migraine frequency. We used a conditional logistic regression model that was self-matched by day of the week, because there might be an influence of weekend versus weekday sleep patterns, as well as migraine, and we adjusted for time-dependent covariates, including daily alcohol and caffeine use.”

High WASO Protected Against Next-Day Headache

The 98 participants included in the analyses reflected the known migraine prevalence. “They were generally younger women with an average age of 35, and generally a healthy population,” Dr. Bertisch said. “About one-third reported a history of migraine with aura, and about one-quarter used daily medications to prevent migraines. About 60% reported that sleeping too little triggered their migraines.”

The researchers collected data by actigraphy and diary during approximately 4,500 nights and found that their cohort’s sleep was relatively healthy. “They slept over seven hours per night, they had few sleep problems, they had high sleep efficiency, and they had modest alcohol or caffeine consumption during the study,” Dr. Bertisch said.

In an analysis of diary data, there was no association between odds of a next-day headache and sleep duration, wake after sleep onset (WASO), sleep efficiency, or sleep quality. “However, when we looked at the actigraphy measures, we did find associations with lower sleep efficiency and higher WASO, each associated with lower risk of next-day headache,” Dr. Bertisch said.

“When we looked at odds of headache two days later, we did find that a low sleep efficiency based on self-report was associated with a higher risk of migraine. We also noted a similar trend with self-reported short sleep duration. For actigraphy data, we found a somewhat similar pattern. We also found that sleep duration greater than 8.5 hours was associated with lower risk of migraine two days later.”

In summary, sleep efficiency and high WASO may be associated with lower odds of next-day headache. For sleep two nights before the headache, low sleep efficiency was associated with higher odds of headache. Long sleep duration, as assessed by actigraphy, was associated with lower odds of headache two days later.

—Glenn S. Williams

BALTIMORE—Multiple dimensions of sleep may temporally precede acute risk of migraine attack among patients with episodic migraine, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies. While some aspects of sleep appear to protect against next-day headache, “these novel pilot data support the hypothesis that self-reported fragmented sleep is associated with higher risk of migraine two days later,” said Suzanne M. Bertisch, MD, MPH, and colleagues. Dr. Bertisch is an Assistant Professor of Medicine at Harvard Medical School and a Director of Behavioral Sleep Medicine at Brigham and Women’s Hospital in Boston.

Retrospective studies have indicated that nearly half of patients with migraine identify too little or too much sleep as a migraine trigger. One prospective study reported a higher incidence of headache, both migraine and tension type, after two consecutive nights of four or fewer hours of sleep, as measured by self-report. This study accounted for daily stress but not other potential triggers of migraine. “To date, there have been no prospective studies on the association between objectively assessed sleep parameters and migraine incidence while accounting for other potential triggers of migraine,” Dr. Bertisch said.

A Cohort Study of Migraine Triggers

She and her colleagues assessed the independent contribution of sleep characteristics as temporal precedents of migraine. “We were particularly interested … in sleep duration, fragmentation, and self-reported quality.” To examine these factors, they developed a cohort study of migraine triggers that they conducted from March 2016 to August 2017.

The researchers enrolled 101 adults with episodic migraine from the greater Boston area. Inclusion criteria included at least two migraines per month but fewer than 15 headache days per month, a history of migraine for at least three years, and fulfillment of ICHD-3 criteria for episodic migraine. Exclusion criteria included untreated obstructive sleep apnea, pregnancy, and current opioid use.

Data were collected for six weeks. Study participants were prompted to complete morning and evening diaries that recorded information on sleep, including the pattern, fragmentation, and sleep quality; physical activity and daily mood; medications; and headache characteristics. Patients also wore wrist actigraphs for the duration of the six-week study. Each patient had about 40 days of diary and actigraphy data.

Patients reported the onset and duration of headaches, associated symptoms, whether their pain was a headache or a migraine, maximum pain intensity, and any abortive medications used. Data on daily covariates such as alcohol and caffeine consumption, self-reported physical activity, menstrual cycle, stress, and mood prior to bedtime also were collected.

Dr. Bertisch and colleagues used self-matched case–crossover analyses. “Each person served as [his or her] own control. This approach accounts for time-invariant confounders, including sex, genetics, and usual migraine frequency. We used a conditional logistic regression model that was self-matched by day of the week, because there might be an influence of weekend versus weekday sleep patterns, as well as migraine, and we adjusted for time-dependent covariates, including daily alcohol and caffeine use.”

High WASO Protected Against Next-Day Headache

The 98 participants included in the analyses reflected the known migraine prevalence. “They were generally younger women with an average age of 35, and generally a healthy population,” Dr. Bertisch said. “About one-third reported a history of migraine with aura, and about one-quarter used daily medications to prevent migraines. About 60% reported that sleeping too little triggered their migraines.”

The researchers collected data by actigraphy and diary during approximately 4,500 nights and found that their cohort’s sleep was relatively healthy. “They slept over seven hours per night, they had few sleep problems, they had high sleep efficiency, and they had modest alcohol or caffeine consumption during the study,” Dr. Bertisch said.

In an analysis of diary data, there was no association between odds of a next-day headache and sleep duration, wake after sleep onset (WASO), sleep efficiency, or sleep quality. “However, when we looked at the actigraphy measures, we did find associations with lower sleep efficiency and higher WASO, each associated with lower risk of next-day headache,” Dr. Bertisch said.

“When we looked at odds of headache two days later, we did find that a low sleep efficiency based on self-report was associated with a higher risk of migraine. We also noted a similar trend with self-reported short sleep duration. For actigraphy data, we found a somewhat similar pattern. We also found that sleep duration greater than 8.5 hours was associated with lower risk of migraine two days later.”

In summary, sleep efficiency and high WASO may be associated with lower odds of next-day headache. For sleep two nights before the headache, low sleep efficiency was associated with higher odds of headache. Long sleep duration, as assessed by actigraphy, was associated with lower odds of headache two days later.

—Glenn S. Williams