Headache & Migraine

Dr. Rapoport: Do you commonly see patients who present with symptoms of both central and peripheral symptoms in practice?

Dr. Romero-Reyes: Yes, I see patients that present with temporomandibular disorders (TMD) and headache comorbidity, as well as patients with migraine, tension-type headache, and cervicogenic headache with myofascial pain.

Dr. Rapoport: Why do you think this condition is so challenging to treat?

Dr. Romero-Reyes: I think this is because of the lack of understanding and awareness that in addition to the multifactorial nature of headache disorders, other types of disorders that are not neurovascular in origin may influence trigeminovascular nociception, and these types of non-neurovascular disorders involve the skill and knowledge of other expertise.

Headaches receiving inputs from extracranial structures such as in TMD (temporomandibular joint [TMJ] and muscles of mastication) and/or cervical structures (cervical spine, cervical muscles) require multidisciplinary evaluation and management. In these cases, the management should involve a neurologist specialized in headache disorders, a dentist trained in TMD and orofacial pain disorders, and a physical therapist with special training in craniofacial and cervical Therapeutics. Multidisciplinary communication is key for successful management.

Another reason is that myofascial pain (MFP) is often overlooked in patients with headache disorders. In my experience, patients with episodic and chronic migraine, episodic and chronic tension-type headache, cervicogenic headache, and patients presenting TMD and headache comorbidity can present trigger points in the craniofacial and cervical muscles, an indication of MFP. It has been reported that these patients present a higher disability impact. The presence of MFP may be contributing to the activation of the trigeminovascular system and therefore facilitate, exacerbate, and perpetuate headache symptomatology and may accelerate the progression to a more chronic form of the disorder.

Dr. Rapoport: In your opinion, is this considered a controversial topic? Why or why not?
 

Dr. Romero-Reyes: Yes, I think it is necessary to clarify that tenderness in the back of the head or of neck muscles present in headache patients does not necessarily imply that it is due to a nerve compression. This could also be caused by local myalgia but more commonly, from latent or active myofascial trigger points present in the muscles of the area being palpated, or by referred pain beyond the area of the muscle being palpated. Suboccipital muscles (in the occiput area) are not the only muscle group that is associated with headache and neck pain symptomatology. For example, the trapezius muscle, which is an overlooked source of tension- type and cervicogenic headache, can present trigger points that can refer pain to the shoulder, neck, head, face and the eye. In addition, other craniofacial and cervical muscles such as the sternocleidomastoid (SCM) and temporalis muscles have been shown to be associated with headache symptomatology in the migraineur, as well as the chronic tension-type headache patient. Other muscles that also refer to the craniofacial area and can elicit headache and neck pain symptomatology include the masseter, occipitofrontalis, splenius capitis, splenius cervicis, semispinalis capitis, semispinalis cervicis and multifidi (cervical). The presence of trigger points in these muscles do not support or warrant the need to be removed or managed with non-conservative approaches.

Myofascial trigger points can result from muscle injury and overload, parafunctional activity, and poor head and neck posture. MFP is characterized by a regional pain and presence of localized tender areas (trigger points) in muscle, fascia or tendons that reproduce pain when palpated, and produce a pattern of regional pain spreading along the muscle palpated, or beyond the location boundary of the muscle palpated. It has been shown by microdyalisis that inflammatory mediators and neuropeptides are present in the area of an active trigger point. In addition, an increase of electromyography activity has been shown in trigger points in patients with chronic tension-type headache when compared with controls.

The importance of an evaluation by a skilled clinician in the craniofacial and cervical area to verify the source of pain is critical.  The patient may be reporting pain in one area, but the source of the pain is in another area, and this is typical symptomatology present when there are active trigger points. In addition, an assessment of any contributing factors arising from the cervical spine (eg, poor posture) and craniofacial area (eg, TMD) that may exacerbate headache symptomatology is vital to proper diagnosis.

In my experience, patients with migraine, tension-type headache, cervicogenic headache, and TMD and headache comorbidity present MFP perpetuating headache symptomatology. MFP is not managed by surgical interventions. This perpetuating factor can be managed effectively with conservative measures. The plan is tailored for each patient’s needs. In general, the plan of management may include trigger point injections in the muscle with anesthetics, dry needling, and a physical therapy plan that may include education regarding habits and posture, exercises and physical therapy modalities, which are crucial to relieve pain and increase function. In cases of TMD and headache comorbidity, an occlusal appliance (stabilization appliance) can be included if necessary. We should also consider behavioral therapies (especially EMG biofeedback training) and some oral anti-inflammatories or muscle relaxants in the beginning of management, together with the plan of management mentioned above.

With these approaches to manage the MFP component in headache patients, I have been able to see that in migraineurs with MFP, the frequency and severity of the attacks decrease significantly. The patient may still experience migraine attacks, but feel happy to have the possibility to reduce medication intake and be in more control of their pain. In patients with tension-type headache, I have seen this even more dramatically.

This is telling us that headache pathophysiology involves a “conversation” between the peripheral and central nervous system, which influence each other. Peripheral nociceptive input coming from extracranial structures can induce trigeminovascular activation and therefore exacerbate a headache disorder and vice versa.  Chronic myofascial pain may be the result of central sensitization due to the protracted peripheral nociceptive input (eg, poor posture, neck strain, parafunctional activity), therefore perpetuating the headache disorder even more.

Dr. Rapoport: Do you have any other comments about the article Treatment Challenges When Headache Has Central and Peripheral Involvement that you would like to share with our readers?

Dr. Romero-Reyes: It is simplistic to say migraine is either a peripheral or a central disorder, or that symptoms are either peripheral or central. Beyond thinking about migraine pain, migraine is fundamentally a brain (central) disorder. Its associated symptoms (nausea, phonophobia, photophobia) tell us this. Migraine headache is complex, and most likely the result of central mechanisms that can be influenced by peripheral inputs from the craniofacial and cervical region.

Embarking on surgical interventions for the management of headache disorders warrants a caution since it is still an experimental research question and the need of such therapies should be evaluated against conservative management. We are in a very exciting and hopeful time for migraine management. New evidence-based options from biological agents, such as anti-calcitonin gene-related peptide (CGRP) therapies, to non-pharmacological approaches, such as neuromodulation, can be offered to the patients. If the patient is experiencing pain in the neck area or other craniofacial area, it is recommended to have a thorough evaluation by a physical therapist with special training in cervical and craniofacial therapeutics and/or a dentist trained in TMD and orofacial pain disorders to work in consultation with a neurologist to elaborate a personalized management plan. Do not overlook the contribution of myofascial pain (trigger points) as well as TMD in the symptomatology of headache disorders. Few patients need to undergo surgical measures of peripheral nerves and muscles for improvement. An exhaustive evaluation must be undertaken first.

Resources for patients:

AHS

https://americanheadachesociety.org/

https://americanheadachesociety.org/wp-content/uploads/2018/06/Choosing-Wisely-Flyer.pdf

AAOP

https://aaop.clubexpress.com/content.aspx?sl=1152088466

PTBCTT

https://ptbcct.org/

Dr. Rapoport: Do you commonly see patients who present with symptoms of both central and peripheral symptoms in practice?

Dr. Romero-Reyes: Yes, I see patients that present with temporomandibular disorders (TMD) and headache comorbidity, as well as patients with migraine, tension-type headache, and cervicogenic headache with myofascial pain.

Dr. Rapoport: Why do you think this condition is so challenging to treat?

Dr. Romero-Reyes: I think this is because of the lack of understanding and awareness that in addition to the multifactorial nature of headache disorders, other types of disorders that are not neurovascular in origin may influence trigeminovascular nociception, and these types of non-neurovascular disorders involve the skill and knowledge of other expertise.

Headaches receiving inputs from extracranial structures such as in TMD (temporomandibular joint [TMJ] and muscles of mastication) and/or cervical structures (cervical spine, cervical muscles) require multidisciplinary evaluation and management. In these cases, the management should involve a neurologist specialized in headache disorders, a dentist trained in TMD and orofacial pain disorders, and a physical therapist with special training in craniofacial and cervical Therapeutics. Multidisciplinary communication is key for successful management.

Another reason is that myofascial pain (MFP) is often overlooked in patients with headache disorders. In my experience, patients with episodic and chronic migraine, episodic and chronic tension-type headache, cervicogenic headache, and patients presenting TMD and headache comorbidity can present trigger points in the craniofacial and cervical muscles, an indication of MFP. It has been reported that these patients present a higher disability impact. The presence of MFP may be contributing to the activation of the trigeminovascular system and therefore facilitate, exacerbate, and perpetuate headache symptomatology and may accelerate the progression to a more chronic form of the disorder.

Dr. Rapoport: In your opinion, is this considered a controversial topic? Why or why not?
 

Dr. Romero-Reyes: Yes, I think it is necessary to clarify that tenderness in the back of the head or of neck muscles present in headache patients does not necessarily imply that it is due to a nerve compression. This could also be caused by local myalgia but more commonly, from latent or active myofascial trigger points present in the muscles of the area being palpated, or by referred pain beyond the area of the muscle being palpated. Suboccipital muscles (in the occiput area) are not the only muscle group that is associated with headache and neck pain symptomatology. For example, the trapezius muscle, which is an overlooked source of tension- type and cervicogenic headache, can present trigger points that can refer pain to the shoulder, neck, head, face and the eye. In addition, other craniofacial and cervical muscles such as the sternocleidomastoid (SCM) and temporalis muscles have been shown to be associated with headache symptomatology in the migraineur, as well as the chronic tension-type headache patient. Other muscles that also refer to the craniofacial area and can elicit headache and neck pain symptomatology include the masseter, occipitofrontalis, splenius capitis, splenius cervicis, semispinalis capitis, semispinalis cervicis and multifidi (cervical). The presence of trigger points in these muscles do not support or warrant the need to be removed or managed with non-conservative approaches.

Myofascial trigger points can result from muscle injury and overload, parafunctional activity, and poor head and neck posture. MFP is characterized by a regional pain and presence of localized tender areas (trigger points) in muscle, fascia or tendons that reproduce pain when palpated, and produce a pattern of regional pain spreading along the muscle palpated, or beyond the location boundary of the muscle palpated. It has been shown by microdyalisis that inflammatory mediators and neuropeptides are present in the area of an active trigger point. In addition, an increase of electromyography activity has been shown in trigger points in patients with chronic tension-type headache when compared with controls.

The importance of an evaluation by a skilled clinician in the craniofacial and cervical area to verify the source of pain is critical.  The patient may be reporting pain in one area, but the source of the pain is in another area, and this is typical symptomatology present when there are active trigger points. In addition, an assessment of any contributing factors arising from the cervical spine (eg, poor posture) and craniofacial area (eg, TMD) that may exacerbate headache symptomatology is vital to proper diagnosis.

In my experience, patients with migraine, tension-type headache, cervicogenic headache, and TMD and headache comorbidity present MFP perpetuating headache symptomatology. MFP is not managed by surgical interventions. This perpetuating factor can be managed effectively with conservative measures. The plan is tailored for each patient’s needs. In general, the plan of management may include trigger point injections in the muscle with anesthetics, dry needling, and a physical therapy plan that may include education regarding habits and posture, exercises and physical therapy modalities, which are crucial to relieve pain and increase function. In cases of TMD and headache comorbidity, an occlusal appliance (stabilization appliance) can be included if necessary. We should also consider behavioral therapies (especially EMG biofeedback training) and some oral anti-inflammatories or muscle relaxants in the beginning of management, together with the plan of management mentioned above.

With these approaches to manage the MFP component in headache patients, I have been able to see that in migraineurs with MFP, the frequency and severity of the attacks decrease significantly. The patient may still experience migraine attacks, but feel happy to have the possibility to reduce medication intake and be in more control of their pain. In patients with tension-type headache, I have seen this even more dramatically.

This is telling us that headache pathophysiology involves a “conversation” between the peripheral and central nervous system, which influence each other. Peripheral nociceptive input coming from extracranial structures can induce trigeminovascular activation and therefore exacerbate a headache disorder and vice versa.  Chronic myofascial pain may be the result of central sensitization due to the protracted peripheral nociceptive input (eg, poor posture, neck strain, parafunctional activity), therefore perpetuating the headache disorder even more.

Dr. Rapoport: Do you have any other comments about the article Treatment Challenges When Headache Has Central and Peripheral Involvement that you would like to share with our readers?

Dr. Romero-Reyes: It is simplistic to say migraine is either a peripheral or a central disorder, or that symptoms are either peripheral or central. Beyond thinking about migraine pain, migraine is fundamentally a brain (central) disorder. Its associated symptoms (nausea, phonophobia, photophobia) tell us this. Migraine headache is complex, and most likely the result of central mechanisms that can be influenced by peripheral inputs from the craniofacial and cervical region.

Embarking on surgical interventions for the management of headache disorders warrants a caution since it is still an experimental research question and the need of such therapies should be evaluated against conservative management. We are in a very exciting and hopeful time for migraine management. New evidence-based options from biological agents, such as anti-calcitonin gene-related peptide (CGRP) therapies, to non-pharmacological approaches, such as neuromodulation, can be offered to the patients. If the patient is experiencing pain in the neck area or other craniofacial area, it is recommended to have a thorough evaluation by a physical therapist with special training in cervical and craniofacial therapeutics and/or a dentist trained in TMD and orofacial pain disorders to work in consultation with a neurologist to elaborate a personalized management plan. Do not overlook the contribution of myofascial pain (trigger points) as well as TMD in the symptomatology of headache disorders. Few patients need to undergo surgical measures of peripheral nerves and muscles for improvement. An exhaustive evaluation must be undertaken first.

Resources for patients:

AHS

https://americanheadachesociety.org/

https://americanheadachesociety.org/wp-content/uploads/2018/06/Choosing-Wisely-Flyer.pdf

AAOP

https://aaop.clubexpress.com/content.aspx?sl=1152088466

PTBCTT

https://ptbcct.org/

Dr. Rapoport: Do you commonly see patients who present with symptoms of both central and peripheral symptoms in practice?

Dr. Romero-Reyes: Yes, I see patients that present with temporomandibular disorders (TMD) and headache comorbidity, as well as patients with migraine, tension-type headache, and cervicogenic headache with myofascial pain.

Dr. Rapoport: Why do you think this condition is so challenging to treat?

Dr. Romero-Reyes: I think this is because of the lack of understanding and awareness that in addition to the multifactorial nature of headache disorders, other types of disorders that are not neurovascular in origin may influence trigeminovascular nociception, and these types of non-neurovascular disorders involve the skill and knowledge of other expertise.

Headaches receiving inputs from extracranial structures such as in TMD (temporomandibular joint [TMJ] and muscles of mastication) and/or cervical structures (cervical spine, cervical muscles) require multidisciplinary evaluation and management. In these cases, the management should involve a neurologist specialized in headache disorders, a dentist trained in TMD and orofacial pain disorders, and a physical therapist with special training in craniofacial and cervical Therapeutics. Multidisciplinary communication is key for successful management.

Another reason is that myofascial pain (MFP) is often overlooked in patients with headache disorders. In my experience, patients with episodic and chronic migraine, episodic and chronic tension-type headache, cervicogenic headache, and patients presenting TMD and headache comorbidity can present trigger points in the craniofacial and cervical muscles, an indication of MFP. It has been reported that these patients present a higher disability impact. The presence of MFP may be contributing to the activation of the trigeminovascular system and therefore facilitate, exacerbate, and perpetuate headache symptomatology and may accelerate the progression to a more chronic form of the disorder.

Dr. Rapoport: In your opinion, is this considered a controversial topic? Why or why not?
 

Dr. Romero-Reyes: Yes, I think it is necessary to clarify that tenderness in the back of the head or of neck muscles present in headache patients does not necessarily imply that it is due to a nerve compression. This could also be caused by local myalgia but more commonly, from latent or active myofascial trigger points present in the muscles of the area being palpated, or by referred pain beyond the area of the muscle being palpated. Suboccipital muscles (in the occiput area) are not the only muscle group that is associated with headache and neck pain symptomatology. For example, the trapezius muscle, which is an overlooked source of tension- type and cervicogenic headache, can present trigger points that can refer pain to the shoulder, neck, head, face and the eye. In addition, other craniofacial and cervical muscles such as the sternocleidomastoid (SCM) and temporalis muscles have been shown to be associated with headache symptomatology in the migraineur, as well as the chronic tension-type headache patient. Other muscles that also refer to the craniofacial area and can elicit headache and neck pain symptomatology include the masseter, occipitofrontalis, splenius capitis, splenius cervicis, semispinalis capitis, semispinalis cervicis and multifidi (cervical). The presence of trigger points in these muscles do not support or warrant the need to be removed or managed with non-conservative approaches.

Myofascial trigger points can result from muscle injury and overload, parafunctional activity, and poor head and neck posture. MFP is characterized by a regional pain and presence of localized tender areas (trigger points) in muscle, fascia or tendons that reproduce pain when palpated, and produce a pattern of regional pain spreading along the muscle palpated, or beyond the location boundary of the muscle palpated. It has been shown by microdyalisis that inflammatory mediators and neuropeptides are present in the area of an active trigger point. In addition, an increase of electromyography activity has been shown in trigger points in patients with chronic tension-type headache when compared with controls.

The importance of an evaluation by a skilled clinician in the craniofacial and cervical area to verify the source of pain is critical.  The patient may be reporting pain in one area, but the source of the pain is in another area, and this is typical symptomatology present when there are active trigger points. In addition, an assessment of any contributing factors arising from the cervical spine (eg, poor posture) and craniofacial area (eg, TMD) that may exacerbate headache symptomatology is vital to proper diagnosis.

In my experience, patients with migraine, tension-type headache, cervicogenic headache, and TMD and headache comorbidity present MFP perpetuating headache symptomatology. MFP is not managed by surgical interventions. This perpetuating factor can be managed effectively with conservative measures. The plan is tailored for each patient’s needs. In general, the plan of management may include trigger point injections in the muscle with anesthetics, dry needling, and a physical therapy plan that may include education regarding habits and posture, exercises and physical therapy modalities, which are crucial to relieve pain and increase function. In cases of TMD and headache comorbidity, an occlusal appliance (stabilization appliance) can be included if necessary. We should also consider behavioral therapies (especially EMG biofeedback training) and some oral anti-inflammatories or muscle relaxants in the beginning of management, together with the plan of management mentioned above.

With these approaches to manage the MFP component in headache patients, I have been able to see that in migraineurs with MFP, the frequency and severity of the attacks decrease significantly. The patient may still experience migraine attacks, but feel happy to have the possibility to reduce medication intake and be in more control of their pain. In patients with tension-type headache, I have seen this even more dramatically.

This is telling us that headache pathophysiology involves a “conversation” between the peripheral and central nervous system, which influence each other. Peripheral nociceptive input coming from extracranial structures can induce trigeminovascular activation and therefore exacerbate a headache disorder and vice versa.  Chronic myofascial pain may be the result of central sensitization due to the protracted peripheral nociceptive input (eg, poor posture, neck strain, parafunctional activity), therefore perpetuating the headache disorder even more.

Dr. Rapoport: Do you have any other comments about the article Treatment Challenges When Headache Has Central and Peripheral Involvement that you would like to share with our readers?

Dr. Romero-Reyes: It is simplistic to say migraine is either a peripheral or a central disorder, or that symptoms are either peripheral or central. Beyond thinking about migraine pain, migraine is fundamentally a brain (central) disorder. Its associated symptoms (nausea, phonophobia, photophobia) tell us this. Migraine headache is complex, and most likely the result of central mechanisms that can be influenced by peripheral inputs from the craniofacial and cervical region.

Embarking on surgical interventions for the management of headache disorders warrants a caution since it is still an experimental research question and the need of such therapies should be evaluated against conservative management. We are in a very exciting and hopeful time for migraine management. New evidence-based options from biological agents, such as anti-calcitonin gene-related peptide (CGRP) therapies, to non-pharmacological approaches, such as neuromodulation, can be offered to the patients. If the patient is experiencing pain in the neck area or other craniofacial area, it is recommended to have a thorough evaluation by a physical therapist with special training in cervical and craniofacial therapeutics and/or a dentist trained in TMD and orofacial pain disorders to work in consultation with a neurologist to elaborate a personalized management plan. Do not overlook the contribution of myofascial pain (trigger points) as well as TMD in the symptomatology of headache disorders. Few patients need to undergo surgical measures of peripheral nerves and muscles for improvement. An exhaustive evaluation must be undertaken first.

Resources for patients:

AHS

https://americanheadachesociety.org/

https://americanheadachesociety.org/wp-content/uploads/2018/06/Choosing-Wisely-Flyer.pdf

AAOP

https://aaop.clubexpress.com/content.aspx?sl=1152088466

PTBCTT

https://ptbcct.org/

Use of rituximab for B-cell depletion was not associated with clinical improvement of fatigue scores for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), according to results from the phase 3 RituxME trial.

Courtesy Kristin Risa

“The lack of clinical effect of B-cell depletion in this trial weakens the case for an important role of B lymphocytes in ME/CFS but does not exclude an immunologic basis,” Øystein Fluge, MD, PhD, of the department of oncology and medical physics at Haukeland University Hospital in Bergen, Norway, and his colleagues wrote April 1 in Annals of Internal Medicine.

The investigators noted that the basis for testing the effects of a B-cell–depleting intervention on clinical symptoms in patients with ME/CFS came from observations of its potential benefit in a subgroup of patients in previous studies. Dr. Fluge and his colleagues performed a three-patient case series in their own group that found benefit for patients who received rituximab for treatment of CFS (BMC Neurol. 2009 May 8;9:28. doi: 10.1186/1471-2377-9-28). A phase 2 trial of 30 patients with CFS also performed by his own group found improved fatigue scores in 66.7% of patients in the rituximab group, compared with placebo (PLOS One. 2011 Oct 19. doi: 10.1371/journal.pone.0026358).

In the double-blinded RituxME trial, 151 patients with ME/CFS from four university hospitals and one general hospital in Norway were recruited and randomized to receive infusions of rituximab (n = 77) or placebo (n = 74). The patients were aged 18-65 years old and had the disease ranging from 2 years to 15 years. Patients reported and rated their ME/CFS symptoms at baseline as well as completed forms for the SF-36, Hospital Anxiety and Depression Scale, Fatigue Severity Scale, and modified DePaul Symptom Questionnaire out to 24 months. The rituximab group received two infusions at 500 mg/m² across body surface area at 2 weeks apart. They then received 500-mg maintenance infusions at 3 months, 6 months, 9 months, and 12 months where they also self-reported changes in ME/CFS symptoms.

There were no significant differences between groups regarding fatigue score at any follow-up period, with an average between-group difference of 0.02 at 24 months (95% confidence interval, –0.27 to 0.31). The overall response rate was 26% with rituximab and 35% with placebo. Dr. Fluge and his colleagues also noted no significant differences regarding SF-36 scores, function level, and fatigue severity between groups.

Adverse event rates were higher in the rituximab group (63 patients; 82%) than in the placebo group (48 patients; 65%), and these were more often attributed to treatment for those taking rituximab (26 patients [34%]) than for placebo (12 patients [16%]). Adverse events requiring hospitalization also occurred more often among those taking rituximab (31 events in 20 patients [26%]) than for those who took placebo (16 events in 14 patients [19%]).

Some of the weaknesses of the trial included its use of self-referral and self-reported symptom scores, which might have been subject to recall bias. In commenting on the difference in outcome between the phase 3 trial and others, Dr. Fluge and his associates said the discrepancy could potentially be high expectations in the placebo group, unknown factors surrounding symptom variation in ME/CFS patients, and unknown patient selection effects.

“[T]he negative outcome of RituxME should spur research to assess patient subgroups and further elucidate disease mechanisms, of which recently disclosed impairment of energy metabolism may be important,” Dr. Fluge and his coauthors wrote.

The trial was funded by grants to the researchers from the Norwegian Research Council, the Norwegian Regional Health Trusts, the MEandYou Foundation, the Norwegian ME Association, and the legacy of Torstein Hereid.

SOURCE: Fluge Ø et al. Ann Intern Med. 2019 Apr 1. doi: 10.7326/M18-1451

Use of rituximab for B-cell depletion was not associated with clinical improvement of fatigue scores for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), according to results from the phase 3 RituxME trial.

Courtesy Kristin Risa

“The lack of clinical effect of B-cell depletion in this trial weakens the case for an important role of B lymphocytes in ME/CFS but does not exclude an immunologic basis,” Øystein Fluge, MD, PhD, of the department of oncology and medical physics at Haukeland University Hospital in Bergen, Norway, and his colleagues wrote April 1 in Annals of Internal Medicine.

The investigators noted that the basis for testing the effects of a B-cell–depleting intervention on clinical symptoms in patients with ME/CFS came from observations of its potential benefit in a subgroup of patients in previous studies. Dr. Fluge and his colleagues performed a three-patient case series in their own group that found benefit for patients who received rituximab for treatment of CFS (BMC Neurol. 2009 May 8;9:28. doi: 10.1186/1471-2377-9-28). A phase 2 trial of 30 patients with CFS also performed by his own group found improved fatigue scores in 66.7% of patients in the rituximab group, compared with placebo (PLOS One. 2011 Oct 19. doi: 10.1371/journal.pone.0026358).

In the double-blinded RituxME trial, 151 patients with ME/CFS from four university hospitals and one general hospital in Norway were recruited and randomized to receive infusions of rituximab (n = 77) or placebo (n = 74). The patients were aged 18-65 years old and had the disease ranging from 2 years to 15 years. Patients reported and rated their ME/CFS symptoms at baseline as well as completed forms for the SF-36, Hospital Anxiety and Depression Scale, Fatigue Severity Scale, and modified DePaul Symptom Questionnaire out to 24 months. The rituximab group received two infusions at 500 mg/m² across body surface area at 2 weeks apart. They then received 500-mg maintenance infusions at 3 months, 6 months, 9 months, and 12 months where they also self-reported changes in ME/CFS symptoms.

There were no significant differences between groups regarding fatigue score at any follow-up period, with an average between-group difference of 0.02 at 24 months (95% confidence interval, –0.27 to 0.31). The overall response rate was 26% with rituximab and 35% with placebo. Dr. Fluge and his colleagues also noted no significant differences regarding SF-36 scores, function level, and fatigue severity between groups.

Adverse event rates were higher in the rituximab group (63 patients; 82%) than in the placebo group (48 patients; 65%), and these were more often attributed to treatment for those taking rituximab (26 patients [34%]) than for placebo (12 patients [16%]). Adverse events requiring hospitalization also occurred more often among those taking rituximab (31 events in 20 patients [26%]) than for those who took placebo (16 events in 14 patients [19%]).

Some of the weaknesses of the trial included its use of self-referral and self-reported symptom scores, which might have been subject to recall bias. In commenting on the difference in outcome between the phase 3 trial and others, Dr. Fluge and his associates said the discrepancy could potentially be high expectations in the placebo group, unknown factors surrounding symptom variation in ME/CFS patients, and unknown patient selection effects.

“[T]he negative outcome of RituxME should spur research to assess patient subgroups and further elucidate disease mechanisms, of which recently disclosed impairment of energy metabolism may be important,” Dr. Fluge and his coauthors wrote.

The trial was funded by grants to the researchers from the Norwegian Research Council, the Norwegian Regional Health Trusts, the MEandYou Foundation, the Norwegian ME Association, and the legacy of Torstein Hereid.

SOURCE: Fluge Ø et al. Ann Intern Med. 2019 Apr 1. doi: 10.7326/M18-1451

Use of rituximab for B-cell depletion was not associated with clinical improvement of fatigue scores for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), according to results from the phase 3 RituxME trial.

Courtesy Kristin Risa

“The lack of clinical effect of B-cell depletion in this trial weakens the case for an important role of B lymphocytes in ME/CFS but does not exclude an immunologic basis,” Øystein Fluge, MD, PhD, of the department of oncology and medical physics at Haukeland University Hospital in Bergen, Norway, and his colleagues wrote April 1 in Annals of Internal Medicine.

The investigators noted that the basis for testing the effects of a B-cell–depleting intervention on clinical symptoms in patients with ME/CFS came from observations of its potential benefit in a subgroup of patients in previous studies. Dr. Fluge and his colleagues performed a three-patient case series in their own group that found benefit for patients who received rituximab for treatment of CFS (BMC Neurol. 2009 May 8;9:28. doi: 10.1186/1471-2377-9-28). A phase 2 trial of 30 patients with CFS also performed by his own group found improved fatigue scores in 66.7% of patients in the rituximab group, compared with placebo (PLOS One. 2011 Oct 19. doi: 10.1371/journal.pone.0026358).

In the double-blinded RituxME trial, 151 patients with ME/CFS from four university hospitals and one general hospital in Norway were recruited and randomized to receive infusions of rituximab (n = 77) or placebo (n = 74). The patients were aged 18-65 years old and had the disease ranging from 2 years to 15 years. Patients reported and rated their ME/CFS symptoms at baseline as well as completed forms for the SF-36, Hospital Anxiety and Depression Scale, Fatigue Severity Scale, and modified DePaul Symptom Questionnaire out to 24 months. The rituximab group received two infusions at 500 mg/m² across body surface area at 2 weeks apart. They then received 500-mg maintenance infusions at 3 months, 6 months, 9 months, and 12 months where they also self-reported changes in ME/CFS symptoms.

There were no significant differences between groups regarding fatigue score at any follow-up period, with an average between-group difference of 0.02 at 24 months (95% confidence interval, –0.27 to 0.31). The overall response rate was 26% with rituximab and 35% with placebo. Dr. Fluge and his colleagues also noted no significant differences regarding SF-36 scores, function level, and fatigue severity between groups.

Adverse event rates were higher in the rituximab group (63 patients; 82%) than in the placebo group (48 patients; 65%), and these were more often attributed to treatment for those taking rituximab (26 patients [34%]) than for placebo (12 patients [16%]). Adverse events requiring hospitalization also occurred more often among those taking rituximab (31 events in 20 patients [26%]) than for those who took placebo (16 events in 14 patients [19%]).

Some of the weaknesses of the trial included its use of self-referral and self-reported symptom scores, which might have been subject to recall bias. In commenting on the difference in outcome between the phase 3 trial and others, Dr. Fluge and his associates said the discrepancy could potentially be high expectations in the placebo group, unknown factors surrounding symptom variation in ME/CFS patients, and unknown patient selection effects.

“[T]he negative outcome of RituxME should spur research to assess patient subgroups and further elucidate disease mechanisms, of which recently disclosed impairment of energy metabolism may be important,” Dr. Fluge and his coauthors wrote.

The trial was funded by grants to the researchers from the Norwegian Research Council, the Norwegian Regional Health Trusts, the MEandYou Foundation, the Norwegian ME Association, and the legacy of Torstein Hereid.

SOURCE: Fluge Ø et al. Ann Intern Med. 2019 Apr 1. doi: 10.7326/M18-1451

Despite their known teratogenic risks, both valproate and topiramate are being prescribed relatively often in women of childbearing age, results of a retrospective analysis suggest.

Antonio_Diaz/Thinkstock

Topiramate, linked to increased risk of cleft palate and smaller-than-gestational-age newborns, was among the top three antiepileptic drugs (AEDs) prescribed to women 15-44 years of age in the population-based cohort study.

Valproate, linked to increases in both anatomic and behavioral teratogenicity, was less often prescribed, but nevertheless still prescribed in a considerable proportion of patients in the study, which looked at U.S. commercial, Medicare, and Medicaid claims data from 2009 to 2013.

Presence of comorbidities could be influencing whether or not a woman of childbearing age receives one of these AEDs, the investigators said. Specifically, they found valproate more often prescribed for women with epilepsy who also had mood or anxiety and dissociative disorder, while topiramate was more often prescribed in women with headaches or migraines.

Taken together, these findings suggest a lack of awareness of the teratogenic risks of valproate and topiramate, said the investigators, led by Hyunmi Kim, MD, PhD, MPH, of the department of neurology at Stanford (Calif.) University.

“To improve current practice, knowledge of the teratogenicity of certain AEDs should be disseminated to health care professionals and patients,” they wrote. The report is in JAMA Neurology.

The findings of Dr. Kim and her colleagues were based on data for 46,767 women of childbearing age: 8,003 incident (new) cases with a mean age of 27 years, and 38,764 prevalent cases with a mean age of 30 years.

Topiramate was the second- or third-most prescribed AED in the analyses, alongside levetiracetam and lamotrigine. In particular, topiramate prescriptions were found in incident cases receiving first-line monotherapy (15%), prevalent cases receiving first-line monotherapy (13%), and prevalent cases receiving polytherapy (29%).

Valproate was the fifth-most prescribed AED for incident and prevalent cases receiving first-line monotherapy (5% and 10%, respectively), and came in fourth place among prevalent cases receiving polytherapy (22%).

The somewhat lower rate of valproate prescriptions tracks with other recent analyses showing that valproate use decreased among women of childbearing age following recommendations against its use during pregnancy, according to Dr. Kim and her coauthors.

However, topiramate is another story: “Although the magnitude of risk and range of adverse reproductive outcomes associated with topiramate use appear substantially less than those associated with valproate, some reduction in the use of topiramate in this population might be expected after evidence emerged in 2008 of its association with cleft palate,” they said in their report.

UCB Pharma sponsored this study. Study authors reported disclosures related to UCB Pharma, Biogen, Eisai, SK Life Science, Brain Sentinel, UCB Pharma, and the University of Alabama at Birmingham.

SOURCE: Kim H et al. JAMA Neurol. 2019 Apr 1. doi: 10.1001/jamaneurol.2019.0447.

Despite their known teratogenic risks, both valproate and topiramate are being prescribed relatively often in women of childbearing age, results of a retrospective analysis suggest.

Antonio_Diaz/Thinkstock

Topiramate, linked to increased risk of cleft palate and smaller-than-gestational-age newborns, was among the top three antiepileptic drugs (AEDs) prescribed to women 15-44 years of age in the population-based cohort study.

Valproate, linked to increases in both anatomic and behavioral teratogenicity, was less often prescribed, but nevertheless still prescribed in a considerable proportion of patients in the study, which looked at U.S. commercial, Medicare, and Medicaid claims data from 2009 to 2013.

Presence of comorbidities could be influencing whether or not a woman of childbearing age receives one of these AEDs, the investigators said. Specifically, they found valproate more often prescribed for women with epilepsy who also had mood or anxiety and dissociative disorder, while topiramate was more often prescribed in women with headaches or migraines.

Taken together, these findings suggest a lack of awareness of the teratogenic risks of valproate and topiramate, said the investigators, led by Hyunmi Kim, MD, PhD, MPH, of the department of neurology at Stanford (Calif.) University.

“To improve current practice, knowledge of the teratogenicity of certain AEDs should be disseminated to health care professionals and patients,” they wrote. The report is in JAMA Neurology.

The findings of Dr. Kim and her colleagues were based on data for 46,767 women of childbearing age: 8,003 incident (new) cases with a mean age of 27 years, and 38,764 prevalent cases with a mean age of 30 years.

Topiramate was the second- or third-most prescribed AED in the analyses, alongside levetiracetam and lamotrigine. In particular, topiramate prescriptions were found in incident cases receiving first-line monotherapy (15%), prevalent cases receiving first-line monotherapy (13%), and prevalent cases receiving polytherapy (29%).

Valproate was the fifth-most prescribed AED for incident and prevalent cases receiving first-line monotherapy (5% and 10%, respectively), and came in fourth place among prevalent cases receiving polytherapy (22%).

The somewhat lower rate of valproate prescriptions tracks with other recent analyses showing that valproate use decreased among women of childbearing age following recommendations against its use during pregnancy, according to Dr. Kim and her coauthors.

However, topiramate is another story: “Although the magnitude of risk and range of adverse reproductive outcomes associated with topiramate use appear substantially less than those associated with valproate, some reduction in the use of topiramate in this population might be expected after evidence emerged in 2008 of its association with cleft palate,” they said in their report.

UCB Pharma sponsored this study. Study authors reported disclosures related to UCB Pharma, Biogen, Eisai, SK Life Science, Brain Sentinel, UCB Pharma, and the University of Alabama at Birmingham.

SOURCE: Kim H et al. JAMA Neurol. 2019 Apr 1. doi: 10.1001/jamaneurol.2019.0447.

Despite their known teratogenic risks, both valproate and topiramate are being prescribed relatively often in women of childbearing age, results of a retrospective analysis suggest.

Antonio_Diaz/Thinkstock

Topiramate, linked to increased risk of cleft palate and smaller-than-gestational-age newborns, was among the top three antiepileptic drugs (AEDs) prescribed to women 15-44 years of age in the population-based cohort study.

Valproate, linked to increases in both anatomic and behavioral teratogenicity, was less often prescribed, but nevertheless still prescribed in a considerable proportion of patients in the study, which looked at U.S. commercial, Medicare, and Medicaid claims data from 2009 to 2013.

Presence of comorbidities could be influencing whether or not a woman of childbearing age receives one of these AEDs, the investigators said. Specifically, they found valproate more often prescribed for women with epilepsy who also had mood or anxiety and dissociative disorder, while topiramate was more often prescribed in women with headaches or migraines.

Taken together, these findings suggest a lack of awareness of the teratogenic risks of valproate and topiramate, said the investigators, led by Hyunmi Kim, MD, PhD, MPH, of the department of neurology at Stanford (Calif.) University.

“To improve current practice, knowledge of the teratogenicity of certain AEDs should be disseminated to health care professionals and patients,” they wrote. The report is in JAMA Neurology.

The findings of Dr. Kim and her colleagues were based on data for 46,767 women of childbearing age: 8,003 incident (new) cases with a mean age of 27 years, and 38,764 prevalent cases with a mean age of 30 years.

Topiramate was the second- or third-most prescribed AED in the analyses, alongside levetiracetam and lamotrigine. In particular, topiramate prescriptions were found in incident cases receiving first-line monotherapy (15%), prevalent cases receiving first-line monotherapy (13%), and prevalent cases receiving polytherapy (29%).

Valproate was the fifth-most prescribed AED for incident and prevalent cases receiving first-line monotherapy (5% and 10%, respectively), and came in fourth place among prevalent cases receiving polytherapy (22%).

The somewhat lower rate of valproate prescriptions tracks with other recent analyses showing that valproate use decreased among women of childbearing age following recommendations against its use during pregnancy, according to Dr. Kim and her coauthors.

However, topiramate is another story: “Although the magnitude of risk and range of adverse reproductive outcomes associated with topiramate use appear substantially less than those associated with valproate, some reduction in the use of topiramate in this population might be expected after evidence emerged in 2008 of its association with cleft palate,” they said in their report.

UCB Pharma sponsored this study. Study authors reported disclosures related to UCB Pharma, Biogen, Eisai, SK Life Science, Brain Sentinel, UCB Pharma, and the University of Alabama at Birmingham.

SOURCE: Kim H et al. JAMA Neurol. 2019 Apr 1. doi: 10.1001/jamaneurol.2019.0447.

Periventricular lesions (PVLs) play a key role in the differential diagnosis between migraine with aura (MA) and clinically isolated syndrome (CIS), particularly when there are greater than 3, according to a recent retrospective study. White matter hyperintensities (WMH) of 84 patients with MA and 79 patients with CIS were assessed using manual segmentation technique. Lesion probability maps (LPMs) and voxel-wise analysis of lesion distribution by diagnosis were obtained. Researchers also performed a logistic regression analysis based on lesion locations and volumes. They found:

• Compared to patients with MA, patients with CIS showed a significant overall higher T2 WMH mean number and volume (17.9 ± 16.9 vs 6.2 ± 11.9 and 3.1 ± 4.2 vs 0.3 ± 0.6 mL) and a significantly higher T2 WMH mean number in infratentorial, periventricular, and juxtacortical areas.
• LPMs identified the periventricular regions as the sites with the highest probability of detecting T2 WMH in patients with CIS.
• Voxel-wise analysis of lesion distribution by diagnosis revealed a statistically significant association exclusively between the diagnosis of CIS and the PVLs.

Lapucci C, Saitta L, Bommarito G, et al. How much do periventricular lesions assist in distinguishing migraine with aura from CIS? [Published online ahead of print March 8, 2019]. Neurology. doi:10.1212/WNL.0000000000007266.

Periventricular lesions (PVLs) play a key role in the differential diagnosis between migraine with aura (MA) and clinically isolated syndrome (CIS), particularly when there are greater than 3, according to a recent retrospective study. White matter hyperintensities (WMH) of 84 patients with MA and 79 patients with CIS were assessed using manual segmentation technique. Lesion probability maps (LPMs) and voxel-wise analysis of lesion distribution by diagnosis were obtained. Researchers also performed a logistic regression analysis based on lesion locations and volumes. They found:

• Compared to patients with MA, patients with CIS showed a significant overall higher T2 WMH mean number and volume (17.9 ± 16.9 vs 6.2 ± 11.9 and 3.1 ± 4.2 vs 0.3 ± 0.6 mL) and a significantly higher T2 WMH mean number in infratentorial, periventricular, and juxtacortical areas.
• LPMs identified the periventricular regions as the sites with the highest probability of detecting T2 WMH in patients with CIS.
• Voxel-wise analysis of lesion distribution by diagnosis revealed a statistically significant association exclusively between the diagnosis of CIS and the PVLs.

Lapucci C, Saitta L, Bommarito G, et al. How much do periventricular lesions assist in distinguishing migraine with aura from CIS? [Published online ahead of print March 8, 2019]. Neurology. doi:10.1212/WNL.0000000000007266.

Periventricular lesions (PVLs) play a key role in the differential diagnosis between migraine with aura (MA) and clinically isolated syndrome (CIS), particularly when there are greater than 3, according to a recent retrospective study. White matter hyperintensities (WMH) of 84 patients with MA and 79 patients with CIS were assessed using manual segmentation technique. Lesion probability maps (LPMs) and voxel-wise analysis of lesion distribution by diagnosis were obtained. Researchers also performed a logistic regression analysis based on lesion locations and volumes. They found:

• Compared to patients with MA, patients with CIS showed a significant overall higher T2 WMH mean number and volume (17.9 ± 16.9 vs 6.2 ± 11.9 and 3.1 ± 4.2 vs 0.3 ± 0.6 mL) and a significantly higher T2 WMH mean number in infratentorial, periventricular, and juxtacortical areas.
• LPMs identified the periventricular regions as the sites with the highest probability of detecting T2 WMH in patients with CIS.
• Voxel-wise analysis of lesion distribution by diagnosis revealed a statistically significant association exclusively between the diagnosis of CIS and the PVLs.

Lapucci C, Saitta L, Bommarito G, et al. How much do periventricular lesions assist in distinguishing migraine with aura from CIS? [Published online ahead of print March 8, 2019]. Neurology. doi:10.1212/WNL.0000000000007266.

Patients with migraine, in particular migraine with aura, were more likely to have elevated high sensitivity C-reactive protein (CRP), evident only among those with insomnia, according to a recent cross-sectional study. A total of 20,486 (63%) out of 32,591 individuals, aged 40 years and older, participated in the seventh wave of the Tromsø study conducted in 2015 and 2016, and had valid information on headache, insomnia, and high sensitivity CRP. Researchers found:

• A total of 6290 participants (30.7%) suffered from headache during the last year.
• Among these, 1736 (8.5%) fulfilled the criteria of migraine, 991 (4.8%) had migraine with aura, 746 (3.6%) migraine without aura (3.8%), and 4554 (22.2%) had non-migrainous headache.
• In the final multi-adjusted analysis, elevated high sensitivity CRP was associated with headache, migraine, and migraine with aura.
• No association was found between elevated high sensitivity CRP and migraine without aura or non-migrainous headache.
• The association between high sensitivity CRP and migraine was strongly dependent on insomnia status.
• Among individuals with insomnia, elevated high sensitivity CRP was associated with migraine, and migraine with aura, whereas no such relationship was found among those without insomnia.

Hagen K, Hopstock LA, Eggen AE, Mathiesen EB, Bilsen KB. Does insomnia modify the association between C-reactive protein and migraine? The Tromsø Study 2015–2016. [Published online ahead of print March 12, 2019]. Cephalalgia. doi:10.1177%2F0333102418825370.

Patients with migraine, in particular migraine with aura, were more likely to have elevated high sensitivity C-reactive protein (CRP), evident only among those with insomnia, according to a recent cross-sectional study. A total of 20,486 (63%) out of 32,591 individuals, aged 40 years and older, participated in the seventh wave of the Tromsø study conducted in 2015 and 2016, and had valid information on headache, insomnia, and high sensitivity CRP. Researchers found:

• A total of 6290 participants (30.7%) suffered from headache during the last year.
• Among these, 1736 (8.5%) fulfilled the criteria of migraine, 991 (4.8%) had migraine with aura, 746 (3.6%) migraine without aura (3.8%), and 4554 (22.2%) had non-migrainous headache.
• In the final multi-adjusted analysis, elevated high sensitivity CRP was associated with headache, migraine, and migraine with aura.
• No association was found between elevated high sensitivity CRP and migraine without aura or non-migrainous headache.
• The association between high sensitivity CRP and migraine was strongly dependent on insomnia status.
• Among individuals with insomnia, elevated high sensitivity CRP was associated with migraine, and migraine with aura, whereas no such relationship was found among those without insomnia.

Hagen K, Hopstock LA, Eggen AE, Mathiesen EB, Bilsen KB. Does insomnia modify the association between C-reactive protein and migraine? The Tromsø Study 2015–2016. [Published online ahead of print March 12, 2019]. Cephalalgia. doi:10.1177%2F0333102418825370.

Patients with migraine, in particular migraine with aura, were more likely to have elevated high sensitivity C-reactive protein (CRP), evident only among those with insomnia, according to a recent cross-sectional study. A total of 20,486 (63%) out of 32,591 individuals, aged 40 years and older, participated in the seventh wave of the Tromsø study conducted in 2015 and 2016, and had valid information on headache, insomnia, and high sensitivity CRP. Researchers found:

• A total of 6290 participants (30.7%) suffered from headache during the last year.
• Among these, 1736 (8.5%) fulfilled the criteria of migraine, 991 (4.8%) had migraine with aura, 746 (3.6%) migraine without aura (3.8%), and 4554 (22.2%) had non-migrainous headache.
• In the final multi-adjusted analysis, elevated high sensitivity CRP was associated with headache, migraine, and migraine with aura.
• No association was found between elevated high sensitivity CRP and migraine without aura or non-migrainous headache.
• The association between high sensitivity CRP and migraine was strongly dependent on insomnia status.
• Among individuals with insomnia, elevated high sensitivity CRP was associated with migraine, and migraine with aura, whereas no such relationship was found among those without insomnia.

Hagen K, Hopstock LA, Eggen AE, Mathiesen EB, Bilsen KB. Does insomnia modify the association between C-reactive protein and migraine? The Tromsø Study 2015–2016. [Published online ahead of print March 12, 2019]. Cephalalgia. doi:10.1177%2F0333102418825370.

Although results of a recent study are preliminary, spinal manipulation may be an effective therapeutic technique to reduce migraine days and pain/intensity. Literature databases were searched for clinical trials that evaluated spinal manipulation and migraine‐related outcomes through April 2017. Search terms included: migraine, spinal manipulation, manual therapy, chiropractic, and osteopathic. Meta‐analytic methods were employed to estimate the effect sizes (Hedges’ g) and heterogeneity (I²) for migraine days, pain, and disability. Researchers found:

• Six randomized clinical trials (RCTs) (pooled n=677; range of n=42‐218) were eligible for meta‐analysis.
• Intervention duration ranged from 2 to 6 months; outcomes included measures of migraine days (primary outcome), migraine pain/intensity, and migraine disability.
• Due to high levels of heterogeneity when all 6 studies were included in the meta‐analysis, the 1 RCT that was performed only among chronic migraineurs was excluded.
• Heterogeneity across the remaining studies was low.
• Spinal manipulation reduced migraine days with an overall small effect size (Hedges’ g=−0.35) as well as migraine pain/intensity.

Rist PM, Hernandez A, Bernstein, C, et al. The impact of spinal manipulation on migraine pain and disability: A systematic review and meta‐analysis. [Published online ahead of print March 14, 2019]. Headache. doi:10.1111/head.13501.

Although results of a recent study are preliminary, spinal manipulation may be an effective therapeutic technique to reduce migraine days and pain/intensity. Literature databases were searched for clinical trials that evaluated spinal manipulation and migraine‐related outcomes through April 2017. Search terms included: migraine, spinal manipulation, manual therapy, chiropractic, and osteopathic. Meta‐analytic methods were employed to estimate the effect sizes (Hedges’ g) and heterogeneity (I²) for migraine days, pain, and disability. Researchers found:

• Six randomized clinical trials (RCTs) (pooled n=677; range of n=42‐218) were eligible for meta‐analysis.
• Intervention duration ranged from 2 to 6 months; outcomes included measures of migraine days (primary outcome), migraine pain/intensity, and migraine disability.
• Due to high levels of heterogeneity when all 6 studies were included in the meta‐analysis, the 1 RCT that was performed only among chronic migraineurs was excluded.
• Heterogeneity across the remaining studies was low.
• Spinal manipulation reduced migraine days with an overall small effect size (Hedges’ g=−0.35) as well as migraine pain/intensity.

Rist PM, Hernandez A, Bernstein, C, et al. The impact of spinal manipulation on migraine pain and disability: A systematic review and meta‐analysis. [Published online ahead of print March 14, 2019]. Headache. doi:10.1111/head.13501.

Although results of a recent study are preliminary, spinal manipulation may be an effective therapeutic technique to reduce migraine days and pain/intensity. Literature databases were searched for clinical trials that evaluated spinal manipulation and migraine‐related outcomes through April 2017. Search terms included: migraine, spinal manipulation, manual therapy, chiropractic, and osteopathic. Meta‐analytic methods were employed to estimate the effect sizes (Hedges’ g) and heterogeneity (I²) for migraine days, pain, and disability. Researchers found:

• Six randomized clinical trials (RCTs) (pooled n=677; range of n=42‐218) were eligible for meta‐analysis.
• Intervention duration ranged from 2 to 6 months; outcomes included measures of migraine days (primary outcome), migraine pain/intensity, and migraine disability.
• Due to high levels of heterogeneity when all 6 studies were included in the meta‐analysis, the 1 RCT that was performed only among chronic migraineurs was excluded.
• Heterogeneity across the remaining studies was low.
• Spinal manipulation reduced migraine days with an overall small effect size (Hedges’ g=−0.35) as well as migraine pain/intensity.

Rist PM, Hernandez A, Bernstein, C, et al. The impact of spinal manipulation on migraine pain and disability: A systematic review and meta‐analysis. [Published online ahead of print March 14, 2019]. Headache. doi:10.1111/head.13501.

STOWE, VT. – “The eye is intimately involved in the migraine process,” said Kathleen Digre, MD, at the annual meeting of the Headache Cooperative of New England. Specifically, she said, dry eye and photophobia are two symptoms that have biologic underpinnings, can be diagnosed, and can be treated. Dr. Digre is a professor of neurology and ophthalmology at the University of Utah, Salt Lake City, and is the current president of the American Headache Society.

Vidyard Video

Dr. Digre explained that dry eyes and migraine could have a cyclical relationship where dry eyes provoke the migraine, and the migraine may provoke the feeling of dry eye, regardless of whether it can be objectively measured.

Regarding photophobia, Dr. Digre stressed the importance of an accurate diagnosis that rules out eye disorders and other causes of photophobia. She discussed the problem of patient overreliance on dark glasses and encourages a return to light to break the cycle of dark adapting the retina.

Finally, Dr. Digre discussed how proper treatment of migraine and any associated anxiety or depression can help resolve eye issues that may be contributing to migraine.

gwilliams@mdedge.com

STOWE, VT. – “The eye is intimately involved in the migraine process,” said Kathleen Digre, MD, at the annual meeting of the Headache Cooperative of New England. Specifically, she said, dry eye and photophobia are two symptoms that have biologic underpinnings, can be diagnosed, and can be treated. Dr. Digre is a professor of neurology and ophthalmology at the University of Utah, Salt Lake City, and is the current president of the American Headache Society.

Vidyard Video

Dr. Digre explained that dry eyes and migraine could have a cyclical relationship where dry eyes provoke the migraine, and the migraine may provoke the feeling of dry eye, regardless of whether it can be objectively measured.

Regarding photophobia, Dr. Digre stressed the importance of an accurate diagnosis that rules out eye disorders and other causes of photophobia. She discussed the problem of patient overreliance on dark glasses and encourages a return to light to break the cycle of dark adapting the retina.

Finally, Dr. Digre discussed how proper treatment of migraine and any associated anxiety or depression can help resolve eye issues that may be contributing to migraine.

gwilliams@mdedge.com

STOWE, VT. – “The eye is intimately involved in the migraine process,” said Kathleen Digre, MD, at the annual meeting of the Headache Cooperative of New England. Specifically, she said, dry eye and photophobia are two symptoms that have biologic underpinnings, can be diagnosed, and can be treated. Dr. Digre is a professor of neurology and ophthalmology at the University of Utah, Salt Lake City, and is the current president of the American Headache Society.

Vidyard Video

Dr. Digre explained that dry eyes and migraine could have a cyclical relationship where dry eyes provoke the migraine, and the migraine may provoke the feeling of dry eye, regardless of whether it can be objectively measured.

Regarding photophobia, Dr. Digre stressed the importance of an accurate diagnosis that rules out eye disorders and other causes of photophobia. She discussed the problem of patient overreliance on dark glasses and encourages a return to light to break the cycle of dark adapting the retina.

Finally, Dr. Digre discussed how proper treatment of migraine and any associated anxiety or depression can help resolve eye issues that may be contributing to migraine.

gwilliams@mdedge.com

STOWE, VT. – These are the early days of the “CGRP monoclonal antibody era,” Peter McAllister, MD, said in a summary of the current status of calcitonin gene-related peptide monoclonal antibodies for migraine prevention. He discussed what has been learned in the clinical trials of these drugs as well as in the first 10 months of having them on the market.

Vidyard Video

In an interview at the annual meeting of the Headache Cooperative of New England, Dr. McAllister said, “We are comforted that we have now 1-year, 3-year, and 5-year data” from clinical trials, but the sample size is small.

In the time since the first three drugs were approved, “we have probably in the ballpark of over 200,000 patients who have received a monoclonal antibody, and so far there has been nothing that makes us stop cold in our tracks and say there’s something wrong here. That is very comforting,” he said. Dr. McAllister is the medical director of the New England Institute for Neurology and Headache in Stamford, Conn.

What is still unknown, however, is the long-term safety and efficacy; what happens in a larger pool of patients taking these drugs; what happens in pregnancy and effects on the fetus; how and when to safely switch from one monoclonal antibody to another; the systemic effects of these drugs; and other concerns that may arise in postmarketing studies.

gwilliams@mdedge.com

STOWE, VT. – These are the early days of the “CGRP monoclonal antibody era,” Peter McAllister, MD, said in a summary of the current status of calcitonin gene-related peptide monoclonal antibodies for migraine prevention. He discussed what has been learned in the clinical trials of these drugs as well as in the first 10 months of having them on the market.

Vidyard Video

In an interview at the annual meeting of the Headache Cooperative of New England, Dr. McAllister said, “We are comforted that we have now 1-year, 3-year, and 5-year data” from clinical trials, but the sample size is small.

In the time since the first three drugs were approved, “we have probably in the ballpark of over 200,000 patients who have received a monoclonal antibody, and so far there has been nothing that makes us stop cold in our tracks and say there’s something wrong here. That is very comforting,” he said. Dr. McAllister is the medical director of the New England Institute for Neurology and Headache in Stamford, Conn.

What is still unknown, however, is the long-term safety and efficacy; what happens in a larger pool of patients taking these drugs; what happens in pregnancy and effects on the fetus; how and when to safely switch from one monoclonal antibody to another; the systemic effects of these drugs; and other concerns that may arise in postmarketing studies.

gwilliams@mdedge.com

STOWE, VT. – These are the early days of the “CGRP monoclonal antibody era,” Peter McAllister, MD, said in a summary of the current status of calcitonin gene-related peptide monoclonal antibodies for migraine prevention. He discussed what has been learned in the clinical trials of these drugs as well as in the first 10 months of having them on the market.

Vidyard Video

In an interview at the annual meeting of the Headache Cooperative of New England, Dr. McAllister said, “We are comforted that we have now 1-year, 3-year, and 5-year data” from clinical trials, but the sample size is small.

In the time since the first three drugs were approved, “we have probably in the ballpark of over 200,000 patients who have received a monoclonal antibody, and so far there has been nothing that makes us stop cold in our tracks and say there’s something wrong here. That is very comforting,” he said. Dr. McAllister is the medical director of the New England Institute for Neurology and Headache in Stamford, Conn.

What is still unknown, however, is the long-term safety and efficacy; what happens in a larger pool of patients taking these drugs; what happens in pregnancy and effects on the fetus; how and when to safely switch from one monoclonal antibody to another; the systemic effects of these drugs; and other concerns that may arise in postmarketing studies.

gwilliams@mdedge.com

Persons with migraine show individual attack patterns and weekend migraine can be determined for a subgroup of participants, while others show accumulations of their attacks on other days of the week. This according to a recent analysis of migraine attacks collected online within the project Migraine Radar in respect to the distribution of migraine attacks throughout the week on a single‐participant level. Researchers recorded data using a web app as well as smartphone apps in order to collect data of 44,639 migraine attacks of 1085 participants who reported 7 or more attacks during a period of at least 90 days. They found:

• For 15.9% of the participants, the attacks were not distributed equally throughout the days of the week.
• Instead, participants show different individual patterns for the distribution of their migraine attacks.
• Furthermore, the modes of the individual distributions are not distributed equally throughout the week.
• Saturday seems to be the predominant day for migraine attacks for a greater proportion of participants (195 of 1085).

Drescher J, Wogenstein F, Gaul C, et al. Distribution of migraine attacks over the days of the week: Preliminary results from a web‐based questionnaire. [Published online ahead of print January 12, 2019]. Acta Neurol Scand. doi:10.1111/ane.13065.

Persons with migraine show individual attack patterns and weekend migraine can be determined for a subgroup of participants, while others show accumulations of their attacks on other days of the week. This according to a recent analysis of migraine attacks collected online within the project Migraine Radar in respect to the distribution of migraine attacks throughout the week on a single‐participant level. Researchers recorded data using a web app as well as smartphone apps in order to collect data of 44,639 migraine attacks of 1085 participants who reported 7 or more attacks during a period of at least 90 days. They found:

• For 15.9% of the participants, the attacks were not distributed equally throughout the days of the week.
• Instead, participants show different individual patterns for the distribution of their migraine attacks.
• Furthermore, the modes of the individual distributions are not distributed equally throughout the week.
• Saturday seems to be the predominant day for migraine attacks for a greater proportion of participants (195 of 1085).

Drescher J, Wogenstein F, Gaul C, et al. Distribution of migraine attacks over the days of the week: Preliminary results from a web‐based questionnaire. [Published online ahead of print January 12, 2019]. Acta Neurol Scand. doi:10.1111/ane.13065.

Persons with migraine show individual attack patterns and weekend migraine can be determined for a subgroup of participants, while others show accumulations of their attacks on other days of the week. This according to a recent analysis of migraine attacks collected online within the project Migraine Radar in respect to the distribution of migraine attacks throughout the week on a single‐participant level. Researchers recorded data using a web app as well as smartphone apps in order to collect data of 44,639 migraine attacks of 1085 participants who reported 7 or more attacks during a period of at least 90 days. They found:

• For 15.9% of the participants, the attacks were not distributed equally throughout the days of the week.
• Instead, participants show different individual patterns for the distribution of their migraine attacks.
• Furthermore, the modes of the individual distributions are not distributed equally throughout the week.
• Saturday seems to be the predominant day for migraine attacks for a greater proportion of participants (195 of 1085).

Drescher J, Wogenstein F, Gaul C, et al. Distribution of migraine attacks over the days of the week: Preliminary results from a web‐based questionnaire. [Published online ahead of print January 12, 2019]. Acta Neurol Scand. doi:10.1111/ane.13065.

Raising awareness among clinicians that many of the potential variables contributing to the presence of migraine are modifiable (eg, psychological problems and lifestyle behaviors) might intensify resources dedicated to assessing and impacting these factors in order to potentially prevent the frequency and severity of migraine. This according to a recent study that aimed to identify the modifiable and non-modifiable variables that are associated with, and might moderate, the presence of migraine in the general population. Using a nationally representative cross-sectional survey, researchers evaluated responses from individuals aged 15 years and older (n=22,842). There was a secondary analysis of data from the second wave of a health interview survey conducted from 2014 to 2015. They found:

• The 1-year prevalence of migraine was 8%.
• The final multivariate model (Wald χ²=693.00, df=15) retained depression severity, chronic anxiety, exercising several times a month or week, and alcohol use as predictors of migraine (odds ratios=2.1–3.5 for positive associations, odds ratios=0.4–0.9 for negative associations).

Roy R, Sánchez-Rodriguez E, Galán S, et al. Factors associated with migraine in the general population of Spain: Results from the European Health Survey 2014. Pain Med. 2019;20(3):555-563. doi:10.1093/pm/pny093.

Raising awareness among clinicians that many of the potential variables contributing to the presence of migraine are modifiable (eg, psychological problems and lifestyle behaviors) might intensify resources dedicated to assessing and impacting these factors in order to potentially prevent the frequency and severity of migraine. This according to a recent study that aimed to identify the modifiable and non-modifiable variables that are associated with, and might moderate, the presence of migraine in the general population. Using a nationally representative cross-sectional survey, researchers evaluated responses from individuals aged 15 years and older (n=22,842). There was a secondary analysis of data from the second wave of a health interview survey conducted from 2014 to 2015. They found:

• The 1-year prevalence of migraine was 8%.
• The final multivariate model (Wald χ²=693.00, df=15) retained depression severity, chronic anxiety, exercising several times a month or week, and alcohol use as predictors of migraine (odds ratios=2.1–3.5 for positive associations, odds ratios=0.4–0.9 for negative associations).

Roy R, Sánchez-Rodriguez E, Galán S, et al. Factors associated with migraine in the general population of Spain: Results from the European Health Survey 2014. Pain Med. 2019;20(3):555-563. doi:10.1093/pm/pny093.

Raising awareness among clinicians that many of the potential variables contributing to the presence of migraine are modifiable (eg, psychological problems and lifestyle behaviors) might intensify resources dedicated to assessing and impacting these factors in order to potentially prevent the frequency and severity of migraine. This according to a recent study that aimed to identify the modifiable and non-modifiable variables that are associated with, and might moderate, the presence of migraine in the general population. Using a nationally representative cross-sectional survey, researchers evaluated responses from individuals aged 15 years and older (n=22,842). There was a secondary analysis of data from the second wave of a health interview survey conducted from 2014 to 2015. They found:

• The 1-year prevalence of migraine was 8%.
• The final multivariate model (Wald χ²=693.00, df=15) retained depression severity, chronic anxiety, exercising several times a month or week, and alcohol use as predictors of migraine (odds ratios=2.1–3.5 for positive associations, odds ratios=0.4–0.9 for negative associations).

Roy R, Sánchez-Rodriguez E, Galán S, et al. Factors associated with migraine in the general population of Spain: Results from the European Health Survey 2014. Pain Med. 2019;20(3):555-563. doi:10.1093/pm/pny093.