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Patent Foramen Ovale, Migraine, and Stroke Examined
In patients with cryptogenic stroke who have migraine, there is a high prevalence (79%) of patent foramen ovale (PFO) with right-to-left shunt, according to a recent study. Furthermore, the timing of the stroke in migraineurs is usually not related to a migraine attack. Patients between the ages of 18 and 60 who presented with an ischemic stroke were characterized based on ASCOD (atherosclerosis, small vessel disease, cardiac pathology, other causes, dissection) phenotyping. A migraine diagnosis was identified by reviewing physician notes, and frequent aura was defined if present in at least 50% of attacks. A PFO with right-to-left shunt diagnosis was identified by the presence of a positive bubble contrast study. Researchers found:
- Of the 712 patients who presented with ischemic stroke, 127 (18%) were diagnosed as cryptogenic; 68 patients had adequate testing for PFO and a documented migraine history.
- The prevalence of PFO in patients with cryptogenic stroke without migraine was elevated (59%) compared with the general population (18%).
- Patients with both cryptogenic stroke and migraine had a higher prevalence of PFO (79%).
In patients with cryptogenic stroke who had migraine with frequent aura, the prevalence of PFO was 93%.
Frequency of patent foramen ovale and migraine in patients with cryptogenic stroke. [Published online ahead of print April 10, 2018]. Stroke. doi:10.1161/STROKEAHA.117.020160.
In patients with cryptogenic stroke who have migraine, there is a high prevalence (79%) of patent foramen ovale (PFO) with right-to-left shunt, according to a recent study. Furthermore, the timing of the stroke in migraineurs is usually not related to a migraine attack. Patients between the ages of 18 and 60 who presented with an ischemic stroke were characterized based on ASCOD (atherosclerosis, small vessel disease, cardiac pathology, other causes, dissection) phenotyping. A migraine diagnosis was identified by reviewing physician notes, and frequent aura was defined if present in at least 50% of attacks. A PFO with right-to-left shunt diagnosis was identified by the presence of a positive bubble contrast study. Researchers found:
- Of the 712 patients who presented with ischemic stroke, 127 (18%) were diagnosed as cryptogenic; 68 patients had adequate testing for PFO and a documented migraine history.
- The prevalence of PFO in patients with cryptogenic stroke without migraine was elevated (59%) compared with the general population (18%).
- Patients with both cryptogenic stroke and migraine had a higher prevalence of PFO (79%).
In patients with cryptogenic stroke who had migraine with frequent aura, the prevalence of PFO was 93%.
Frequency of patent foramen ovale and migraine in patients with cryptogenic stroke. [Published online ahead of print April 10, 2018]. Stroke. doi:10.1161/STROKEAHA.117.020160.
In patients with cryptogenic stroke who have migraine, there is a high prevalence (79%) of patent foramen ovale (PFO) with right-to-left shunt, according to a recent study. Furthermore, the timing of the stroke in migraineurs is usually not related to a migraine attack. Patients between the ages of 18 and 60 who presented with an ischemic stroke were characterized based on ASCOD (atherosclerosis, small vessel disease, cardiac pathology, other causes, dissection) phenotyping. A migraine diagnosis was identified by reviewing physician notes, and frequent aura was defined if present in at least 50% of attacks. A PFO with right-to-left shunt diagnosis was identified by the presence of a positive bubble contrast study. Researchers found:
- Of the 712 patients who presented with ischemic stroke, 127 (18%) were diagnosed as cryptogenic; 68 patients had adequate testing for PFO and a documented migraine history.
- The prevalence of PFO in patients with cryptogenic stroke without migraine was elevated (59%) compared with the general population (18%).
- Patients with both cryptogenic stroke and migraine had a higher prevalence of PFO (79%).
In patients with cryptogenic stroke who had migraine with frequent aura, the prevalence of PFO was 93%.
Frequency of patent foramen ovale and migraine in patients with cryptogenic stroke. [Published online ahead of print April 10, 2018]. Stroke. doi:10.1161/STROKEAHA.117.020160.
Does Migraine Transiently Open the Blood–Brain Barrier?
STOWE, VT—Experimental evidence suggests that migraine, particularly migraine with aura, is associated with cortical spreading depression (CSD) that transiently disrupts the blood–brain barrier (BBB). For some, the question is not whether this disruption occurs, but whether it is clinically relevant. For others, even the basic premise of a CSD-mediated disruption of the BBB is suspect. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, a debate between two researchers from opposing sides of this controversy indicated that there was little common ground.
“Experiments in mice suggest that CSD might open the BBB and activate pain-sensitive fibers. However, you have heard nothing about data from humans, and in fact, many migraine patients report aura symptoms without head pain,” said Messoud Ashina, MD, PhD, Director of the Human Migraine Research Unit at the Danish Headache Center in Glostrup.
On the contrary, the scientific evidence that CSD opens the BBB is “incontrovertible,” according to Cenk Ayata, MD, PhD, Director of the Neurovascular Research Unit at Massachusetts General Hospital in Charlestown. “It is not a matter of whether the BBB opens, it is a matter of magnitude,” he said. “The critical question is whether it is clinically relevant.”
This controversy is of particular current interest. Although CSD has long been suspected to mediate migraine pain, a transient opening of the BBB may greatly affect the efficacy of monoclonal antibodies in development for migraine prophylaxis and treatment. Monoclonal antibodies that target the calcitonin gene-related peptide (CGRP) have shown promise in ongoing trials, but an opportunity to target the CNS directly could improve their efficacy. Monoclonal antibodies are too large to cross the BBB without increasing the latter’s permeability.
What Is CSD?
CSD is a wave of intense neurologic depolarization that is considered the electrophysiologic substrate of migraine aura, according to Dr. Ayata. The “massive transmembrane ion and water shifts hit the cerebral vasculature during CSD like a tsunami,” he said. Citing more than two decades’ worth of research, Dr. Ayata explained that CSD is accompanied by upregulation of multiple neurotransmitters and neuromodulators that trigger large blood flow responses and disrupt cerebrovascular reflexes, such as neurovascular coupling.
Initial studies of the role of CSD and its potential for disrupting the BBB were primarily related to stroke and head trauma. Numerous studies have supported the hypothesis that CSD is the underlying mechanism of migraine aura and a putative trigger for migraine headache. The specific sequence of events leading to CSD in migraine remains unclear, but Dr. Ayata and colleagues have conducted experiments that suggest that “CSD alone, without attendant tissue injury, can produce a transient opening of the BBB.”
In murine models of migraine, Evans blue leaked into the CNS after noninvasive induction of CSD. No leakage was observed in control animals that underwent a sham induction. Other controlled experiments that included objective measures of brain edema after CSD corroborated the association between CSD and BBB disruption.
“The opening of the BBB starts sometime between three and six hours [after induction of CSD], reaches a peak at six to 12 hours, and then gradually declines over the next 24 hours or so,” said Dr. Ayata. The BBB is completely restored at 48 hours, he added.
The Potential Role of Transcytosis
The BBB consists of astrocytes, pericytes, and endothelial cells with tight junctions that prevent most blood-borne substances from crossing into the CNS. Various processes can breach the BBB, and Dr. Ayata’s group is focusing on transcytosis. They hypothesize that ion pumps and other transporters cannot explain their observations that molecules as large as 70 kDa can pass through the BBB.
Transcytosis permits macromolecules from the luminal side of the endothelial cell to be brought into the cell by pinocytotic vesicles and to be released on the other side. It is a plausible mechanism for passage through the BBB, according to Dr. Ayata. Electron microscopy studies of BBB tissue from murine models strongly support this hypothesis.
“We found a significant increase in pinocytotic vesicles starting between three and six hours, but then a gradual decline to normal levels over the next 48 hours. This time course is exactly what we found in terms of leakage,” said Dr. Ayata. There was no evident change in endothelial tight junctions or in any other structure likely to provide an alternative mechanism for the observed BBB disruption, he added.
Although BBB disruption in an animal model of migraine is not proof of the same phenomenon in humans, Dr. Ayata suggested that the results are consistent with clinical observations. For example, a series of papers from 1985 to the present, including studies undertaken with gadolinium enhancement, found an association between severe migraine and documented edema. A twin study and studies of familial hemiplegic migraine also showed that CSD contributes to migraine pathogenesis and causes disruption of the BBB, he said.
Human Data Are Lacking
Although early studies provide a basis for the hypothesis that CSD is associated with migraine and might disrupt the BBB, clinical studies have consistently failed to link CSD with evidence of BBB disruption, said Dr. Ashina. In 1981, Olesen and colleagues reported cerebral hypoperfusion, a potential sign of CSD, followed by transient increases in cerebral perfusion (ie, hyperemia) during experimentally induced migraine aura.
“In some patients, headache disappeared when the hyperemia was observed, so there was no correlation,” said Dr. Ashina. Moreover, no changes in blood flow were observed when the same studies were conducted in patients with migraine without aura, and none of the studies reported changes in the permeability of the BBB in migraineurs with and without aura, according to Dr. Ashina. He and his colleagues at the Danish Headache Center remain active in this research.
He cited a 2017 study by Hougaard et al of 19 migraineurs with aura and 19 migraineurs without aura. Tissue perfusion in various parts of the brain was measured to assess change in BBB permeability. Patients underwent 3-T MRI during and in the absence of migraine attacks. “In aura patients, we found hyperperfusion in the brainstem during the headache phase of migraine with aura, while the BBB remained intact during attacks of migraine with aura,” said Dr. Ashina. Using sensitivity analyses, they looked for changes as small as 15%, but found nothing.
Other studies have looked more indirectly at the likelihood that the BBB is disrupted during migraine, but these, such as one that evaluated extracranial arterial dilatation during migraine attacks, have also been negative, according to Dr. Ashina. Studies of putative mechanisms for BBB disruption, such as one that evaluated the upregulation of matrix metalloproteinases, have also failed to support BBB disruption. “Nothing out there provides any evidence whatsoever that relates directly to BBB opening during migraine attacks with or without aura,” said Dr. Ashina.
If the BBB undergoes a transient disruption during migraine, it remains unclear whether this disruption is clinically meaningful or provides new opportunities to time treatment. The introduction of monoclonal antibodies for migraine may inspire the research needed to resolve this question.
Dr. Ashina has financial relationships with Alder BioPharmaceuticals, Allergan, Amgen, Eli Lilly, Novartis, and Teva. Dr. Ayata has no financial relationships relevant to this topic.
—Ted Bosworth
Amin FM, Asghar MS, Hougaard A, et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 2013;12(5):454-461.
Amin FM, Hougaard A, Cramer SP, et al. Intact blood-brain barrier during spontaneous attacks of migraine without aura: a 3T DCE-MRI study. Eur J Neurol. 2017;24(9):1116-1124.
Ashina M, Tvedskov JF, Lipka K, et al. Matrix metalloproteinases during and outside of migraine attacks without aura. Cephalalgia. 2010;30(3):303-310.
Ayata C, Lauritzen M. Spreading depression, spreading depolarizations, and the cerebral vasculature. Physiol Rev. 2015;95(3):953-993.
Hougaard A, Amin FM, Christensen CE, et al. Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura. Brain. 2017;140(6):1633-1642.
Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol. 1981;9(4):344-352.
STOWE, VT—Experimental evidence suggests that migraine, particularly migraine with aura, is associated with cortical spreading depression (CSD) that transiently disrupts the blood–brain barrier (BBB). For some, the question is not whether this disruption occurs, but whether it is clinically relevant. For others, even the basic premise of a CSD-mediated disruption of the BBB is suspect. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, a debate between two researchers from opposing sides of this controversy indicated that there was little common ground.
“Experiments in mice suggest that CSD might open the BBB and activate pain-sensitive fibers. However, you have heard nothing about data from humans, and in fact, many migraine patients report aura symptoms without head pain,” said Messoud Ashina, MD, PhD, Director of the Human Migraine Research Unit at the Danish Headache Center in Glostrup.
On the contrary, the scientific evidence that CSD opens the BBB is “incontrovertible,” according to Cenk Ayata, MD, PhD, Director of the Neurovascular Research Unit at Massachusetts General Hospital in Charlestown. “It is not a matter of whether the BBB opens, it is a matter of magnitude,” he said. “The critical question is whether it is clinically relevant.”
This controversy is of particular current interest. Although CSD has long been suspected to mediate migraine pain, a transient opening of the BBB may greatly affect the efficacy of monoclonal antibodies in development for migraine prophylaxis and treatment. Monoclonal antibodies that target the calcitonin gene-related peptide (CGRP) have shown promise in ongoing trials, but an opportunity to target the CNS directly could improve their efficacy. Monoclonal antibodies are too large to cross the BBB without increasing the latter’s permeability.
What Is CSD?
CSD is a wave of intense neurologic depolarization that is considered the electrophysiologic substrate of migraine aura, according to Dr. Ayata. The “massive transmembrane ion and water shifts hit the cerebral vasculature during CSD like a tsunami,” he said. Citing more than two decades’ worth of research, Dr. Ayata explained that CSD is accompanied by upregulation of multiple neurotransmitters and neuromodulators that trigger large blood flow responses and disrupt cerebrovascular reflexes, such as neurovascular coupling.
Initial studies of the role of CSD and its potential for disrupting the BBB were primarily related to stroke and head trauma. Numerous studies have supported the hypothesis that CSD is the underlying mechanism of migraine aura and a putative trigger for migraine headache. The specific sequence of events leading to CSD in migraine remains unclear, but Dr. Ayata and colleagues have conducted experiments that suggest that “CSD alone, without attendant tissue injury, can produce a transient opening of the BBB.”
In murine models of migraine, Evans blue leaked into the CNS after noninvasive induction of CSD. No leakage was observed in control animals that underwent a sham induction. Other controlled experiments that included objective measures of brain edema after CSD corroborated the association between CSD and BBB disruption.
“The opening of the BBB starts sometime between three and six hours [after induction of CSD], reaches a peak at six to 12 hours, and then gradually declines over the next 24 hours or so,” said Dr. Ayata. The BBB is completely restored at 48 hours, he added.
The Potential Role of Transcytosis
The BBB consists of astrocytes, pericytes, and endothelial cells with tight junctions that prevent most blood-borne substances from crossing into the CNS. Various processes can breach the BBB, and Dr. Ayata’s group is focusing on transcytosis. They hypothesize that ion pumps and other transporters cannot explain their observations that molecules as large as 70 kDa can pass through the BBB.
Transcytosis permits macromolecules from the luminal side of the endothelial cell to be brought into the cell by pinocytotic vesicles and to be released on the other side. It is a plausible mechanism for passage through the BBB, according to Dr. Ayata. Electron microscopy studies of BBB tissue from murine models strongly support this hypothesis.
“We found a significant increase in pinocytotic vesicles starting between three and six hours, but then a gradual decline to normal levels over the next 48 hours. This time course is exactly what we found in terms of leakage,” said Dr. Ayata. There was no evident change in endothelial tight junctions or in any other structure likely to provide an alternative mechanism for the observed BBB disruption, he added.
Although BBB disruption in an animal model of migraine is not proof of the same phenomenon in humans, Dr. Ayata suggested that the results are consistent with clinical observations. For example, a series of papers from 1985 to the present, including studies undertaken with gadolinium enhancement, found an association between severe migraine and documented edema. A twin study and studies of familial hemiplegic migraine also showed that CSD contributes to migraine pathogenesis and causes disruption of the BBB, he said.
Human Data Are Lacking
Although early studies provide a basis for the hypothesis that CSD is associated with migraine and might disrupt the BBB, clinical studies have consistently failed to link CSD with evidence of BBB disruption, said Dr. Ashina. In 1981, Olesen and colleagues reported cerebral hypoperfusion, a potential sign of CSD, followed by transient increases in cerebral perfusion (ie, hyperemia) during experimentally induced migraine aura.
“In some patients, headache disappeared when the hyperemia was observed, so there was no correlation,” said Dr. Ashina. Moreover, no changes in blood flow were observed when the same studies were conducted in patients with migraine without aura, and none of the studies reported changes in the permeability of the BBB in migraineurs with and without aura, according to Dr. Ashina. He and his colleagues at the Danish Headache Center remain active in this research.
He cited a 2017 study by Hougaard et al of 19 migraineurs with aura and 19 migraineurs without aura. Tissue perfusion in various parts of the brain was measured to assess change in BBB permeability. Patients underwent 3-T MRI during and in the absence of migraine attacks. “In aura patients, we found hyperperfusion in the brainstem during the headache phase of migraine with aura, while the BBB remained intact during attacks of migraine with aura,” said Dr. Ashina. Using sensitivity analyses, they looked for changes as small as 15%, but found nothing.
Other studies have looked more indirectly at the likelihood that the BBB is disrupted during migraine, but these, such as one that evaluated extracranial arterial dilatation during migraine attacks, have also been negative, according to Dr. Ashina. Studies of putative mechanisms for BBB disruption, such as one that evaluated the upregulation of matrix metalloproteinases, have also failed to support BBB disruption. “Nothing out there provides any evidence whatsoever that relates directly to BBB opening during migraine attacks with or without aura,” said Dr. Ashina.
If the BBB undergoes a transient disruption during migraine, it remains unclear whether this disruption is clinically meaningful or provides new opportunities to time treatment. The introduction of monoclonal antibodies for migraine may inspire the research needed to resolve this question.
Dr. Ashina has financial relationships with Alder BioPharmaceuticals, Allergan, Amgen, Eli Lilly, Novartis, and Teva. Dr. Ayata has no financial relationships relevant to this topic.
—Ted Bosworth
Amin FM, Asghar MS, Hougaard A, et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 2013;12(5):454-461.
Amin FM, Hougaard A, Cramer SP, et al. Intact blood-brain barrier during spontaneous attacks of migraine without aura: a 3T DCE-MRI study. Eur J Neurol. 2017;24(9):1116-1124.
Ashina M, Tvedskov JF, Lipka K, et al. Matrix metalloproteinases during and outside of migraine attacks without aura. Cephalalgia. 2010;30(3):303-310.
Ayata C, Lauritzen M. Spreading depression, spreading depolarizations, and the cerebral vasculature. Physiol Rev. 2015;95(3):953-993.
Hougaard A, Amin FM, Christensen CE, et al. Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura. Brain. 2017;140(6):1633-1642.
Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol. 1981;9(4):344-352.
STOWE, VT—Experimental evidence suggests that migraine, particularly migraine with aura, is associated with cortical spreading depression (CSD) that transiently disrupts the blood–brain barrier (BBB). For some, the question is not whether this disruption occurs, but whether it is clinically relevant. For others, even the basic premise of a CSD-mediated disruption of the BBB is suspect. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, a debate between two researchers from opposing sides of this controversy indicated that there was little common ground.
“Experiments in mice suggest that CSD might open the BBB and activate pain-sensitive fibers. However, you have heard nothing about data from humans, and in fact, many migraine patients report aura symptoms without head pain,” said Messoud Ashina, MD, PhD, Director of the Human Migraine Research Unit at the Danish Headache Center in Glostrup.
On the contrary, the scientific evidence that CSD opens the BBB is “incontrovertible,” according to Cenk Ayata, MD, PhD, Director of the Neurovascular Research Unit at Massachusetts General Hospital in Charlestown. “It is not a matter of whether the BBB opens, it is a matter of magnitude,” he said. “The critical question is whether it is clinically relevant.”
This controversy is of particular current interest. Although CSD has long been suspected to mediate migraine pain, a transient opening of the BBB may greatly affect the efficacy of monoclonal antibodies in development for migraine prophylaxis and treatment. Monoclonal antibodies that target the calcitonin gene-related peptide (CGRP) have shown promise in ongoing trials, but an opportunity to target the CNS directly could improve their efficacy. Monoclonal antibodies are too large to cross the BBB without increasing the latter’s permeability.
What Is CSD?
CSD is a wave of intense neurologic depolarization that is considered the electrophysiologic substrate of migraine aura, according to Dr. Ayata. The “massive transmembrane ion and water shifts hit the cerebral vasculature during CSD like a tsunami,” he said. Citing more than two decades’ worth of research, Dr. Ayata explained that CSD is accompanied by upregulation of multiple neurotransmitters and neuromodulators that trigger large blood flow responses and disrupt cerebrovascular reflexes, such as neurovascular coupling.
Initial studies of the role of CSD and its potential for disrupting the BBB were primarily related to stroke and head trauma. Numerous studies have supported the hypothesis that CSD is the underlying mechanism of migraine aura and a putative trigger for migraine headache. The specific sequence of events leading to CSD in migraine remains unclear, but Dr. Ayata and colleagues have conducted experiments that suggest that “CSD alone, without attendant tissue injury, can produce a transient opening of the BBB.”
In murine models of migraine, Evans blue leaked into the CNS after noninvasive induction of CSD. No leakage was observed in control animals that underwent a sham induction. Other controlled experiments that included objective measures of brain edema after CSD corroborated the association between CSD and BBB disruption.
“The opening of the BBB starts sometime between three and six hours [after induction of CSD], reaches a peak at six to 12 hours, and then gradually declines over the next 24 hours or so,” said Dr. Ayata. The BBB is completely restored at 48 hours, he added.
The Potential Role of Transcytosis
The BBB consists of astrocytes, pericytes, and endothelial cells with tight junctions that prevent most blood-borne substances from crossing into the CNS. Various processes can breach the BBB, and Dr. Ayata’s group is focusing on transcytosis. They hypothesize that ion pumps and other transporters cannot explain their observations that molecules as large as 70 kDa can pass through the BBB.
Transcytosis permits macromolecules from the luminal side of the endothelial cell to be brought into the cell by pinocytotic vesicles and to be released on the other side. It is a plausible mechanism for passage through the BBB, according to Dr. Ayata. Electron microscopy studies of BBB tissue from murine models strongly support this hypothesis.
“We found a significant increase in pinocytotic vesicles starting between three and six hours, but then a gradual decline to normal levels over the next 48 hours. This time course is exactly what we found in terms of leakage,” said Dr. Ayata. There was no evident change in endothelial tight junctions or in any other structure likely to provide an alternative mechanism for the observed BBB disruption, he added.
Although BBB disruption in an animal model of migraine is not proof of the same phenomenon in humans, Dr. Ayata suggested that the results are consistent with clinical observations. For example, a series of papers from 1985 to the present, including studies undertaken with gadolinium enhancement, found an association between severe migraine and documented edema. A twin study and studies of familial hemiplegic migraine also showed that CSD contributes to migraine pathogenesis and causes disruption of the BBB, he said.
Human Data Are Lacking
Although early studies provide a basis for the hypothesis that CSD is associated with migraine and might disrupt the BBB, clinical studies have consistently failed to link CSD with evidence of BBB disruption, said Dr. Ashina. In 1981, Olesen and colleagues reported cerebral hypoperfusion, a potential sign of CSD, followed by transient increases in cerebral perfusion (ie, hyperemia) during experimentally induced migraine aura.
“In some patients, headache disappeared when the hyperemia was observed, so there was no correlation,” said Dr. Ashina. Moreover, no changes in blood flow were observed when the same studies were conducted in patients with migraine without aura, and none of the studies reported changes in the permeability of the BBB in migraineurs with and without aura, according to Dr. Ashina. He and his colleagues at the Danish Headache Center remain active in this research.
He cited a 2017 study by Hougaard et al of 19 migraineurs with aura and 19 migraineurs without aura. Tissue perfusion in various parts of the brain was measured to assess change in BBB permeability. Patients underwent 3-T MRI during and in the absence of migraine attacks. “In aura patients, we found hyperperfusion in the brainstem during the headache phase of migraine with aura, while the BBB remained intact during attacks of migraine with aura,” said Dr. Ashina. Using sensitivity analyses, they looked for changes as small as 15%, but found nothing.
Other studies have looked more indirectly at the likelihood that the BBB is disrupted during migraine, but these, such as one that evaluated extracranial arterial dilatation during migraine attacks, have also been negative, according to Dr. Ashina. Studies of putative mechanisms for BBB disruption, such as one that evaluated the upregulation of matrix metalloproteinases, have also failed to support BBB disruption. “Nothing out there provides any evidence whatsoever that relates directly to BBB opening during migraine attacks with or without aura,” said Dr. Ashina.
If the BBB undergoes a transient disruption during migraine, it remains unclear whether this disruption is clinically meaningful or provides new opportunities to time treatment. The introduction of monoclonal antibodies for migraine may inspire the research needed to resolve this question.
Dr. Ashina has financial relationships with Alder BioPharmaceuticals, Allergan, Amgen, Eli Lilly, Novartis, and Teva. Dr. Ayata has no financial relationships relevant to this topic.
—Ted Bosworth
Amin FM, Asghar MS, Hougaard A, et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 2013;12(5):454-461.
Amin FM, Hougaard A, Cramer SP, et al. Intact blood-brain barrier during spontaneous attacks of migraine without aura: a 3T DCE-MRI study. Eur J Neurol. 2017;24(9):1116-1124.
Ashina M, Tvedskov JF, Lipka K, et al. Matrix metalloproteinases during and outside of migraine attacks without aura. Cephalalgia. 2010;30(3):303-310.
Ayata C, Lauritzen M. Spreading depression, spreading depolarizations, and the cerebral vasculature. Physiol Rev. 2015;95(3):953-993.
Hougaard A, Amin FM, Christensen CE, et al. Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura. Brain. 2017;140(6):1633-1642.
Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol. 1981;9(4):344-352.
MRI Techniques Could Help Distinguish Between MS and Migraine
STOWE, VT—Some patients with migraine receive an inappropriate diagnosis of multiple sclerosis (MS). The two disorders share certain clinical and radiologic features, and misdiagnosis is a significant problem. Using MRI scanners widely available to clinicians, researchers are developing several imaging techniques that can provide an objective basis for distinguishing between MS and migraine, according to an overview provided at the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium.
The imaging techniques evaluate different aspects of MS pathology, said Andrew J. Solomon, MD, Associate Professor of Neurological Sciences at the University of Vermont College of Medicine in Burlington. The techniques have been automated to a large extent, which reduces the need for human interpretation of data. The incorporation of machine learning could further aid differential diagnosis.
Grounds for Confusion
Various similarities between migraine and MS increase the likelihood of misdiagnosis. The two disorders are chronic and entail attacks and remissions. Both are associated with changes in brain structure and white matter abnormalities that may be subclinical.
In a study of patients with migraine by Liu et al, between 25% and 35% of participants met MRI criteria for dissemination in space for MS, depending on how lesions were defined. The first report of natalizumab-associated progressive multifocal leukoencephalopathy occurred in a patient who, on autopsy, was found not to have had MS. In a 1988 study, Engell and colleagues found that of 518 consecutive patients who had died with a diagnosis of clinically definite MS, the diagnosis was incorrect for 6%.
In 2005, Carmosino and colleagues evaluated 281 patients who had been referred to an MS center and found that 67% of them did not have MS. The investigators identified 37 alternative diagnoses, of which migraine was the second most common. About 10% of participants had a final diagnosis of migraine.
In a recent survey, Dr. Solomon and colleagues asked more than 100 MS specialists whether they had seen patients who had had a diagnosis of MS for more than one year, but, on evaluation, determined that they did not have MS. Approximately 95% of respondents answered affirmatively. About 40% of respondents reported having seen three to five such patients in the previous year.
The current diagnostic criteria for MS rely on clinicians to interpret clinical and radiologic data and contain many caveats regarding their application, said Dr. Solomon. The criteria “were not developed to differentiate MS from other disorders,” but to predict which patients with an initial neurologic syndrome typical for MS will subsequently develop MS, he added. Physicians who are unfamiliar with the diagnostic criteria may misapply them and make an incorrect diagnosis.
The Central Vein Sign
Autopsy studies have indicated that MS lesions generally center around veins. Researchers have recently been able to visualize these veins within MS lesions using 7-T MRI. This finding, which investigators have called the central vein sign, could be a way to distinguish MS from other disorders. But 7-T MRI generally is not available to clinical neurologists. In 2012, scientists at the NIH developed a method that combines T2* imaging, which helps visualize veins, and fluid-attenuated inversion recovery (FLAIR) imaging that visualizes MS lesions. This method visualizes veins within lesions, or central vein sign, using 3-T MRI, which is more commonly available to clinical neurologists. The researchers called this sequence FLAIR*, and numerous studies have suggested that it may differentiate MS from other diagnoses.
Dr. Solomon and collaborators tested this technique on a group of 10 patients with MS who had no other comorbidities for white matter disease and 10 patients with migraine and white matter abnormalities who also had no other comorbidities for white matter disease. The mean percentage of lesions with central vessels per participant was 80% in patients with MS and 34% in migraineurs. The patients with migraine had fewer juxtacortical, periventricular, and infratentorial lesions, compared with patients with MS.
Because researchers have used various definitions of the central vein sign, Dr. Solomon and colleagues published a consensus statement to improve the interpretation of the imaging findings. They recommended that neurologists disregard periventricular lesions and concentrate on subcortical and white matter lesions that are visible from two perspectives.
Another limitation of this diagnostic imaging technique is that it “requires evaluation of every single lesion to determine if a central vein was present,” said Dr. Solomon. He and his colleagues developed a simplified algorithm that required the examination of three lesions. To test this algorithm, they examined their original cohort plus 10 patients with MS and comorbidities for white matter disease (eg, migraine or hypertension) and 10 patients who had been misdiagnosed with MS (most of whom had migraine). Three blinded raters examined three lesions chosen at random from each MRI. This method had a 0.98 specificity for MS and a sensitivity of 0.52. The study demonstrated problems with inter-rater reliability, however.
Dr. Solomon later collaborated with researchers at the University of Pennsylvania to develop a machine learning technique that could identify the central vein sign. When they applied the technique to the expanded cohort of 40 patients, it identified the sign accurately with an area under the curve of about 0.86. The central vein sign may be a good biomarker for MS, and using this automated technique to assess 3-T MRI images appears to be clinically applicable, said Dr. Solomon.
Thalamic Volume
Thalamic atrophy is common in the early stages of relapsing-remitting MS. The thalamus also is implicated in migraine. Although studies have examined volumetric brain changes in migraine, none has examined thalamic volume specifically, said Dr. Solomon.
He and his colleagues used an automatic segmentation method to analyze thalamic volume in their cohort of 40 patients. Analysis of variance indicated that thalamic volume was significantly smaller in patients with MS, compared with patients without MS. When the researchers used a thalamic volume less than 0.0077 as a cutoff, the technique’s sensitivity and specificity for the diagnosis of MS were 0.75.
Recent data suggest that thalamic atrophy in MS does not result from thalamic lesions, but from diffuse white matter abnormalities. Like the central vein sign, thalamic atrophy may reflect MS pathophysiology and could be incorporated into MS diagnostic criteria, said Dr. Solomon.
Cortical Lesions
Autopsy and MRI studies have shown that cortical lesions are characteristic of MS, but MRI studies have suggested that migraineurs generally do not have cortical lesions. Although neurologists can see these lesions in vivo on 7-T MRI, 3-T MRI is not as sensitive and makes cortical lesion detection challenging.
In 2017, Nakamura and colleagues found that ratio maps of T1- and T2-weighted 3-T MRI, images that are acquired in routine clinical care for MS, could identify areas of cortical demyelination. Dr. Solomon and colleagues tested whether this method could distinguish MS from migraine. They defined a z score of less than 3 as an indication of low myelin density. When they examined the cohort of 40 patients, they were able to correlate areas with z scores below the cutoff with cortical lesions that were visible on conventional imaging. The technique accurately distinguished patients with MS from patients with migraine.
None of these emerging imaging techniques is 100% accurate. In the future, however, combining several of these techniques in conjunction with tests of blood biomarkers such as microRNA could accurately distinguish between MS and other disorders with high specificity and sensitivity, Dr. Solomon concluded.
—Erik Greb
Carmosino MJ, Brousseau KM, Arciniegas DB, Corboy JR. Initial evaluations for multiple sclerosis in a university multiple sclerosis center: outcomes and role of magnetic resonance imaging in referral. Arch Neurol. 2005;62(4):585-590.
Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.
Liu S, Kullnat J, Bourdette D, et al. Prevalence of brain magnetic resonance imaging meeting Barkhof and McDonald criteria for dissemination in space among headache patients. Mult Scler. 2013;19(8):1101-1105.
Nakamura K, Chen JT, Ontaneda D, et al. T1-/T2-weighted ratio differs in demyelinated cortex in multiple sclerosis. Ann Neurol. 2017;82(4):635-639.
Sati P, Oh J, Constable RT, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.
Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
Solomon AJ, Schindler MK, Howard DB, et al. “Central vessel sign” on 3T FLAIR* MRI for the differentiation of multiple sclerosis from migraine. Ann Clin Transl Neurol. 2015;3(2):82-87.
Solomon AJ, Watts R, Dewey BE, Reich DS. MRI evaluation of thalamic volume differentiates MS from common mimics. Neurol Neuroimmunol Neuroinflamm. 2017;4(5):e387.
STOWE, VT—Some patients with migraine receive an inappropriate diagnosis of multiple sclerosis (MS). The two disorders share certain clinical and radiologic features, and misdiagnosis is a significant problem. Using MRI scanners widely available to clinicians, researchers are developing several imaging techniques that can provide an objective basis for distinguishing between MS and migraine, according to an overview provided at the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium.
The imaging techniques evaluate different aspects of MS pathology, said Andrew J. Solomon, MD, Associate Professor of Neurological Sciences at the University of Vermont College of Medicine in Burlington. The techniques have been automated to a large extent, which reduces the need for human interpretation of data. The incorporation of machine learning could further aid differential diagnosis.
Grounds for Confusion
Various similarities between migraine and MS increase the likelihood of misdiagnosis. The two disorders are chronic and entail attacks and remissions. Both are associated with changes in brain structure and white matter abnormalities that may be subclinical.
In a study of patients with migraine by Liu et al, between 25% and 35% of participants met MRI criteria for dissemination in space for MS, depending on how lesions were defined. The first report of natalizumab-associated progressive multifocal leukoencephalopathy occurred in a patient who, on autopsy, was found not to have had MS. In a 1988 study, Engell and colleagues found that of 518 consecutive patients who had died with a diagnosis of clinically definite MS, the diagnosis was incorrect for 6%.
In 2005, Carmosino and colleagues evaluated 281 patients who had been referred to an MS center and found that 67% of them did not have MS. The investigators identified 37 alternative diagnoses, of which migraine was the second most common. About 10% of participants had a final diagnosis of migraine.
In a recent survey, Dr. Solomon and colleagues asked more than 100 MS specialists whether they had seen patients who had had a diagnosis of MS for more than one year, but, on evaluation, determined that they did not have MS. Approximately 95% of respondents answered affirmatively. About 40% of respondents reported having seen three to five such patients in the previous year.
The current diagnostic criteria for MS rely on clinicians to interpret clinical and radiologic data and contain many caveats regarding their application, said Dr. Solomon. The criteria “were not developed to differentiate MS from other disorders,” but to predict which patients with an initial neurologic syndrome typical for MS will subsequently develop MS, he added. Physicians who are unfamiliar with the diagnostic criteria may misapply them and make an incorrect diagnosis.
The Central Vein Sign
Autopsy studies have indicated that MS lesions generally center around veins. Researchers have recently been able to visualize these veins within MS lesions using 7-T MRI. This finding, which investigators have called the central vein sign, could be a way to distinguish MS from other disorders. But 7-T MRI generally is not available to clinical neurologists. In 2012, scientists at the NIH developed a method that combines T2* imaging, which helps visualize veins, and fluid-attenuated inversion recovery (FLAIR) imaging that visualizes MS lesions. This method visualizes veins within lesions, or central vein sign, using 3-T MRI, which is more commonly available to clinical neurologists. The researchers called this sequence FLAIR*, and numerous studies have suggested that it may differentiate MS from other diagnoses.
Dr. Solomon and collaborators tested this technique on a group of 10 patients with MS who had no other comorbidities for white matter disease and 10 patients with migraine and white matter abnormalities who also had no other comorbidities for white matter disease. The mean percentage of lesions with central vessels per participant was 80% in patients with MS and 34% in migraineurs. The patients with migraine had fewer juxtacortical, periventricular, and infratentorial lesions, compared with patients with MS.
Because researchers have used various definitions of the central vein sign, Dr. Solomon and colleagues published a consensus statement to improve the interpretation of the imaging findings. They recommended that neurologists disregard periventricular lesions and concentrate on subcortical and white matter lesions that are visible from two perspectives.
Another limitation of this diagnostic imaging technique is that it “requires evaluation of every single lesion to determine if a central vein was present,” said Dr. Solomon. He and his colleagues developed a simplified algorithm that required the examination of three lesions. To test this algorithm, they examined their original cohort plus 10 patients with MS and comorbidities for white matter disease (eg, migraine or hypertension) and 10 patients who had been misdiagnosed with MS (most of whom had migraine). Three blinded raters examined three lesions chosen at random from each MRI. This method had a 0.98 specificity for MS and a sensitivity of 0.52. The study demonstrated problems with inter-rater reliability, however.
Dr. Solomon later collaborated with researchers at the University of Pennsylvania to develop a machine learning technique that could identify the central vein sign. When they applied the technique to the expanded cohort of 40 patients, it identified the sign accurately with an area under the curve of about 0.86. The central vein sign may be a good biomarker for MS, and using this automated technique to assess 3-T MRI images appears to be clinically applicable, said Dr. Solomon.
Thalamic Volume
Thalamic atrophy is common in the early stages of relapsing-remitting MS. The thalamus also is implicated in migraine. Although studies have examined volumetric brain changes in migraine, none has examined thalamic volume specifically, said Dr. Solomon.
He and his colleagues used an automatic segmentation method to analyze thalamic volume in their cohort of 40 patients. Analysis of variance indicated that thalamic volume was significantly smaller in patients with MS, compared with patients without MS. When the researchers used a thalamic volume less than 0.0077 as a cutoff, the technique’s sensitivity and specificity for the diagnosis of MS were 0.75.
Recent data suggest that thalamic atrophy in MS does not result from thalamic lesions, but from diffuse white matter abnormalities. Like the central vein sign, thalamic atrophy may reflect MS pathophysiology and could be incorporated into MS diagnostic criteria, said Dr. Solomon.
Cortical Lesions
Autopsy and MRI studies have shown that cortical lesions are characteristic of MS, but MRI studies have suggested that migraineurs generally do not have cortical lesions. Although neurologists can see these lesions in vivo on 7-T MRI, 3-T MRI is not as sensitive and makes cortical lesion detection challenging.
In 2017, Nakamura and colleagues found that ratio maps of T1- and T2-weighted 3-T MRI, images that are acquired in routine clinical care for MS, could identify areas of cortical demyelination. Dr. Solomon and colleagues tested whether this method could distinguish MS from migraine. They defined a z score of less than 3 as an indication of low myelin density. When they examined the cohort of 40 patients, they were able to correlate areas with z scores below the cutoff with cortical lesions that were visible on conventional imaging. The technique accurately distinguished patients with MS from patients with migraine.
None of these emerging imaging techniques is 100% accurate. In the future, however, combining several of these techniques in conjunction with tests of blood biomarkers such as microRNA could accurately distinguish between MS and other disorders with high specificity and sensitivity, Dr. Solomon concluded.
—Erik Greb
Carmosino MJ, Brousseau KM, Arciniegas DB, Corboy JR. Initial evaluations for multiple sclerosis in a university multiple sclerosis center: outcomes and role of magnetic resonance imaging in referral. Arch Neurol. 2005;62(4):585-590.
Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.
Liu S, Kullnat J, Bourdette D, et al. Prevalence of brain magnetic resonance imaging meeting Barkhof and McDonald criteria for dissemination in space among headache patients. Mult Scler. 2013;19(8):1101-1105.
Nakamura K, Chen JT, Ontaneda D, et al. T1-/T2-weighted ratio differs in demyelinated cortex in multiple sclerosis. Ann Neurol. 2017;82(4):635-639.
Sati P, Oh J, Constable RT, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.
Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
Solomon AJ, Schindler MK, Howard DB, et al. “Central vessel sign” on 3T FLAIR* MRI for the differentiation of multiple sclerosis from migraine. Ann Clin Transl Neurol. 2015;3(2):82-87.
Solomon AJ, Watts R, Dewey BE, Reich DS. MRI evaluation of thalamic volume differentiates MS from common mimics. Neurol Neuroimmunol Neuroinflamm. 2017;4(5):e387.
STOWE, VT—Some patients with migraine receive an inappropriate diagnosis of multiple sclerosis (MS). The two disorders share certain clinical and radiologic features, and misdiagnosis is a significant problem. Using MRI scanners widely available to clinicians, researchers are developing several imaging techniques that can provide an objective basis for distinguishing between MS and migraine, according to an overview provided at the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium.
The imaging techniques evaluate different aspects of MS pathology, said Andrew J. Solomon, MD, Associate Professor of Neurological Sciences at the University of Vermont College of Medicine in Burlington. The techniques have been automated to a large extent, which reduces the need for human interpretation of data. The incorporation of machine learning could further aid differential diagnosis.
Grounds for Confusion
Various similarities between migraine and MS increase the likelihood of misdiagnosis. The two disorders are chronic and entail attacks and remissions. Both are associated with changes in brain structure and white matter abnormalities that may be subclinical.
In a study of patients with migraine by Liu et al, between 25% and 35% of participants met MRI criteria for dissemination in space for MS, depending on how lesions were defined. The first report of natalizumab-associated progressive multifocal leukoencephalopathy occurred in a patient who, on autopsy, was found not to have had MS. In a 1988 study, Engell and colleagues found that of 518 consecutive patients who had died with a diagnosis of clinically definite MS, the diagnosis was incorrect for 6%.
In 2005, Carmosino and colleagues evaluated 281 patients who had been referred to an MS center and found that 67% of them did not have MS. The investigators identified 37 alternative diagnoses, of which migraine was the second most common. About 10% of participants had a final diagnosis of migraine.
In a recent survey, Dr. Solomon and colleagues asked more than 100 MS specialists whether they had seen patients who had had a diagnosis of MS for more than one year, but, on evaluation, determined that they did not have MS. Approximately 95% of respondents answered affirmatively. About 40% of respondents reported having seen three to five such patients in the previous year.
The current diagnostic criteria for MS rely on clinicians to interpret clinical and radiologic data and contain many caveats regarding their application, said Dr. Solomon. The criteria “were not developed to differentiate MS from other disorders,” but to predict which patients with an initial neurologic syndrome typical for MS will subsequently develop MS, he added. Physicians who are unfamiliar with the diagnostic criteria may misapply them and make an incorrect diagnosis.
The Central Vein Sign
Autopsy studies have indicated that MS lesions generally center around veins. Researchers have recently been able to visualize these veins within MS lesions using 7-T MRI. This finding, which investigators have called the central vein sign, could be a way to distinguish MS from other disorders. But 7-T MRI generally is not available to clinical neurologists. In 2012, scientists at the NIH developed a method that combines T2* imaging, which helps visualize veins, and fluid-attenuated inversion recovery (FLAIR) imaging that visualizes MS lesions. This method visualizes veins within lesions, or central vein sign, using 3-T MRI, which is more commonly available to clinical neurologists. The researchers called this sequence FLAIR*, and numerous studies have suggested that it may differentiate MS from other diagnoses.
Dr. Solomon and collaborators tested this technique on a group of 10 patients with MS who had no other comorbidities for white matter disease and 10 patients with migraine and white matter abnormalities who also had no other comorbidities for white matter disease. The mean percentage of lesions with central vessels per participant was 80% in patients with MS and 34% in migraineurs. The patients with migraine had fewer juxtacortical, periventricular, and infratentorial lesions, compared with patients with MS.
Because researchers have used various definitions of the central vein sign, Dr. Solomon and colleagues published a consensus statement to improve the interpretation of the imaging findings. They recommended that neurologists disregard periventricular lesions and concentrate on subcortical and white matter lesions that are visible from two perspectives.
Another limitation of this diagnostic imaging technique is that it “requires evaluation of every single lesion to determine if a central vein was present,” said Dr. Solomon. He and his colleagues developed a simplified algorithm that required the examination of three lesions. To test this algorithm, they examined their original cohort plus 10 patients with MS and comorbidities for white matter disease (eg, migraine or hypertension) and 10 patients who had been misdiagnosed with MS (most of whom had migraine). Three blinded raters examined three lesions chosen at random from each MRI. This method had a 0.98 specificity for MS and a sensitivity of 0.52. The study demonstrated problems with inter-rater reliability, however.
Dr. Solomon later collaborated with researchers at the University of Pennsylvania to develop a machine learning technique that could identify the central vein sign. When they applied the technique to the expanded cohort of 40 patients, it identified the sign accurately with an area under the curve of about 0.86. The central vein sign may be a good biomarker for MS, and using this automated technique to assess 3-T MRI images appears to be clinically applicable, said Dr. Solomon.
Thalamic Volume
Thalamic atrophy is common in the early stages of relapsing-remitting MS. The thalamus also is implicated in migraine. Although studies have examined volumetric brain changes in migraine, none has examined thalamic volume specifically, said Dr. Solomon.
He and his colleagues used an automatic segmentation method to analyze thalamic volume in their cohort of 40 patients. Analysis of variance indicated that thalamic volume was significantly smaller in patients with MS, compared with patients without MS. When the researchers used a thalamic volume less than 0.0077 as a cutoff, the technique’s sensitivity and specificity for the diagnosis of MS were 0.75.
Recent data suggest that thalamic atrophy in MS does not result from thalamic lesions, but from diffuse white matter abnormalities. Like the central vein sign, thalamic atrophy may reflect MS pathophysiology and could be incorporated into MS diagnostic criteria, said Dr. Solomon.
Cortical Lesions
Autopsy and MRI studies have shown that cortical lesions are characteristic of MS, but MRI studies have suggested that migraineurs generally do not have cortical lesions. Although neurologists can see these lesions in vivo on 7-T MRI, 3-T MRI is not as sensitive and makes cortical lesion detection challenging.
In 2017, Nakamura and colleagues found that ratio maps of T1- and T2-weighted 3-T MRI, images that are acquired in routine clinical care for MS, could identify areas of cortical demyelination. Dr. Solomon and colleagues tested whether this method could distinguish MS from migraine. They defined a z score of less than 3 as an indication of low myelin density. When they examined the cohort of 40 patients, they were able to correlate areas with z scores below the cutoff with cortical lesions that were visible on conventional imaging. The technique accurately distinguished patients with MS from patients with migraine.
None of these emerging imaging techniques is 100% accurate. In the future, however, combining several of these techniques in conjunction with tests of blood biomarkers such as microRNA could accurately distinguish between MS and other disorders with high specificity and sensitivity, Dr. Solomon concluded.
—Erik Greb
Carmosino MJ, Brousseau KM, Arciniegas DB, Corboy JR. Initial evaluations for multiple sclerosis in a university multiple sclerosis center: outcomes and role of magnetic resonance imaging in referral. Arch Neurol. 2005;62(4):585-590.
Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.
Liu S, Kullnat J, Bourdette D, et al. Prevalence of brain magnetic resonance imaging meeting Barkhof and McDonald criteria for dissemination in space among headache patients. Mult Scler. 2013;19(8):1101-1105.
Nakamura K, Chen JT, Ontaneda D, et al. T1-/T2-weighted ratio differs in demyelinated cortex in multiple sclerosis. Ann Neurol. 2017;82(4):635-639.
Sati P, Oh J, Constable RT, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.
Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
Solomon AJ, Schindler MK, Howard DB, et al. “Central vessel sign” on 3T FLAIR* MRI for the differentiation of multiple sclerosis from migraine. Ann Clin Transl Neurol. 2015;3(2):82-87.
Solomon AJ, Watts R, Dewey BE, Reich DS. MRI evaluation of thalamic volume differentiates MS from common mimics. Neurol Neuroimmunol Neuroinflamm. 2017;4(5):e387.
Headache Remains a Significant Public Health Problem
Severe headache and migraine remain significant public health problems, and their prevalence has been stable for years, according to a review published online ahead of print March 12 in Headache. Results confirm that “migraine disproportionately affects women and several other historically disadvantaged segments of the population,” according to the authors. “These inequities could be exacerbated if new high-cost treatments are inaccessible to those who need them most.”
Rebecca Burch, MD, Instructor in Neurology at Harvard Medical School in Boston, and colleagues reviewed population-based US government surveys to obtain updated estimates of the prevalence of migraine and severe headache in adults. The authors examined the most recent data from the National Health Interview Survey, the National Hospital Ambulatory Medical Care Survey, and the National Ambulatory Medical Care Survey.
The most recent National Health Interview Survey data were from 2015. They indicated that the overall prevalence of migraine or severe headache was 15.3%. The prevalence was 20.7% in women and 9.7% in men. The age group with the highest prevalence of migraine (17.9%) included patients between ages 18 and 44. Prevalence was 15.9% in people between ages 45 and 64.
The prevalence of migraine or severe headache also varied by race. The highest prevalence (20.3%) was among native Hawaiians and other Pacific islanders. Prevalence was 18.4% among American Indians or Alaska natives, 16.2% among blacks or African Americans, 15.4% among whites, and 11.3% among Asians.
Data indicated that prevalence varied with income and insurance status. People living below the poverty line had a prevalence of 21.7%, and those with an annual family income of less than $35,000 had a prevalence of 19.9%. For people younger than 65, prevalence was higher in people insured by Medicaid (26.0%), compared with people with private insurance (15.1%) or no insurance (17.1%).
The most recent data for the National Hospital Ambulatory Medical Care Survey were from 2014. In that year, headache or pain in the head prompted approximately four million emergency department visits. Women of childbearing age made more than half of emergency department visits for headache.
Headache or pain in the head accounted for 3.0% of all emergency department visits and was the fifth leading cause of visits to the emergency department, as reported by patients. Headache was the 12th most common diagnosis among emergency department physicians (1.8% of all visits). It was the sixth most common diagnosis for women aged 15 to 64 (1.7%), and migraine was the 15th most common for this population (0.8%). Headache was the 19th most common diagnosis among men between ages 15 and 64 (0.5%).
No new data about headache or head pain from the National Ambulatory Medical Care Survey were available. Headache has not been among the top 20 reasons for outpatient visits since the 2009–2010 survey.
“It is important to understand the distribution of headache in specific segments of the population,” said Dr. Burch and colleagues. “This can guide efforts to ensure that treatments are accessible to those with the highest level of need.”
—Erik Greb
Suggested Reading
Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: figures and trends from government health studies. Headache. 2018 Mar 12 [Epub ahead of print].
Severe headache and migraine remain significant public health problems, and their prevalence has been stable for years, according to a review published online ahead of print March 12 in Headache. Results confirm that “migraine disproportionately affects women and several other historically disadvantaged segments of the population,” according to the authors. “These inequities could be exacerbated if new high-cost treatments are inaccessible to those who need them most.”
Rebecca Burch, MD, Instructor in Neurology at Harvard Medical School in Boston, and colleagues reviewed population-based US government surveys to obtain updated estimates of the prevalence of migraine and severe headache in adults. The authors examined the most recent data from the National Health Interview Survey, the National Hospital Ambulatory Medical Care Survey, and the National Ambulatory Medical Care Survey.
The most recent National Health Interview Survey data were from 2015. They indicated that the overall prevalence of migraine or severe headache was 15.3%. The prevalence was 20.7% in women and 9.7% in men. The age group with the highest prevalence of migraine (17.9%) included patients between ages 18 and 44. Prevalence was 15.9% in people between ages 45 and 64.
The prevalence of migraine or severe headache also varied by race. The highest prevalence (20.3%) was among native Hawaiians and other Pacific islanders. Prevalence was 18.4% among American Indians or Alaska natives, 16.2% among blacks or African Americans, 15.4% among whites, and 11.3% among Asians.
Data indicated that prevalence varied with income and insurance status. People living below the poverty line had a prevalence of 21.7%, and those with an annual family income of less than $35,000 had a prevalence of 19.9%. For people younger than 65, prevalence was higher in people insured by Medicaid (26.0%), compared with people with private insurance (15.1%) or no insurance (17.1%).
The most recent data for the National Hospital Ambulatory Medical Care Survey were from 2014. In that year, headache or pain in the head prompted approximately four million emergency department visits. Women of childbearing age made more than half of emergency department visits for headache.
Headache or pain in the head accounted for 3.0% of all emergency department visits and was the fifth leading cause of visits to the emergency department, as reported by patients. Headache was the 12th most common diagnosis among emergency department physicians (1.8% of all visits). It was the sixth most common diagnosis for women aged 15 to 64 (1.7%), and migraine was the 15th most common for this population (0.8%). Headache was the 19th most common diagnosis among men between ages 15 and 64 (0.5%).
No new data about headache or head pain from the National Ambulatory Medical Care Survey were available. Headache has not been among the top 20 reasons for outpatient visits since the 2009–2010 survey.
“It is important to understand the distribution of headache in specific segments of the population,” said Dr. Burch and colleagues. “This can guide efforts to ensure that treatments are accessible to those with the highest level of need.”
—Erik Greb
Suggested Reading
Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: figures and trends from government health studies. Headache. 2018 Mar 12 [Epub ahead of print].
Severe headache and migraine remain significant public health problems, and their prevalence has been stable for years, according to a review published online ahead of print March 12 in Headache. Results confirm that “migraine disproportionately affects women and several other historically disadvantaged segments of the population,” according to the authors. “These inequities could be exacerbated if new high-cost treatments are inaccessible to those who need them most.”
Rebecca Burch, MD, Instructor in Neurology at Harvard Medical School in Boston, and colleagues reviewed population-based US government surveys to obtain updated estimates of the prevalence of migraine and severe headache in adults. The authors examined the most recent data from the National Health Interview Survey, the National Hospital Ambulatory Medical Care Survey, and the National Ambulatory Medical Care Survey.
The most recent National Health Interview Survey data were from 2015. They indicated that the overall prevalence of migraine or severe headache was 15.3%. The prevalence was 20.7% in women and 9.7% in men. The age group with the highest prevalence of migraine (17.9%) included patients between ages 18 and 44. Prevalence was 15.9% in people between ages 45 and 64.
The prevalence of migraine or severe headache also varied by race. The highest prevalence (20.3%) was among native Hawaiians and other Pacific islanders. Prevalence was 18.4% among American Indians or Alaska natives, 16.2% among blacks or African Americans, 15.4% among whites, and 11.3% among Asians.
Data indicated that prevalence varied with income and insurance status. People living below the poverty line had a prevalence of 21.7%, and those with an annual family income of less than $35,000 had a prevalence of 19.9%. For people younger than 65, prevalence was higher in people insured by Medicaid (26.0%), compared with people with private insurance (15.1%) or no insurance (17.1%).
The most recent data for the National Hospital Ambulatory Medical Care Survey were from 2014. In that year, headache or pain in the head prompted approximately four million emergency department visits. Women of childbearing age made more than half of emergency department visits for headache.
Headache or pain in the head accounted for 3.0% of all emergency department visits and was the fifth leading cause of visits to the emergency department, as reported by patients. Headache was the 12th most common diagnosis among emergency department physicians (1.8% of all visits). It was the sixth most common diagnosis for women aged 15 to 64 (1.7%), and migraine was the 15th most common for this population (0.8%). Headache was the 19th most common diagnosis among men between ages 15 and 64 (0.5%).
No new data about headache or head pain from the National Ambulatory Medical Care Survey were available. Headache has not been among the top 20 reasons for outpatient visits since the 2009–2010 survey.
“It is important to understand the distribution of headache in specific segments of the population,” said Dr. Burch and colleagues. “This can guide efforts to ensure that treatments are accessible to those with the highest level of need.”
—Erik Greb
Suggested Reading
Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: figures and trends from government health studies. Headache. 2018 Mar 12 [Epub ahead of print].
Is Chronification the Natural History of Migraine?
OJAI, CA—Diagnosis, while critically important in the management of migraine, “is just half the picture,” said Robert Cowan, MD, Higgins Professor of Neurology and Neurosciences and Director of the Division of Headache and Facial Pain at Stanford University in California. Changes over time, attack frequency, chronification, comorbidity, and disability complicate the management of this disorder. At the 11th Annual Headache Cooperative of the Pacific’s Winter Conference, Dr. Cowan reviewed the clinical evidence suggesting that episodic and chronic migraine are two distinct entities, stressed the importance of classification and staging in the diagnosis and treatment of migraine, and elucidated the signs and symptoms of migraine chronification.
Challenging Assumptions
For years, the prevailing perception among clinicians has been that patients with migraine progress from episodic migraine into a state of chronic headache at an annual conversion rate of about 3%. A wealth of data supports this concept. But recent studies have challenged the idea that episodic migraine and chronic migraine are the same entity differentiated only by attack frequency. Research by Schwedt and colleagues, for example, seemed to differentiate between episodic and chronic migraine purely on the basis of anatomy. Additionally, evidence suggests that there are differences between episodic and chronic migraine in regard to connectivity based on functional MRI mapping of pain processing networks. Chronic and episodic migraine seem to affect the brain in different ways, Dr. Cowan said. Structural, functional, and pharmacologic changes in the brain differentiate chronic migraine from episodic migraine.
Classification and Staging
There is evidence that years of headache may make a difference. “Over time, headache after headache can remodel certain areas of the brain, in some areas thickening cortex, and in others, thinning it. This is likely the result of recurrent migraine attacks over time,” Dr. Cowan said. “The patient who has had chronic headache for 30 years is likely to process sensory input differently from the patient who has gone from eight to 14 headaches per month in the last thr
The Physician’s Role in Chronification
Physicians themselves can play a role in migraine chronification. Misdiagnosis and underdiagnosis increase the risk of migraine chronification. “When a patient is not doing well, I think it is important to go back and revisit the diagnosis. Make sure that you have the right diagnosis and that the diagnosis has not changed. Are there additional diagnoses?” Other pitfalls that may lead to chronification include failure to recognize treatable comorbidities, inadequate or inappropriate medication use, and signs of chronification such as central sensitization. Weak or recall-biased intervisit data collection also may be a problem.
Risk Factors for Chronification
“It is useful to differentiate between modifiable and nonmodifiable factors,” Dr. Cowan said. Modifiable risk factors include medication overuse, ineffective acute treatment, obesity, depression, stressful life events, and low educational level. Nonmodifiable risk factors include age and female sex. “Another approach is to look at state-specific factors versus process-related factors,” Dr. Cowan said. State-specific factors include obesity, history of abuse, comorbid pain, and head injury. Process-related factors include years of headache, increasing frequency, catastrophizing, and medication overuse.
Chronification Patterns
Clinical clues that chronification may be occurring include increasing headache frequency, severity, or duration, emergence of a second headache type, and a change in pattern of symptoms unrelated to pain. Additionally, allodynia may be a marker of chronification, and central sensitization plays a large role in chronification. “These are things we can assess clinically,” Dr. Cowan said. “We should be thinking about all these things and asking our patients about them as we follow them from visit to visit.” As headache specialists, “our job is not done once we have a diagnosis and go through the Rolodex of treatments for that diagnosis.” NR
—Glenn S. Williams
Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine transformation. Neurology. 2008;71(11)848-855.
Mainero C, Boshyan J, Hadjikhani N. Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Ann Neurol. 2011;70(5):838-845.
May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol. 2016;12(8):455-464.
Schwedt TJ, Chong CD, Wu T, et al. Accurate classification of chronic migraine via brain magnetic resonance imaging. Headache. 2015;55(6):762-777.
OJAI, CA—Diagnosis, while critically important in the management of migraine, “is just half the picture,” said Robert Cowan, MD, Higgins Professor of Neurology and Neurosciences and Director of the Division of Headache and Facial Pain at Stanford University in California. Changes over time, attack frequency, chronification, comorbidity, and disability complicate the management of this disorder. At the 11th Annual Headache Cooperative of the Pacific’s Winter Conference, Dr. Cowan reviewed the clinical evidence suggesting that episodic and chronic migraine are two distinct entities, stressed the importance of classification and staging in the diagnosis and treatment of migraine, and elucidated the signs and symptoms of migraine chronification.
Challenging Assumptions
For years, the prevailing perception among clinicians has been that patients with migraine progress from episodic migraine into a state of chronic headache at an annual conversion rate of about 3%. A wealth of data supports this concept. But recent studies have challenged the idea that episodic migraine and chronic migraine are the same entity differentiated only by attack frequency. Research by Schwedt and colleagues, for example, seemed to differentiate between episodic and chronic migraine purely on the basis of anatomy. Additionally, evidence suggests that there are differences between episodic and chronic migraine in regard to connectivity based on functional MRI mapping of pain processing networks. Chronic and episodic migraine seem to affect the brain in different ways, Dr. Cowan said. Structural, functional, and pharmacologic changes in the brain differentiate chronic migraine from episodic migraine.
Classification and Staging
There is evidence that years of headache may make a difference. “Over time, headache after headache can remodel certain areas of the brain, in some areas thickening cortex, and in others, thinning it. This is likely the result of recurrent migraine attacks over time,” Dr. Cowan said. “The patient who has had chronic headache for 30 years is likely to process sensory input differently from the patient who has gone from eight to 14 headaches per month in the last thr
The Physician’s Role in Chronification
Physicians themselves can play a role in migraine chronification. Misdiagnosis and underdiagnosis increase the risk of migraine chronification. “When a patient is not doing well, I think it is important to go back and revisit the diagnosis. Make sure that you have the right diagnosis and that the diagnosis has not changed. Are there additional diagnoses?” Other pitfalls that may lead to chronification include failure to recognize treatable comorbidities, inadequate or inappropriate medication use, and signs of chronification such as central sensitization. Weak or recall-biased intervisit data collection also may be a problem.
Risk Factors for Chronification
“It is useful to differentiate between modifiable and nonmodifiable factors,” Dr. Cowan said. Modifiable risk factors include medication overuse, ineffective acute treatment, obesity, depression, stressful life events, and low educational level. Nonmodifiable risk factors include age and female sex. “Another approach is to look at state-specific factors versus process-related factors,” Dr. Cowan said. State-specific factors include obesity, history of abuse, comorbid pain, and head injury. Process-related factors include years of headache, increasing frequency, catastrophizing, and medication overuse.
Chronification Patterns
Clinical clues that chronification may be occurring include increasing headache frequency, severity, or duration, emergence of a second headache type, and a change in pattern of symptoms unrelated to pain. Additionally, allodynia may be a marker of chronification, and central sensitization plays a large role in chronification. “These are things we can assess clinically,” Dr. Cowan said. “We should be thinking about all these things and asking our patients about them as we follow them from visit to visit.” As headache specialists, “our job is not done once we have a diagnosis and go through the Rolodex of treatments for that diagnosis.” NR
—Glenn S. Williams
Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine transformation. Neurology. 2008;71(11)848-855.
Mainero C, Boshyan J, Hadjikhani N. Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Ann Neurol. 2011;70(5):838-845.
May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol. 2016;12(8):455-464.
Schwedt TJ, Chong CD, Wu T, et al. Accurate classification of chronic migraine via brain magnetic resonance imaging. Headache. 2015;55(6):762-777.
OJAI, CA—Diagnosis, while critically important in the management of migraine, “is just half the picture,” said Robert Cowan, MD, Higgins Professor of Neurology and Neurosciences and Director of the Division of Headache and Facial Pain at Stanford University in California. Changes over time, attack frequency, chronification, comorbidity, and disability complicate the management of this disorder. At the 11th Annual Headache Cooperative of the Pacific’s Winter Conference, Dr. Cowan reviewed the clinical evidence suggesting that episodic and chronic migraine are two distinct entities, stressed the importance of classification and staging in the diagnosis and treatment of migraine, and elucidated the signs and symptoms of migraine chronification.
Challenging Assumptions
For years, the prevailing perception among clinicians has been that patients with migraine progress from episodic migraine into a state of chronic headache at an annual conversion rate of about 3%. A wealth of data supports this concept. But recent studies have challenged the idea that episodic migraine and chronic migraine are the same entity differentiated only by attack frequency. Research by Schwedt and colleagues, for example, seemed to differentiate between episodic and chronic migraine purely on the basis of anatomy. Additionally, evidence suggests that there are differences between episodic and chronic migraine in regard to connectivity based on functional MRI mapping of pain processing networks. Chronic and episodic migraine seem to affect the brain in different ways, Dr. Cowan said. Structural, functional, and pharmacologic changes in the brain differentiate chronic migraine from episodic migraine.
Classification and Staging
There is evidence that years of headache may make a difference. “Over time, headache after headache can remodel certain areas of the brain, in some areas thickening cortex, and in others, thinning it. This is likely the result of recurrent migraine attacks over time,” Dr. Cowan said. “The patient who has had chronic headache for 30 years is likely to process sensory input differently from the patient who has gone from eight to 14 headaches per month in the last thr
The Physician’s Role in Chronification
Physicians themselves can play a role in migraine chronification. Misdiagnosis and underdiagnosis increase the risk of migraine chronification. “When a patient is not doing well, I think it is important to go back and revisit the diagnosis. Make sure that you have the right diagnosis and that the diagnosis has not changed. Are there additional diagnoses?” Other pitfalls that may lead to chronification include failure to recognize treatable comorbidities, inadequate or inappropriate medication use, and signs of chronification such as central sensitization. Weak or recall-biased intervisit data collection also may be a problem.
Risk Factors for Chronification
“It is useful to differentiate between modifiable and nonmodifiable factors,” Dr. Cowan said. Modifiable risk factors include medication overuse, ineffective acute treatment, obesity, depression, stressful life events, and low educational level. Nonmodifiable risk factors include age and female sex. “Another approach is to look at state-specific factors versus process-related factors,” Dr. Cowan said. State-specific factors include obesity, history of abuse, comorbid pain, and head injury. Process-related factors include years of headache, increasing frequency, catastrophizing, and medication overuse.
Chronification Patterns
Clinical clues that chronification may be occurring include increasing headache frequency, severity, or duration, emergence of a second headache type, and a change in pattern of symptoms unrelated to pain. Additionally, allodynia may be a marker of chronification, and central sensitization plays a large role in chronification. “These are things we can assess clinically,” Dr. Cowan said. “We should be thinking about all these things and asking our patients about them as we follow them from visit to visit.” As headache specialists, “our job is not done once we have a diagnosis and go through the Rolodex of treatments for that diagnosis.” NR
—Glenn S. Williams
Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine transformation. Neurology. 2008;71(11)848-855.
Mainero C, Boshyan J, Hadjikhani N. Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Ann Neurol. 2011;70(5):838-845.
May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol. 2016;12(8):455-464.
Schwedt TJ, Chong CD, Wu T, et al. Accurate classification of chronic migraine via brain magnetic resonance imaging. Headache. 2015;55(6):762-777.
MRI Reveals Less Cortical Thickness Among Patients With Persistent Posttraumatic Headache
Patients with persistent posttraumatic headache have less cortical thickness in bilateral frontal regions and right hemisphere parietal regions of the brain, compared with healthy controls, according to research published in the January issue of Headache. Among patients with persistent posttraumatic headache, more frequent headaches are associated with less cortical thickness in the left and right superior frontal regions, the researchers said
“These results indicate that, although general linear model vertex-by-vertex comparisons indicate that large areas over the frontal cortex are overall thinner in patients with persistent posttraumatic headache, it is specifically the frequency of headaches that associates with cortical thinning in the superior frontal regions,” said Catherine D. Chong, PhD, a researcher at the Mayo Clinic in Phoenix.
Patients With Persistent Posttraumatic Headache vs Healthy Controls
Posttraumatic headaches are common after concussion. When these headaches persist for longer than three months, they are classified as persistent posttraumatic headaches. Studies have shown functional changes and anatomical changes such as volume loss and cortical thinning following concussion, but there are insufficient data about the association between brain morphologic changes and headache symptoms in patients with persistent posttraumatic headache, the researchers said.
To investigate differences in cortical thickness between patients with persistent posttraumatic headaches and healthy controls and to assess whether cortical morphology relates to headache burden, Dr. Chong and colleagues studied 33 patients with persistent posttraumatic headache and 33 healthy controls. Healthy controls had never had headaches or had infrequent tension-type headache. Exclusion criteria for all subjects included pregnancy, contraindications to MRI, moderate or severe head trauma, and previous history of migraine. Patients with persistent posttraumatic headache who were taking abortive or preventive headache medications were not excluded.
Patients with persistent posttraumatic headache were diagnosed according to ICHD-3 beta criteria. Participants underwent brain MRI on a 3-T scanner. Researchers calculated vertex-by-vertex whole brain estimates of cortical thickness. They used a general linear model design to determine differences in cortical thickness between patients with persistent posttraumatic headache and healthy controls.
Anxiety and Depression Scores Differed Between Groups
Researchers enrolled 68 patients into the study. They excluded data for two because of abnormal findings. The median age of participants with persistent posttraumatic headache was 36, and the median age of healthy controls was 33. About 39% of subjects with persistent posttraumatic headaches were female, and about 58% of healthy controls were female. Six participants reported one traumatic brain injury (TBI) in their lifetime, 15 reported two TBIs, three reported five TBIs, and six participants reported six or more TBIs. Concussions that led to persistent posttraumatic headache were due to explosion or blast injuries, sports-related accidents, falls, and motor vehicle accidents. In addition, there were significant between-group differences in levels of anxiety and depression.
“Patients with persistent posttraumatic headache had comorbid symptoms of mild depression and anxiety. Although there was not an association between mood alteration and headache frequency in patients with persistent posttraumatic headache, it is impossible to completely disentangle the effect that mood dysfunctions may have had on altering cortical thickness patterns in patients with persistent posttraumatic headache,” said the researchers.
Thinner Cortex in Patients With Persistent Posttraumatic Headache
Overall, patients with persistent posttraumatic headache had less cortical thickness in the left and right frontal (superior frontal, caudal middle frontal, and precentral) regions and right parietal (precuneus supramarginal, inferior, and superior parietal) regions. In addition, there were no regions in which patients with persistent posttraumatic headache had more cortical thickness, relative to healthy controls.
A correlation analysis of regions with less cortical thickness in patients with persistent posttraumatic headache found a negative correlation between left and right superior frontal thickness and headache frequency. No association was observed between regional cortical thickness and years lived with persistent posttraumatic headache.
“Further investigation is required to determine if the findings of our study are specific for persistent posttraumatic headache or if they are generalizable to other chronic pain conditions and other symptoms that occur following concussion,” said Dr. Chong and colleagues.
“Future studies using larger patient cohorts will be needed to better detect how repetitive concussions, concussion mechanism (sports-related vs motor vehicle accident vs blast injuries vs falls), and medical history alter brain pathophysiological processes, as well as affect headache patterns in patients with persistent posttraumatic headache.”
—Erica Tricarico
Suggested Reading
Chong CD, Berisha V, Chiang CC, et al. Less cortical thickness in patients with persistent posttraumatic headache compared with healthy controls: an MRI study. Headache. 2018;58(1):53-61.
Patients with persistent posttraumatic headache have less cortical thickness in bilateral frontal regions and right hemisphere parietal regions of the brain, compared with healthy controls, according to research published in the January issue of Headache. Among patients with persistent posttraumatic headache, more frequent headaches are associated with less cortical thickness in the left and right superior frontal regions, the researchers said
“These results indicate that, although general linear model vertex-by-vertex comparisons indicate that large areas over the frontal cortex are overall thinner in patients with persistent posttraumatic headache, it is specifically the frequency of headaches that associates with cortical thinning in the superior frontal regions,” said Catherine D. Chong, PhD, a researcher at the Mayo Clinic in Phoenix.
Patients With Persistent Posttraumatic Headache vs Healthy Controls
Posttraumatic headaches are common after concussion. When these headaches persist for longer than three months, they are classified as persistent posttraumatic headaches. Studies have shown functional changes and anatomical changes such as volume loss and cortical thinning following concussion, but there are insufficient data about the association between brain morphologic changes and headache symptoms in patients with persistent posttraumatic headache, the researchers said.
To investigate differences in cortical thickness between patients with persistent posttraumatic headaches and healthy controls and to assess whether cortical morphology relates to headache burden, Dr. Chong and colleagues studied 33 patients with persistent posttraumatic headache and 33 healthy controls. Healthy controls had never had headaches or had infrequent tension-type headache. Exclusion criteria for all subjects included pregnancy, contraindications to MRI, moderate or severe head trauma, and previous history of migraine. Patients with persistent posttraumatic headache who were taking abortive or preventive headache medications were not excluded.
Patients with persistent posttraumatic headache were diagnosed according to ICHD-3 beta criteria. Participants underwent brain MRI on a 3-T scanner. Researchers calculated vertex-by-vertex whole brain estimates of cortical thickness. They used a general linear model design to determine differences in cortical thickness between patients with persistent posttraumatic headache and healthy controls.
Anxiety and Depression Scores Differed Between Groups
Researchers enrolled 68 patients into the study. They excluded data for two because of abnormal findings. The median age of participants with persistent posttraumatic headache was 36, and the median age of healthy controls was 33. About 39% of subjects with persistent posttraumatic headaches were female, and about 58% of healthy controls were female. Six participants reported one traumatic brain injury (TBI) in their lifetime, 15 reported two TBIs, three reported five TBIs, and six participants reported six or more TBIs. Concussions that led to persistent posttraumatic headache were due to explosion or blast injuries, sports-related accidents, falls, and motor vehicle accidents. In addition, there were significant between-group differences in levels of anxiety and depression.
“Patients with persistent posttraumatic headache had comorbid symptoms of mild depression and anxiety. Although there was not an association between mood alteration and headache frequency in patients with persistent posttraumatic headache, it is impossible to completely disentangle the effect that mood dysfunctions may have had on altering cortical thickness patterns in patients with persistent posttraumatic headache,” said the researchers.
Thinner Cortex in Patients With Persistent Posttraumatic Headache
Overall, patients with persistent posttraumatic headache had less cortical thickness in the left and right frontal (superior frontal, caudal middle frontal, and precentral) regions and right parietal (precuneus supramarginal, inferior, and superior parietal) regions. In addition, there were no regions in which patients with persistent posttraumatic headache had more cortical thickness, relative to healthy controls.
A correlation analysis of regions with less cortical thickness in patients with persistent posttraumatic headache found a negative correlation between left and right superior frontal thickness and headache frequency. No association was observed between regional cortical thickness and years lived with persistent posttraumatic headache.
“Further investigation is required to determine if the findings of our study are specific for persistent posttraumatic headache or if they are generalizable to other chronic pain conditions and other symptoms that occur following concussion,” said Dr. Chong and colleagues.
“Future studies using larger patient cohorts will be needed to better detect how repetitive concussions, concussion mechanism (sports-related vs motor vehicle accident vs blast injuries vs falls), and medical history alter brain pathophysiological processes, as well as affect headache patterns in patients with persistent posttraumatic headache.”
—Erica Tricarico
Suggested Reading
Chong CD, Berisha V, Chiang CC, et al. Less cortical thickness in patients with persistent posttraumatic headache compared with healthy controls: an MRI study. Headache. 2018;58(1):53-61.
Patients with persistent posttraumatic headache have less cortical thickness in bilateral frontal regions and right hemisphere parietal regions of the brain, compared with healthy controls, according to research published in the January issue of Headache. Among patients with persistent posttraumatic headache, more frequent headaches are associated with less cortical thickness in the left and right superior frontal regions, the researchers said
“These results indicate that, although general linear model vertex-by-vertex comparisons indicate that large areas over the frontal cortex are overall thinner in patients with persistent posttraumatic headache, it is specifically the frequency of headaches that associates with cortical thinning in the superior frontal regions,” said Catherine D. Chong, PhD, a researcher at the Mayo Clinic in Phoenix.
Patients With Persistent Posttraumatic Headache vs Healthy Controls
Posttraumatic headaches are common after concussion. When these headaches persist for longer than three months, they are classified as persistent posttraumatic headaches. Studies have shown functional changes and anatomical changes such as volume loss and cortical thinning following concussion, but there are insufficient data about the association between brain morphologic changes and headache symptoms in patients with persistent posttraumatic headache, the researchers said.
To investigate differences in cortical thickness between patients with persistent posttraumatic headaches and healthy controls and to assess whether cortical morphology relates to headache burden, Dr. Chong and colleagues studied 33 patients with persistent posttraumatic headache and 33 healthy controls. Healthy controls had never had headaches or had infrequent tension-type headache. Exclusion criteria for all subjects included pregnancy, contraindications to MRI, moderate or severe head trauma, and previous history of migraine. Patients with persistent posttraumatic headache who were taking abortive or preventive headache medications were not excluded.
Patients with persistent posttraumatic headache were diagnosed according to ICHD-3 beta criteria. Participants underwent brain MRI on a 3-T scanner. Researchers calculated vertex-by-vertex whole brain estimates of cortical thickness. They used a general linear model design to determine differences in cortical thickness between patients with persistent posttraumatic headache and healthy controls.
Anxiety and Depression Scores Differed Between Groups
Researchers enrolled 68 patients into the study. They excluded data for two because of abnormal findings. The median age of participants with persistent posttraumatic headache was 36, and the median age of healthy controls was 33. About 39% of subjects with persistent posttraumatic headaches were female, and about 58% of healthy controls were female. Six participants reported one traumatic brain injury (TBI) in their lifetime, 15 reported two TBIs, three reported five TBIs, and six participants reported six or more TBIs. Concussions that led to persistent posttraumatic headache were due to explosion or blast injuries, sports-related accidents, falls, and motor vehicle accidents. In addition, there were significant between-group differences in levels of anxiety and depression.
“Patients with persistent posttraumatic headache had comorbid symptoms of mild depression and anxiety. Although there was not an association between mood alteration and headache frequency in patients with persistent posttraumatic headache, it is impossible to completely disentangle the effect that mood dysfunctions may have had on altering cortical thickness patterns in patients with persistent posttraumatic headache,” said the researchers.
Thinner Cortex in Patients With Persistent Posttraumatic Headache
Overall, patients with persistent posttraumatic headache had less cortical thickness in the left and right frontal (superior frontal, caudal middle frontal, and precentral) regions and right parietal (precuneus supramarginal, inferior, and superior parietal) regions. In addition, there were no regions in which patients with persistent posttraumatic headache had more cortical thickness, relative to healthy controls.
A correlation analysis of regions with less cortical thickness in patients with persistent posttraumatic headache found a negative correlation between left and right superior frontal thickness and headache frequency. No association was observed between regional cortical thickness and years lived with persistent posttraumatic headache.
“Further investigation is required to determine if the findings of our study are specific for persistent posttraumatic headache or if they are generalizable to other chronic pain conditions and other symptoms that occur following concussion,” said Dr. Chong and colleagues.
“Future studies using larger patient cohorts will be needed to better detect how repetitive concussions, concussion mechanism (sports-related vs motor vehicle accident vs blast injuries vs falls), and medical history alter brain pathophysiological processes, as well as affect headache patterns in patients with persistent posttraumatic headache.”
—Erica Tricarico
Suggested Reading
Chong CD, Berisha V, Chiang CC, et al. Less cortical thickness in patients with persistent posttraumatic headache compared with healthy controls: an MRI study. Headache. 2018;58(1):53-61.
Migraine and Elevated Vascular Biomarkers Linked
Elevated vascular biomarkers were associated with migraine, a recent study found, particularly migraine with aura (MA), as well as with years of aura and number of aura attacks. Participants (300 women, 117 men) were aged 30–60 (mean 48) years, 155 MA, 128 migraine without aura (MO), and 134 were controls with no severe headaches. Plasma concentrations of fibrinogen, Factor II, D-dimer, high sensitivity C-reactive protein (hs-CRP), and von Willebrand factor antigen were compared between groups, also stratifying by sex. Researchers found:
- Fibrinogen and hs-CRP were elevated in migraineurs compared to controls.
- In logistic regression analyses, MO and MA had increased likelihood of elevated fibrinogen, and MA had increased likelihood of elevated Factor II and hs-CRP.
- Fibrinogen and Factor II were associated with MA in women but not men.
- In the migraine subgroup, the total number of years of aura, but not headache, predicted elevated hs-CRP, and the average number of aura, but not headache, attacks predicted all biomarkers but Factor II.
Migraine and vascular disease biomarkers: A population-based case-control study. Cephalalgia. 2018;38(3):511-518. doi:10.1177/0333102417698936.
Elevated vascular biomarkers were associated with migraine, a recent study found, particularly migraine with aura (MA), as well as with years of aura and number of aura attacks. Participants (300 women, 117 men) were aged 30–60 (mean 48) years, 155 MA, 128 migraine without aura (MO), and 134 were controls with no severe headaches. Plasma concentrations of fibrinogen, Factor II, D-dimer, high sensitivity C-reactive protein (hs-CRP), and von Willebrand factor antigen were compared between groups, also stratifying by sex. Researchers found:
- Fibrinogen and hs-CRP were elevated in migraineurs compared to controls.
- In logistic regression analyses, MO and MA had increased likelihood of elevated fibrinogen, and MA had increased likelihood of elevated Factor II and hs-CRP.
- Fibrinogen and Factor II were associated with MA in women but not men.
- In the migraine subgroup, the total number of years of aura, but not headache, predicted elevated hs-CRP, and the average number of aura, but not headache, attacks predicted all biomarkers but Factor II.
Migraine and vascular disease biomarkers: A population-based case-control study. Cephalalgia. 2018;38(3):511-518. doi:10.1177/0333102417698936.
Elevated vascular biomarkers were associated with migraine, a recent study found, particularly migraine with aura (MA), as well as with years of aura and number of aura attacks. Participants (300 women, 117 men) were aged 30–60 (mean 48) years, 155 MA, 128 migraine without aura (MO), and 134 were controls with no severe headaches. Plasma concentrations of fibrinogen, Factor II, D-dimer, high sensitivity C-reactive protein (hs-CRP), and von Willebrand factor antigen were compared between groups, also stratifying by sex. Researchers found:
- Fibrinogen and hs-CRP were elevated in migraineurs compared to controls.
- In logistic regression analyses, MO and MA had increased likelihood of elevated fibrinogen, and MA had increased likelihood of elevated Factor II and hs-CRP.
- Fibrinogen and Factor II were associated with MA in women but not men.
- In the migraine subgroup, the total number of years of aura, but not headache, predicted elevated hs-CRP, and the average number of aura, but not headache, attacks predicted all biomarkers but Factor II.
Migraine and vascular disease biomarkers: A population-based case-control study. Cephalalgia. 2018;38(3):511-518. doi:10.1177/0333102417698936.
Migraine Linked with Increased Risk of Stroke, MI
Migraine headache was associated with an increased long-term risk of cardiovascular and cerebrovascular events, a recent study found. This effect was due to an increased risk of stroke (both ischemic and hemorrhagic) and myocardial infarction (MI). There was a moderate to severe degree of heterogeneity for the outcomes, which was partly explained by the presence of aura. A total of 16 cohort studies (18 study records) with 394,942 migraineurs and 757,465 non-migraineurs were analyzed. Researchers found:
- Migraine was associated with a higher risk of a major adverse cardiovascular and cerebrovascular event driven by a higher risk of stroke and MI.
- There was no difference in the risk of all-cause mortality, with a considerable degree of statistical heterogeneity between the studies.
- The presence of aura was an effect modifier for stroke and all-cause mortality.
Migraine and the risk of cardiovascular and cerebrovascular events: A meta-analysis of 16 cohort studies including 1,152,407 subjects. [Published online ahead of print March 27, 2018]. BMJ Open. doi:10.1136/bmjopen-2017-020498.
Migraine headache was associated with an increased long-term risk of cardiovascular and cerebrovascular events, a recent study found. This effect was due to an increased risk of stroke (both ischemic and hemorrhagic) and myocardial infarction (MI). There was a moderate to severe degree of heterogeneity for the outcomes, which was partly explained by the presence of aura. A total of 16 cohort studies (18 study records) with 394,942 migraineurs and 757,465 non-migraineurs were analyzed. Researchers found:
- Migraine was associated with a higher risk of a major adverse cardiovascular and cerebrovascular event driven by a higher risk of stroke and MI.
- There was no difference in the risk of all-cause mortality, with a considerable degree of statistical heterogeneity between the studies.
- The presence of aura was an effect modifier for stroke and all-cause mortality.
Migraine and the risk of cardiovascular and cerebrovascular events: A meta-analysis of 16 cohort studies including 1,152,407 subjects. [Published online ahead of print March 27, 2018]. BMJ Open. doi:10.1136/bmjopen-2017-020498.
Migraine headache was associated with an increased long-term risk of cardiovascular and cerebrovascular events, a recent study found. This effect was due to an increased risk of stroke (both ischemic and hemorrhagic) and myocardial infarction (MI). There was a moderate to severe degree of heterogeneity for the outcomes, which was partly explained by the presence of aura. A total of 16 cohort studies (18 study records) with 394,942 migraineurs and 757,465 non-migraineurs were analyzed. Researchers found:
- Migraine was associated with a higher risk of a major adverse cardiovascular and cerebrovascular event driven by a higher risk of stroke and MI.
- There was no difference in the risk of all-cause mortality, with a considerable degree of statistical heterogeneity between the studies.
- The presence of aura was an effect modifier for stroke and all-cause mortality.
Migraine and the risk of cardiovascular and cerebrovascular events: A meta-analysis of 16 cohort studies including 1,152,407 subjects. [Published online ahead of print March 27, 2018]. BMJ Open. doi:10.1136/bmjopen-2017-020498.
Migraine Common in Patients with Sarcoidosis
Migraine is a common comorbidity in patients with sarcoidosis, according to a recent study. As such, better recognition and targeted treatment of migraine has the potential to improve quality of life as part of a comprehensive care plan for those with sarcoidosis. The ID Migraine questionnaire was administered to a well-phenotyped observational cohort of patients with sarcoidosis (most of whom were seeking specialty care) and healthy controls. Predictors of migraine status were examined using univariate and multivariable logistic regression. Researchers found:
- Migraine was seen in 29% of 96 patients with sarcoidosis and 13% of 39 healthy controls.
- Among those with sarcoidosis, in univariate regression analysis only female sex was predictive of having migraine, and in a multivariable regression female sex remained significant.
There was no association between migraine and age, depression, dyspnea, immunosuppression use, or erythrocyte sedimentation rate.
Migraine is common in patients with sarcoidosis. [Published online ahead of print March 26, 2018]. Cephalalgia. doi:10.1177/0333102418768037.
Migraine is a common comorbidity in patients with sarcoidosis, according to a recent study. As such, better recognition and targeted treatment of migraine has the potential to improve quality of life as part of a comprehensive care plan for those with sarcoidosis. The ID Migraine questionnaire was administered to a well-phenotyped observational cohort of patients with sarcoidosis (most of whom were seeking specialty care) and healthy controls. Predictors of migraine status were examined using univariate and multivariable logistic regression. Researchers found:
- Migraine was seen in 29% of 96 patients with sarcoidosis and 13% of 39 healthy controls.
- Among those with sarcoidosis, in univariate regression analysis only female sex was predictive of having migraine, and in a multivariable regression female sex remained significant.
There was no association between migraine and age, depression, dyspnea, immunosuppression use, or erythrocyte sedimentation rate.
Migraine is common in patients with sarcoidosis. [Published online ahead of print March 26, 2018]. Cephalalgia. doi:10.1177/0333102418768037.
Migraine is a common comorbidity in patients with sarcoidosis, according to a recent study. As such, better recognition and targeted treatment of migraine has the potential to improve quality of life as part of a comprehensive care plan for those with sarcoidosis. The ID Migraine questionnaire was administered to a well-phenotyped observational cohort of patients with sarcoidosis (most of whom were seeking specialty care) and healthy controls. Predictors of migraine status were examined using univariate and multivariable logistic regression. Researchers found:
- Migraine was seen in 29% of 96 patients with sarcoidosis and 13% of 39 healthy controls.
- Among those with sarcoidosis, in univariate regression analysis only female sex was predictive of having migraine, and in a multivariable regression female sex remained significant.
There was no association between migraine and age, depression, dyspnea, immunosuppression use, or erythrocyte sedimentation rate.
Migraine is common in patients with sarcoidosis. [Published online ahead of print March 26, 2018]. Cephalalgia. doi:10.1177/0333102418768037.
Commentary—Could Prazosin Play a Role in Treating Chronic Posttraumatic Headache?
Headache is a common symptom after any severity traumatic brain injury in the civilian and military populations. Currently, there is no evidence-based treatment protocol for posttraumatic headache, and management largely is based on therapies used in the primary headache disorders.
There is a complex interaction between mood disorders, posttraumatic stress disorder (PTSD), sleep disorders, and headache. Depression and PTSD are frequently seen in civilian and military populations accompanying chronic posttraumatic headache. In civilians, about one-third of patients with posttraumatic headache meet criteria for depression and PTSD. A longitudinal study of Iraq and Afghanistan veterans followed over three years found that co-occurrence of depression, PTSD, or both would increase the risk of chronic posttraumatic headache more than TBI alone. Another meta-analysis of civilian and military TBI found that, though PTSD could affect intensity and severity of chronic posttraumatic headache, TBI was an independent risk factor for chronic posttraumatic headache. PTSD and depression can cause sleep disruption and intensify pain syndromes, including headache.
Though prazosin had been shown to be effective in decreasing nightmares, improving sleep, or decreasing daytime sleepiness in many prior studies, the PACT trial, a randomized, double-blind controlled trial of 304 participants at Veterans Affairs medical centers, did not meet its primary end points of less frequent and less intense trauma-related nightmares, greater improvement in sleep quality, and overall clinical status among veterans assigned to prazosin, compared with veterans assigned to placebo. While disappointing, and surprising given the results of the preceding studies, do these results predict a similar failure in the use of prazosin for treatment of posttraumatic headache?
In an observational study of 126 veterans with blast-related mild TBI during Operation Iraqi Freedom or Operation Enduring Freedom, 82% of participants had co-occurring conditions, including frequent, severe headache, neurologic exam abnormalities, or cognitive disorders. This pilot study found that treatment with prazosin and sleep hygiene counseling improved sleep, but also decreased headache pain and frequency, as well as improved cognitive function over nine weeks. Improvements were maintained for six months. Though difficult to determine the interplay of sleep, posttraumatic headache, and depression, could prazosin independently reduce the burden of headache? Currently, a double-blind, randomized, controlled trial in veterans is examining the effectiveness of prazosin as a preventive agent in treating combat-related posttraumatic headache. This study was scheduled to enroll its last patient at the end of 2017, and results may be out soon.
There may be specific pharmacologic properties that make prazosin a useful drug for headache treatment. Prazosin is a very potent, selective alpha 1-adrenergic antagonist that passes through the blood–brain barrier. It is highly protein bound (97%), so absolute amounts in the CNS are likely to be low. Its use in the treatment of hypertension is based on decreased peripheral vascular resistance as a result of arteriolar and venous receptor blockade. It also can act in the CNS to decrease sympathetic outflow. While an effect on headache could be central, peripheral, or both, other drugs with alpha-adrenergic blocking effects have been used in the treatment of migraine for decades. The ergots, for example, were the first alpha-adrenergic agents to be discovered acting as partial agonists or antagonists at adrenergic, tryptaminergic, and dopaminergic receptors. The hydrogenated ergot alkaloids are among the most potent alpha-adrenergic blocking agents, but adverse effects prevent doses that can cause more than minimal blockade. Chlorpromazine and other dopamine (D2) receptor antagonists, which are highly effective in acute treatment of migraine, particularly with parenteral delivery, also produce significant alpha-adrenergic receptor blockade, while trazodone, amitriptyline, and the atypical antipsychotics, with various levels of alpha-adrenergic antagonism, have found some success in migraine prevention.
Clinical experience has shown that there is wide response variability to acute and chronic medication for migraine. Genetic studies of patients with migraine, though at an early stage, have identified genes involved with vascular and neuronal function. It is likely that clinical observation will be borne out by individual responses to drug classes based on individual genetic profiles, so that subtypes of patients in clinical trial populations may show efficacy based on these profiles. It is likely that prazosin will be useful in certain patient subtypes for the treatment of headache. Posttraumatic headache, which may share some similar pathways of headache physiology with primary headache disorders, adds another layer of response complexity.
—Sylvia Lucas, MD, PhD
Clinical Professor of Neurology and Neurological Surgery
University of Washington
Seattle
Suggested Reading
Nampiaparampil DE. Prevalence of chronic pain after traumatic brain injury: a systematic review. JAMA. 2008;300(6):711-719.
Peterlin BL, Nijjar SS, Tietjen GE. Post-traumatic stress disorder and migraine: epidemiology, sex differences, and potential mechanisms. Headache. 2011;51(6):860-868.
Ruff RL, Riechers RG, Wang XF, et al. For veterans with mild traumatic brain injury, improved posttraumatic stress disorder severity and sleep correlated with symptomatic improvement. J Rehabil Res Dev. 2012;49(9):1305-1320.
Headache is a common symptom after any severity traumatic brain injury in the civilian and military populations. Currently, there is no evidence-based treatment protocol for posttraumatic headache, and management largely is based on therapies used in the primary headache disorders.
There is a complex interaction between mood disorders, posttraumatic stress disorder (PTSD), sleep disorders, and headache. Depression and PTSD are frequently seen in civilian and military populations accompanying chronic posttraumatic headache. In civilians, about one-third of patients with posttraumatic headache meet criteria for depression and PTSD. A longitudinal study of Iraq and Afghanistan veterans followed over three years found that co-occurrence of depression, PTSD, or both would increase the risk of chronic posttraumatic headache more than TBI alone. Another meta-analysis of civilian and military TBI found that, though PTSD could affect intensity and severity of chronic posttraumatic headache, TBI was an independent risk factor for chronic posttraumatic headache. PTSD and depression can cause sleep disruption and intensify pain syndromes, including headache.
Though prazosin had been shown to be effective in decreasing nightmares, improving sleep, or decreasing daytime sleepiness in many prior studies, the PACT trial, a randomized, double-blind controlled trial of 304 participants at Veterans Affairs medical centers, did not meet its primary end points of less frequent and less intense trauma-related nightmares, greater improvement in sleep quality, and overall clinical status among veterans assigned to prazosin, compared with veterans assigned to placebo. While disappointing, and surprising given the results of the preceding studies, do these results predict a similar failure in the use of prazosin for treatment of posttraumatic headache?
In an observational study of 126 veterans with blast-related mild TBI during Operation Iraqi Freedom or Operation Enduring Freedom, 82% of participants had co-occurring conditions, including frequent, severe headache, neurologic exam abnormalities, or cognitive disorders. This pilot study found that treatment with prazosin and sleep hygiene counseling improved sleep, but also decreased headache pain and frequency, as well as improved cognitive function over nine weeks. Improvements were maintained for six months. Though difficult to determine the interplay of sleep, posttraumatic headache, and depression, could prazosin independently reduce the burden of headache? Currently, a double-blind, randomized, controlled trial in veterans is examining the effectiveness of prazosin as a preventive agent in treating combat-related posttraumatic headache. This study was scheduled to enroll its last patient at the end of 2017, and results may be out soon.
There may be specific pharmacologic properties that make prazosin a useful drug for headache treatment. Prazosin is a very potent, selective alpha 1-adrenergic antagonist that passes through the blood–brain barrier. It is highly protein bound (97%), so absolute amounts in the CNS are likely to be low. Its use in the treatment of hypertension is based on decreased peripheral vascular resistance as a result of arteriolar and venous receptor blockade. It also can act in the CNS to decrease sympathetic outflow. While an effect on headache could be central, peripheral, or both, other drugs with alpha-adrenergic blocking effects have been used in the treatment of migraine for decades. The ergots, for example, were the first alpha-adrenergic agents to be discovered acting as partial agonists or antagonists at adrenergic, tryptaminergic, and dopaminergic receptors. The hydrogenated ergot alkaloids are among the most potent alpha-adrenergic blocking agents, but adverse effects prevent doses that can cause more than minimal blockade. Chlorpromazine and other dopamine (D2) receptor antagonists, which are highly effective in acute treatment of migraine, particularly with parenteral delivery, also produce significant alpha-adrenergic receptor blockade, while trazodone, amitriptyline, and the atypical antipsychotics, with various levels of alpha-adrenergic antagonism, have found some success in migraine prevention.
Clinical experience has shown that there is wide response variability to acute and chronic medication for migraine. Genetic studies of patients with migraine, though at an early stage, have identified genes involved with vascular and neuronal function. It is likely that clinical observation will be borne out by individual responses to drug classes based on individual genetic profiles, so that subtypes of patients in clinical trial populations may show efficacy based on these profiles. It is likely that prazosin will be useful in certain patient subtypes for the treatment of headache. Posttraumatic headache, which may share some similar pathways of headache physiology with primary headache disorders, adds another layer of response complexity.
—Sylvia Lucas, MD, PhD
Clinical Professor of Neurology and Neurological Surgery
University of Washington
Seattle
Suggested Reading
Nampiaparampil DE. Prevalence of chronic pain after traumatic brain injury: a systematic review. JAMA. 2008;300(6):711-719.
Peterlin BL, Nijjar SS, Tietjen GE. Post-traumatic stress disorder and migraine: epidemiology, sex differences, and potential mechanisms. Headache. 2011;51(6):860-868.
Ruff RL, Riechers RG, Wang XF, et al. For veterans with mild traumatic brain injury, improved posttraumatic stress disorder severity and sleep correlated with symptomatic improvement. J Rehabil Res Dev. 2012;49(9):1305-1320.
Headache is a common symptom after any severity traumatic brain injury in the civilian and military populations. Currently, there is no evidence-based treatment protocol for posttraumatic headache, and management largely is based on therapies used in the primary headache disorders.
There is a complex interaction between mood disorders, posttraumatic stress disorder (PTSD), sleep disorders, and headache. Depression and PTSD are frequently seen in civilian and military populations accompanying chronic posttraumatic headache. In civilians, about one-third of patients with posttraumatic headache meet criteria for depression and PTSD. A longitudinal study of Iraq and Afghanistan veterans followed over three years found that co-occurrence of depression, PTSD, or both would increase the risk of chronic posttraumatic headache more than TBI alone. Another meta-analysis of civilian and military TBI found that, though PTSD could affect intensity and severity of chronic posttraumatic headache, TBI was an independent risk factor for chronic posttraumatic headache. PTSD and depression can cause sleep disruption and intensify pain syndromes, including headache.
Though prazosin had been shown to be effective in decreasing nightmares, improving sleep, or decreasing daytime sleepiness in many prior studies, the PACT trial, a randomized, double-blind controlled trial of 304 participants at Veterans Affairs medical centers, did not meet its primary end points of less frequent and less intense trauma-related nightmares, greater improvement in sleep quality, and overall clinical status among veterans assigned to prazosin, compared with veterans assigned to placebo. While disappointing, and surprising given the results of the preceding studies, do these results predict a similar failure in the use of prazosin for treatment of posttraumatic headache?
In an observational study of 126 veterans with blast-related mild TBI during Operation Iraqi Freedom or Operation Enduring Freedom, 82% of participants had co-occurring conditions, including frequent, severe headache, neurologic exam abnormalities, or cognitive disorders. This pilot study found that treatment with prazosin and sleep hygiene counseling improved sleep, but also decreased headache pain and frequency, as well as improved cognitive function over nine weeks. Improvements were maintained for six months. Though difficult to determine the interplay of sleep, posttraumatic headache, and depression, could prazosin independently reduce the burden of headache? Currently, a double-blind, randomized, controlled trial in veterans is examining the effectiveness of prazosin as a preventive agent in treating combat-related posttraumatic headache. This study was scheduled to enroll its last patient at the end of 2017, and results may be out soon.
There may be specific pharmacologic properties that make prazosin a useful drug for headache treatment. Prazosin is a very potent, selective alpha 1-adrenergic antagonist that passes through the blood–brain barrier. It is highly protein bound (97%), so absolute amounts in the CNS are likely to be low. Its use in the treatment of hypertension is based on decreased peripheral vascular resistance as a result of arteriolar and venous receptor blockade. It also can act in the CNS to decrease sympathetic outflow. While an effect on headache could be central, peripheral, or both, other drugs with alpha-adrenergic blocking effects have been used in the treatment of migraine for decades. The ergots, for example, were the first alpha-adrenergic agents to be discovered acting as partial agonists or antagonists at adrenergic, tryptaminergic, and dopaminergic receptors. The hydrogenated ergot alkaloids are among the most potent alpha-adrenergic blocking agents, but adverse effects prevent doses that can cause more than minimal blockade. Chlorpromazine and other dopamine (D2) receptor antagonists, which are highly effective in acute treatment of migraine, particularly with parenteral delivery, also produce significant alpha-adrenergic receptor blockade, while trazodone, amitriptyline, and the atypical antipsychotics, with various levels of alpha-adrenergic antagonism, have found some success in migraine prevention.
Clinical experience has shown that there is wide response variability to acute and chronic medication for migraine. Genetic studies of patients with migraine, though at an early stage, have identified genes involved with vascular and neuronal function. It is likely that clinical observation will be borne out by individual responses to drug classes based on individual genetic profiles, so that subtypes of patients in clinical trial populations may show efficacy based on these profiles. It is likely that prazosin will be useful in certain patient subtypes for the treatment of headache. Posttraumatic headache, which may share some similar pathways of headache physiology with primary headache disorders, adds another layer of response complexity.
—Sylvia Lucas, MD, PhD
Clinical Professor of Neurology and Neurological Surgery
University of Washington
Seattle
Suggested Reading
Nampiaparampil DE. Prevalence of chronic pain after traumatic brain injury: a systematic review. JAMA. 2008;300(6):711-719.
Peterlin BL, Nijjar SS, Tietjen GE. Post-traumatic stress disorder and migraine: epidemiology, sex differences, and potential mechanisms. Headache. 2011;51(6):860-868.
Ruff RL, Riechers RG, Wang XF, et al. For veterans with mild traumatic brain injury, improved posttraumatic stress disorder severity and sleep correlated with symptomatic improvement. J Rehabil Res Dev. 2012;49(9):1305-1320.