J Neurol DOI 10.1007/s00415-014-7348-1
JOURNAL CLUB
Evolving concepts in migraine K. Ali • N. P. Robertson
Ó Springer-Verlag Berlin Heidelberg 2014
Migraine is a common cause of primary headache accounting for approximately 30 % of neurology outpatient appointments and 4 % of primary care consultations. It causes significant pain and disability, and additional socioeconomic difficulty associated with poor performance and absence from work or school is well recognised. However, despite the high prevalence of migraine, there remains a lack of understanding concerning basic aspects of aetiology and pathophysiology. Whereas activation of the trigeminovascular system is thought to be responsible for the typical pain migraineurs experience, the aetiology of the disorder, like many poorly understood diseases, can only be ascribed to a poorly defined interaction of environmental and genetic factors. To make matters more complex, the diagnosis of migraine remains largely subjective, and is commonly established by the fulfillment of a recognised international classification, since there are no useful and widely available supportive paraclinical investigations. In addition, certain aspects of treatment are based on limited evidence, and there is a paucity of informative, good quality randomised controlled trials, particularly for acute management. There is clearly a requirement to develop a better understanding of disease pathogenesis in migraine, which, it is hoped, will help to develop more effective, targeted therapies with limited side effects. In this month’s journal club, we discuss three papers related to this topic; two of the papers introduce and develop novel concepts in migraine pathophysiology, one of which also suggests a possible radiological biomarker. The third paper is a headK. Ali N. P. Robertson (&) Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK e-mail: [email protected]
to-head comparative study of three anti-migraine medications used in the emergency department.
Structural brain MRI abnormalities in pediatric patients with migraine Morphometric MRI studies in adult migraine sufferers have previously demonstrated a specific pattern of regional grey matter atrophy, which is thought to be related to pain processing. In this study, the authors compared MRI volumetric studies of white and grey matter regions of 12 paediatric patients with episodic migraine (seven with aura and five without aura) with 15 normal controls matched for other demographic characteristics. The study attempted to answer two main questions: How early do these regional changes occur, and what, if any, correlations exist with the duration of the illness and the frequency of the attacks. All patients had 3T cranial MRI with a specially designed protocol for volumetric analysis. Four of the patients classified as having migraine without aura had white matter lesions, but regional analysis of the topography of the white matter abnormalities showed no difference between the two groups. However, results of the grey matter regional analysis demonstrated atrophy of the left middle temporal gyrus, left inferior frontal gyrus, right orbitofrontal gyrus and the subgenual cingulum. It also revealed increased volume of the right putamen in both migraine groups compared to the healthy subjects, and increased volume of the left fusiform gyrus in patients with migraine with aura compared to the other two groups. Furthermore, in migraine without aura, the left fusiform gyrus showed atrophy compared to the other two groups. Conclusions and discussion. This study sheds some light on the possible pathogenesis of migraine and the
123
J Neurol
involvement of the supraspinal nociceptive pathway. It confirms a similar specific pattern of grey matter regional changes in paediatric migraine patients to that previously described in adults, suggesting early involvement of pain pathways. Increased volume of the right putamen supports prior studies suggesting a role for the basal ganglia in pain and pain modulation. However, in general, the study was unable to demonstrate a correlation between available clinical data and the patterns of grey matter atrophy, also the left fusiform gyrus, which contributes to high-order visual processing, was found to have an increased volume in migraine with aura patients and a reduced volume in migraine without aura. The small number of patients and the lack of data regarding the last migraine episode prior to imaging represent the most important limitations of this study. J Neurol (2014) 261:350–357.
Investigations of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38 Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) is a neuropeptide which has been shown to induce migraine. Vasoactive intestinal polypeptide (VIP) is structurally similar to PACAP-38, but does not induce migraine. Both neuropeptides cause cephalic vasodilatation, which in the case of PACAP-38, is prolonged, possibly due to its affinity to PAC1 receptors. In this doubleblind cross-over study, 24 female patients with migraine without aura (according to the international classification of headache disorders) received either PACAP-38 10 pmol/kg/min or VIP 8 pmol/kg/min for 20 min in random order on two days, separated by one week. Baseline characteristics including specially designed MR angiography performed on a 3T scanner, physiological parameters, headache severity scales, blood levels for PACAP-38, VIP, and tryptase were taken prior to the infusion. MRA was repeated at 20 min, 2 and 5 h. Subjects reporting migraine within 5 h of infusion were scanned immediately and then again 30 min after subcutaneous sumatriptan. Physiological variables were monitored closely throughout the process at regular intervals. Blood levels for PACAP-38, VIP, and Tryptase were taken at baseline and regular intervals thereafter. Early phase up to 2 h and late phase between 2 and 5 h were defined. The primary endpoints were the difference in the incidence of migraine, the difference in incidence of headache, and the difference in the area under the curve for the headache scores between the two groups in the early and late phases. A variety of secondary endpoints using arterial imaging and physiological and serological variables were employed. Seventy-three percent of
123
subjects developed migraine after PACAP-38, compared to only 18 % following VIP, but overall 91 % developed headache following PACAP-38 compared to 82 % following VIP. An area under the curve analysis for time with headache was larger for both the early and late phase following PACAP-38 infusion. There was also a significant increase in the PACAP-38 plasma level at 60 min in the group of patients who reported late onset migraine attack. Patients who developed migraine attack exhibited dilatation of the extracranial arteries, whereas there was significant constriction following sumatriptan. Conclusions and discussion. The main finding of this head-to-head study is that PACAP-38 induced migraine and extended extracranial arterial dilatation more frequently that VIP. The authors also noted a significant rise of the PACAP-38 plasma level prior to migraine attack. However, it remains unclear how extracranial vascular dilatation induces migraine, although theories include PACAP-38 induced neurogenic inflammatory changes affecting perivascular trigeminal afferents; a systemic effect of PACAP-38; and an interaction between PACAP38 and the nociceptive system through PAC1 receptors in the dorsal root. Further work to identify PACAP-38 antagonists might offer a promising field for a highly specific migraine therapy. Brain (2014) 137:779–794.
Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine Acute migraine commonly presents to primary care physicians and emergency departments (ED). Open label and anecdotal experience suggest that sodium valproate might be useful as an abortive treatment of acute migraine. This is a double-blind randomised study comparing IV sodium valproate against two established parenteral migraine treatments (IV metoclopramide and IV ketorolac). Three hundred thirty patients with comparable baseline characteristics were recruited, 110 patients into each arm of the study. Migraine pain was assessed using a verbal numerical rating scale from 0 to 10 as well as a descriptive scale in which patients classified their headache as severe, moderate, mild, or none. Patients were assessed at baseline and then every 30 min following treatment with either 1,000 mg of sodium valproate, 10 mg of metoclopramide, or 30 mg of ketorolac. The primary outcome measure was the in-between difference of improvement of headache 1 h after baseline. A variety of secondary outcome measures were also assessed including the use of rescue medication at any time during the ED visit, the patient’s overall assessment, and sustained headache freedom at 2 and 24 h after drug administration.
J Neurol
Patients allocated to the valproate arm improved by 2.8 points on the verbal rating sale, compared to 4.7 points and 3.9 points for the patients who received metoclopramide and ketorolac, respectively. The sodium valproate arm also performed worse when assessed by secondary outcome measures than the other two arms. Twenty-eight percent of the patients in the sodium valproate arm stated affirmatively that they could return to daily activities 1 h after drug administration, compared to 39 and 53 % for the ketorolac and the metoclopramide arms, respectively. Six percent of patients receiving metoclopramide experienced restlessness at 24 h. Approximately two-thirds of patients receiving valproate required rescue medications, and only 4 % achieved sustained headache freedom. Conclusions and discussion. The overall conclusion from this study is that sodium valproate should not be considered as a first-line monotherapy for the management of acute migraine. The authors also noted that
metoclopramide had a tendency to superiority over ketorolac at the primary and a number of secondary outcome measures, but this did not reach significance. The study has some limitations; it was done in a single department, which limits claims to external validity. In addition, patients who were using one of the investigational drugs as a preventative treatment were excluded, creating a selection bias. Some follow-up data at 24 h is missing, and the large number of secondary endpoints also causes some problems in interpreting results. However, this work provides important information for the acute management of migraine. None of the investigational drugs achieved high rates of headache freedom at 24 h, highlighting the continued problems in management of the acute presentation of migraine patients. Studies examining combination therapies might be of future interest. Neurology (2014) 82(11):976–983.
123
JOURNAL CLUB
Evolving concepts in migraine K. Ali • N. P. Robertson
Ó Springer-Verlag Berlin Heidelberg 2014
Migraine is a common cause of primary headache accounting for approximately 30 % of neurology outpatient appointments and 4 % of primary care consultations. It causes significant pain and disability, and additional socioeconomic difficulty associated with poor performance and absence from work or school is well recognised. However, despite the high prevalence of migraine, there remains a lack of understanding concerning basic aspects of aetiology and pathophysiology. Whereas activation of the trigeminovascular system is thought to be responsible for the typical pain migraineurs experience, the aetiology of the disorder, like many poorly understood diseases, can only be ascribed to a poorly defined interaction of environmental and genetic factors. To make matters more complex, the diagnosis of migraine remains largely subjective, and is commonly established by the fulfillment of a recognised international classification, since there are no useful and widely available supportive paraclinical investigations. In addition, certain aspects of treatment are based on limited evidence, and there is a paucity of informative, good quality randomised controlled trials, particularly for acute management. There is clearly a requirement to develop a better understanding of disease pathogenesis in migraine, which, it is hoped, will help to develop more effective, targeted therapies with limited side effects. In this month’s journal club, we discuss three papers related to this topic; two of the papers introduce and develop novel concepts in migraine pathophysiology, one of which also suggests a possible radiological biomarker. The third paper is a headK. Ali N. P. Robertson (&) Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK e-mail: [email protected]
to-head comparative study of three anti-migraine medications used in the emergency department.
Structural brain MRI abnormalities in pediatric patients with migraine Morphometric MRI studies in adult migraine sufferers have previously demonstrated a specific pattern of regional grey matter atrophy, which is thought to be related to pain processing. In this study, the authors compared MRI volumetric studies of white and grey matter regions of 12 paediatric patients with episodic migraine (seven with aura and five without aura) with 15 normal controls matched for other demographic characteristics. The study attempted to answer two main questions: How early do these regional changes occur, and what, if any, correlations exist with the duration of the illness and the frequency of the attacks. All patients had 3T cranial MRI with a specially designed protocol for volumetric analysis. Four of the patients classified as having migraine without aura had white matter lesions, but regional analysis of the topography of the white matter abnormalities showed no difference between the two groups. However, results of the grey matter regional analysis demonstrated atrophy of the left middle temporal gyrus, left inferior frontal gyrus, right orbitofrontal gyrus and the subgenual cingulum. It also revealed increased volume of the right putamen in both migraine groups compared to the healthy subjects, and increased volume of the left fusiform gyrus in patients with migraine with aura compared to the other two groups. Furthermore, in migraine without aura, the left fusiform gyrus showed atrophy compared to the other two groups. Conclusions and discussion. This study sheds some light on the possible pathogenesis of migraine and the
123
J Neurol
involvement of the supraspinal nociceptive pathway. It confirms a similar specific pattern of grey matter regional changes in paediatric migraine patients to that previously described in adults, suggesting early involvement of pain pathways. Increased volume of the right putamen supports prior studies suggesting a role for the basal ganglia in pain and pain modulation. However, in general, the study was unable to demonstrate a correlation between available clinical data and the patterns of grey matter atrophy, also the left fusiform gyrus, which contributes to high-order visual processing, was found to have an increased volume in migraine with aura patients and a reduced volume in migraine without aura. The small number of patients and the lack of data regarding the last migraine episode prior to imaging represent the most important limitations of this study. J Neurol (2014) 261:350–357.
Investigations of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38 Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) is a neuropeptide which has been shown to induce migraine. Vasoactive intestinal polypeptide (VIP) is structurally similar to PACAP-38, but does not induce migraine. Both neuropeptides cause cephalic vasodilatation, which in the case of PACAP-38, is prolonged, possibly due to its affinity to PAC1 receptors. In this doubleblind cross-over study, 24 female patients with migraine without aura (according to the international classification of headache disorders) received either PACAP-38 10 pmol/kg/min or VIP 8 pmol/kg/min for 20 min in random order on two days, separated by one week. Baseline characteristics including specially designed MR angiography performed on a 3T scanner, physiological parameters, headache severity scales, blood levels for PACAP-38, VIP, and tryptase were taken prior to the infusion. MRA was repeated at 20 min, 2 and 5 h. Subjects reporting migraine within 5 h of infusion were scanned immediately and then again 30 min after subcutaneous sumatriptan. Physiological variables were monitored closely throughout the process at regular intervals. Blood levels for PACAP-38, VIP, and Tryptase were taken at baseline and regular intervals thereafter. Early phase up to 2 h and late phase between 2 and 5 h were defined. The primary endpoints were the difference in the incidence of migraine, the difference in incidence of headache, and the difference in the area under the curve for the headache scores between the two groups in the early and late phases. A variety of secondary endpoints using arterial imaging and physiological and serological variables were employed. Seventy-three percent of
123
subjects developed migraine after PACAP-38, compared to only 18 % following VIP, but overall 91 % developed headache following PACAP-38 compared to 82 % following VIP. An area under the curve analysis for time with headache was larger for both the early and late phase following PACAP-38 infusion. There was also a significant increase in the PACAP-38 plasma level at 60 min in the group of patients who reported late onset migraine attack. Patients who developed migraine attack exhibited dilatation of the extracranial arteries, whereas there was significant constriction following sumatriptan. Conclusions and discussion. The main finding of this head-to-head study is that PACAP-38 induced migraine and extended extracranial arterial dilatation more frequently that VIP. The authors also noted a significant rise of the PACAP-38 plasma level prior to migraine attack. However, it remains unclear how extracranial vascular dilatation induces migraine, although theories include PACAP-38 induced neurogenic inflammatory changes affecting perivascular trigeminal afferents; a systemic effect of PACAP-38; and an interaction between PACAP38 and the nociceptive system through PAC1 receptors in the dorsal root. Further work to identify PACAP-38 antagonists might offer a promising field for a highly specific migraine therapy. Brain (2014) 137:779–794.
Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine Acute migraine commonly presents to primary care physicians and emergency departments (ED). Open label and anecdotal experience suggest that sodium valproate might be useful as an abortive treatment of acute migraine. This is a double-blind randomised study comparing IV sodium valproate against two established parenteral migraine treatments (IV metoclopramide and IV ketorolac). Three hundred thirty patients with comparable baseline characteristics were recruited, 110 patients into each arm of the study. Migraine pain was assessed using a verbal numerical rating scale from 0 to 10 as well as a descriptive scale in which patients classified their headache as severe, moderate, mild, or none. Patients were assessed at baseline and then every 30 min following treatment with either 1,000 mg of sodium valproate, 10 mg of metoclopramide, or 30 mg of ketorolac. The primary outcome measure was the in-between difference of improvement of headache 1 h after baseline. A variety of secondary outcome measures were also assessed including the use of rescue medication at any time during the ED visit, the patient’s overall assessment, and sustained headache freedom at 2 and 24 h after drug administration.
J Neurol
Patients allocated to the valproate arm improved by 2.8 points on the verbal rating sale, compared to 4.7 points and 3.9 points for the patients who received metoclopramide and ketorolac, respectively. The sodium valproate arm also performed worse when assessed by secondary outcome measures than the other two arms. Twenty-eight percent of the patients in the sodium valproate arm stated affirmatively that they could return to daily activities 1 h after drug administration, compared to 39 and 53 % for the ketorolac and the metoclopramide arms, respectively. Six percent of patients receiving metoclopramide experienced restlessness at 24 h. Approximately two-thirds of patients receiving valproate required rescue medications, and only 4 % achieved sustained headache freedom. Conclusions and discussion. The overall conclusion from this study is that sodium valproate should not be considered as a first-line monotherapy for the management of acute migraine. The authors also noted that
metoclopramide had a tendency to superiority over ketorolac at the primary and a number of secondary outcome measures, but this did not reach significance. The study has some limitations; it was done in a single department, which limits claims to external validity. In addition, patients who were using one of the investigational drugs as a preventative treatment were excluded, creating a selection bias. Some follow-up data at 24 h is missing, and the large number of secondary endpoints also causes some problems in interpreting results. However, this work provides important information for the acute management of migraine. None of the investigational drugs achieved high rates of headache freedom at 24 h, highlighting the continued problems in management of the acute presentation of migraine patients. Studies examining combination therapies might be of future interest. Neurology (2014) 82(11):976–983.
123
