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1.  Chronic migraine classification: current knowledge and future perspectives 
The Journal of Headache and Pain  2011;12(6):585-592.
In the field of so-called chronic daily headache, it is not easy for migraine that worsens progressively until it becomes daily or almost daily to find a precise and universally recognized place within the current international headache classification systems. In line with the 2006 revision of the second edition of the International Classification of Headache Disorders (ICHD-2R), the current prevailing opinion is that this headache type should be named chronic migraine (CM) and be characterized by the presence of at least 15 days of headache per month for at least 3 consecutive months, with headache having the same clinical features of migraine without aura for at least 8 of those 15 days. Based on much evidence, though, a CM with the above characteristics appears to be a heterogeneous entity and the obvious risk is that its definition may be extended to include a variety of different clinical entities. A proposal is advanced to consider CM a subtype of migraine without aura that is characterized by a high frequency of attacks (10–20 days of headache per month for at least 3 months) and is distinct from transformed migraine (TM), which in turn should be included in the classification as a complication of migraine. Therefore, CM should be removed from its current coding position in the ICHD-2 and be replaced by TM, which has more restrictive diagnostic criteria (at least 20 days of headache per month for at least 1 year, with no more than 5 consecutive days free of symptoms; same clinical features of migraine without aura for at least 10 of those 20 days).
doi:10.1007/s10194-011-0393-6
PMCID: PMC3208036  PMID: 22028184
Chronic migraine; Transformed migraine; Chronic daily headache; Chronic headache; Headache; Migraine
2.  Neuroimaging for the Evaluation of Chronic Headaches 
Executive Summary
Objective
The objectives of this evidence based review are:
i) To determine the effectiveness of computed tomography (CT) and magnetic resonance imaging (MRI) scans in the evaluation of persons with a chronic headache and a normal neurological examination.
ii) To determine the comparative effectiveness of CT and MRI scans for detecting significant intracranial abnormalities in persons with chronic headache and a normal neurological exam.
iii) To determine the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam.
Clinical Need: Condition and Target Population
Headaches disorders are generally classified as either primary or secondary with further sub-classifications into specific headache types. Primary headaches are those not caused by a disease or medical condition and include i) tension-type headache, ii) migraine, iii) cluster headache and, iv) other primary headaches, such as hemicrania continua and new daily persistent headache. Secondary headaches include those headaches caused by an underlying medical condition. While primary headaches disorders are far more frequent than secondary headache disorders, there is an urge to carry out neuroimaging studies (CT and/or MRI scans) out of fear of missing uncommon secondary causes and often to relieve patient anxiety.
Tension type headaches are the most common primary headache disorder and migraines are the most common severe primary headache disorder. Cluster headaches are a type of trigeminal autonomic cephalalgia and are less common than migraines and tension type headaches. Chronic headaches are defined as headaches present for at least 3 months and lasting greater than or equal to 15 days per month. The International Classification of Headache Disorders states that for most secondary headaches the characteristics of the headache are poorly described in the literature and for those headache disorders where it is well described there are few diagnostically important features.
The global prevalence of headache in general in the adult population is estimated at 46%, for tension-type headache it is 42% and 11% for migraine headache. The estimated prevalence of cluster headaches is 0.1% or 1 in 1000 persons. The prevalence of chronic daily headache is estimated at 3%.
Neuroimaging
Computed Tomography
Computed tomography (CT) is a medical imaging technique used to aid diagnosis and to guide interventional and therapeutic procedures. It allows rapid acquisition of high-resolution three-dimensional images, providing radiologists and other physicians with cross-sectional views of a person’s anatomy. CT scanning poses risk of radiation exposure. The radiation exposure from a conventional CT scanner may emit effective doses of 2-4mSv for a typical head CT.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used to aid diagnosis but unlike CT it does not use ionizing radiation. Instead, it uses a strong magnetic field to image a person’s anatomy. Compared to CT, MRI can provide increased contrast between the soft tissues of the body. Because of the persistent magnetic field, extra care is required in the magnetic resonance environment to ensure that injury or harm does not come to any personnel while in the environment.
Research Questions
What is the effectiveness of CT and MRI scanning in the evaluation of persons with a chronic headache and a normal neurological examination?
What is the comparative effectiveness of CT and MRI scanning for detecting significant intracranial abnormality in persons with chronic headache and a normal neurological exam?
What is the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam.
Research Methods
Literature Search
Search Strategy
A literature search was performed on February 18, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January, 2005 to February, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established.
Inclusion Criteria
Systematic reviews, randomized controlled trials, observational studies
Outpatient adult population with chronic headache and normal neurological exam
Studies reporting likelihood ratio of clinical variables for a significant intracranial abnormality
English language studies
2005-present
Exclusion Criteria
Studies which report outcomes for persons with seizures, focal symptoms, recent/new onset headache, change in presentation, thunderclap headache, and headache due to trauma
Persons with abnormal neurological examination
Case reports
Outcomes of Interest
Primary Outcome
Probability for intracranial abnormality
Secondary Outcome
Patient relief from anxiety
System service use
System costs
Detection rates for significant abnormalities in MRI and CT scans
Summary of Findings
Effectiveness
One systematic review, 1 small RCT, and 1 observational study met the inclusion and exclusion criteria. The systematic review completed by Detsky, et al. reported the likelihood ratios of specific clinical variables to predict significant intracranial abnormalities. The RCT completed by Howard et al., evaluated whether neuroimaging persons with chronic headache increased or reduced patient anxiety. The prospective observational study by Sempere et al., provided evidence for the pre-test probability of intracranial abnormalities in persons with chronic headache as well as minimal data on the comparative effectiveness of CT and MRI to detect intracranial abnormalities.
Outcome 1: Pre-test Probability.
The pre-test probability is usually related to the prevalence of the disease and can be adjusted depending on the characteristics of the population. The study by Sempere et al. determined the pre-test probability (prevalence) of significant intracranial abnormalities in persons with chronic headaches defined as headache experienced for at least a 4 week duration with a normal neurological exam. There is a pre-test probability of 0.9% (95% CI 0.5, 1.4) in persons with chronic headache and normal neurological exam. The highest pre-test probability of 5 found in persons with cluster headaches. The second highest, that of 3.7, was reported in persons with indeterminate type headache. There was a 0.75% rate of incidental findings.
Likelihood ratios for detecting a significant abnormality
Clinical findings from the history and physical may be used as screening test to predict abnormalities on neuroimaging. The extent to which the clinical variable may be a good predictive variable can be captured by reporting its likelihood ratio. The likelihood ratio provides an estimate of how much a test result will change the odds of having a disease or condition. The positive likelihood ratio (LR+) tells you how much the odds of having the disease increases when a test is positive. The negative likelihood ratio (LR-) tells you how much the odds of having the disease decreases when the test is negative.
Detsky et al., determined the likelihood ratio for specific clinical variable from 11 studies. There were 4 clinical variables with both statistically significant positive and negative likelihood ratios. These included: abnormal neurological exam (LR+ 5.3, LR- 0.72), undefined headache (LR+ 3.8, LR- 0.66), headache aggravated by exertion or valsalva (LR+ 2.3, LR- 0.70), and headache with vomiting (LR+ 1.8, and LR- 0.47). There were two clinical variables with a statistically significant positive likelihood ratio and non significant negative likelihood ratio. These included: cluster-type headache (LR+ 11, LR- 0.95), and headache with aura (LR+ 12.9, LR- 0.52). Finally, there were 8 clinical variables with both statistically non significant positive and negative likelihood ratios. These included: headache with focal symptoms, new onset headache, quick onset headache, worsening headache, male gender, headache with nausea, increased headache severity, and migraine type headache.
Outcome 2: Relief from Anxiety
Howard et al. completed an RCT of 150 persons to determine if neuroimaging for headaches was anxiolytic or anxiogenic. Persons were randomized to receiving either an MRI scan or no scan for investigation of their headache. The study population was stratified into those persons with a Hospital Anxiety and Depression scale (HADS) > 11 (the high anxiety and depression group) and those < 11 (the low anxiety and depression) so that there were 4 groups:
Group 1: High anxiety and depression, no scan group
Group 2: High anxiety and depression, scan group
Group 3: Low anxiety and depression, no scan group
Group 4: Low anxiety and depression, scan group
Anxiety
There was no evidence for any overall reduction in anxiety at 1 year as measured by a visual analogue scale of ‘level of worry’ when analysed by whether the person received a scan or not. Similarly, there was no interaction between anxiety and depression status and whether a scan was offered or not on patient anxiety. Anxiety did not decrease at 1 year to any statistically significant degree in the high anxiety and depression group (HADS positive) compared with the low anxiety and depression group (HADS negative).
There are serious methodological limitations in this study design which may have contributed to these negative results. First, when considering the comparison of ‘scan’ vs. ‘no scan’ groups, 12 people (16%) in the ‘no scan group’ actually received a scan within the follow up year. If indeed scanning does reduce anxiety then this contamination of the ‘no scan’ group may have reduced the effect between the groups results resulting in a non significant difference in anxiety scores between the ‘scanned’ and the ‘no scan’ group. Second, there was an inadequate sample size at 1 year follow up in each of the 4 groups which may have contributed to a Type II statistical error (missing a difference when one may exist) when comparing scan vs. no scan by anxiety and depression status. Therefore, based on the results and study limitations it is inconclusive as to whether scanning reduces anxiety.
Outcome 3: System Services
Howard et al., considered services used and system costs a secondary outcome. These were determined by examining primary care case notes at 1 year for consultation rates, symptoms, further investigations, and contact with secondary and tertiary care.
System Services
The authors report that the use of neurologist and psychiatrist services was significantly higher for those persons not offered as scan, regardless of their anxiety and depression status (P<0.001 for neurologist, and P=0.033 for psychiatrist)
Outcome 4: System Costs
System Costs
There was evidence of statistically significantly lower system costs if persons with high levels of anxiety and depression (Hospital Anxiety and Depression Scale score >11) were provided with a scan (P=0.03 including inpatient costs, and 0.047 excluding inpatient costs).
Comparative Effectiveness of CT and MRI Scans
One study reported the detection rate for significant intracranial abnormalities using CT and MRI. In a cohort of 1876 persons with a non acute headache defined as any type of headache that had begun at least 4 weeks before enrolment Sempere et al. reported that the detection rate was 19/1432 (1.3%) using CT and 4/444 (0.9%) using MRI. Of 119 normal CT scans 2 (1.7%) had significant intracranial abnormality on MRI. The 2 cases were a small meningioma, and an acoustic neurinoma.
Summary
The evidence presented can be summarized as follows:
Pre-test Probability
Based on the results by Sempere et al., there is a low pre-test probability for intracranial abnormalities in persons with chronic headaches and a normal neurological exam (defined as headaches experiences for a minimum of 4 weeks). The Grade quality of evidence supporting this outcome is very low.
Likelihood Ratios
Based on the systematic review by Detsky et al., there is a statistically significant positive and negative likelihood ratio for the following clinical variables: abnormal neurological exam, undefined headache, headache aggravated by exertion or valsalva, headache with vomiting. Grade quality of evidence supporting this outcome is very low.
Based on the systematic review by Detsky et al. there is a statistically significant positive likelihood ratio but non statistically significant negative likelihood ratio for the following clinical variables: cluster headache and headache with aura. The Grade quality of evidence supporting this outcome is very low.
Based on the systematic review by Detsky et al., there is a non significant positive and negative likelihood ratio for the following clinical variables: headache with focal symptoms, new onset headache, quick onset headache, worsening headache, male gender, headache with nausea, increased headache severity, migraine type headache. The Grade quality of evidence supporting this outcome is very low.
Relief from Anxiety
Based on the RCT by Howard et al., it is inconclusive whether neuroimaging scans in persons with a chronic headache are anxiolytic. The Grade quality of evidence supporting this outcome is low.
System Services
Based on the RCT by Howard et al. scanning persons with chronic headache regardless of their anxiety and/or depression level reduces service use. The Grade quality of evidence is low.
System Costs
Based on the RCT by Howard et al., scanning persons with a score greater than 11 on the High Anxiety and Depression Scale reduces system costs. The Grade quality of evidence is moderate.
Comparative Effectiveness of CT and MRI Scans
There is sparse evidence to determine the relative effectiveness of CT compared with MRI scanning for the detection of intracranial abnormalities. The Grade quality of evidence supporting this is very low.
Economic Analysis
Ontario Perspective
Volumes for neuroimaging of the head i.e. CT and MRI scans, from the Ontario Health Insurance Plan (OHIP) data set were used to investigate trends in the province for Fiscal Years (FY) 2004-2009.
Assumptions were made in order to investigate neuroimaging of the head for the indication of headache. From the literature, 27% of all CT and 13% of all MRI scans for the head were assumed to include an indication of headache. From that same retrospective chart review and personal communication with the author 16% of CT scans and 4% of MRI scans for the head were for the sole indication of headache. From the Ministry of Health and Long-Term Care (MOHLTC) wait times data, 73% of all CT and 93% of all MRI scans in the province, irrespective of indication were outpatient procedures.
The expenditure for each FY reflects the volume for that year and since volumes have increased in the past 6 FYs, the expenditure has also increased with a pay-out reaching 3.0M and 2.8M for CT and MRI services of the head respectively for the indication of headache and a pay-out reaching 1.8M and 0.9M for CT and MRI services of the head respectively for the indication of headache only in FY 08/09.
Cost per Abnormal Finding
The yield of abnormal finding for a CT and MRI scan of the head for the indication of headache only is 2% and 5% respectively. Based on these yield a high-level estimate of the cost per abnormal finding with neuroimaging of the head for headache only can be calculated for each FY. In FY 08/09 there were 37,434 CT and 16,197 MRI scans of the head for headache only. These volumes would generate a yield of abnormal finding of 749 and 910 with a CT scan and MRI scan respectively. The expenditure for FY 08/09 was 1.8M and 0.9M for CT and MRI services respectively. Therefore the cost per abnormal finding would be $2,409 for CT and $957 for MRI. These cost per abnormal finding estimates were limited because they did not factor in comparators or the consequences associated with an abnormal reading or FNs. The estimates only consider the cost of the neuroimaging procedure and the yield of abnormal finding with the respective procedure.
PMCID: PMC3377587  PMID: 23074404
3.  Classification and clinical features of headache patients: an outpatient clinic study from China 
The Journal of Headache and Pain  2011;12(5):561-567.
This study aimed to analyze and classify the clinical features of headache in neurological outpatients. A cross-sectional study was conducted consecutively from March to May 2010 for headache among general neurological outpatients attending the First Affiliated Hospital of Chongqing Medical University. Personal interviews were carried out and a questionnaire was used to collect medical records. Diagnosis of headache was according to the International classification of headache disorders, 2nd edition (ICHD-II). Headache patients accounted for 19.5% of the general neurology clinic outpatients. A total of 843 (50.1%) patients were defined as having primary headache, 454 (27%) secondary headache, and 386 (23%) headache not otherwise specified (headache NOS). For primary headache, 401 (23.8%) had migraine, 399 (23.7%) tension-type headache (TTH), 8 (0.5%) cluster headache and 35 (2.1%) other headache types. Overall, migraine patients suffered (1) more severe headache intensity, (2) longer than 6 years of headache history and (3) more common analgesic medications use than TTH ones (p < 0.001).TTH patients had more frequent episodes of headaches than migraine patients, and typically headache frequency exceeded 15 days/month (p < 0.001); 22.8% of primary headache patients were defined as chronic daily headache. Almost 20% of outpatient visits to the general neurology department were of headache patients, predominantly primary headache of migraine and TTH. In outpatient headaches, more attention should be given to headache intensity and duration of headache history for migraine patients, while more attention to headache frequency should be given for the TTH ones.
doi:10.1007/s10194-011-0360-2
PMCID: PMC3173628  PMID: 21744226
Outpatient; Headache; Cross-sectional study; Clinical feature; Migraine
4.  Classification and clinical features of headache patients: an outpatient clinic study from China 
The Journal of Headache and Pain  2011;12(5):561-567.
This study aimed to analyze and classify the clinical features of headache in neurological outpatients. A cross-sectional study was conducted consecutively from March to May 2010 for headache among general neurological outpatients attending the First Affiliated Hospital of Chongqing Medical University. Personal interviews were carried out and a questionnaire was used to collect medical records. Diagnosis of headache was according to the International classification of headache disorders, 2nd edition (ICHD-II). Headache patients accounted for 19.5% of the general neurology clinic outpatients. A total of 843 (50.1%) patients were defined as having primary headache, 454 (27%) secondary headache, and 386 (23%) headache not otherwise specified (headache NOS). For primary headache, 401 (23.8%) had migraine, 399 (23.7%) tension-type headache (TTH), 8 (0.5%) cluster headache and 35 (2.1%) other headache types. Overall, migraine patients suffered (1) more severe headache intensity, (2) longer than 6 years of headache history and (3) more common analgesic medications use than TTH ones (p < 0.001).TTH patients had more frequent episodes of headaches than migraine patients, and typically headache frequency exceeded 15 days/month (p < 0.001); 22.8% of primary headache patients were defined as chronic daily headache. Almost 20% of outpatient visits to the general neurology department were of headache patients, predominantly primary headache of migraine and TTH. In outpatient headaches, more attention should be given to headache intensity and duration of headache history for migraine patients, while more attention to headache frequency should be given for the TTH ones.
doi:10.1007/s10194-011-0360-2
PMCID: PMC3173628  PMID: 21744226
Outpatient; Headache; Cross-sectional study; Clinical feature; Migraine
5.  Craniosacral therapy for migraine: Protocol development for an exploratory controlled clinical trial 
Background
Migraine affects approximately 20% of the population. Conventional care for migraine is suboptimal; overuse of medications for the treatment of episodic migraines is a risk factor for developing chronic daily headache. The study of non-pharmaceutical approaches for prevention of migraine headaches is therefore warranted. Craniosacral therapy (CST) is a popular non-pharmacological approach to the treatment or prevention of migraine headaches for which there is limited evidence of safety and efficacy. In this paper, we describe an ongoing feasibility study to assess the safety and efficacy of CST in the treatment of migraine, using a rigorous and innovative randomized controlled study design involving low-strength static magnets (LSSM) as an attention control intervention.
Methods
The trial is designed to test the hypothesis that, compared to those receiving usual care plus a treatment with low-strength static magnets (attention-control complementary therapy), subjects receiving usual medical care plus CST will demonstrate significant improvement in: quality-of-life as measured by the Headache Impact Test (HIT-6); reduced frequency of migraine; and a perception of clinical benefit. Criteria for inclusion are either gender, age > 11, English or Spanish speaking, meeting the International Classification of Headache Disorders (ICHD) criteria for migraine with or without aura, a headache frequency of 5 to 15 per month over at least two years. After an 8 week baseline phase, eligible subjects are randomized to either CST or an attention control intervention, low strength static magnets (LSSM). To evaluate possible therapist bias, videotaped encounters are analyzed to assess for any systematic group differences in interactions with subjects.
Results
169 individuals have been screened for eligibility, of which 109 were eligible for the study. Five did not qualify during the baseline phase because of inadequate headache frequency. Nineteen have withdrawn from the study after giving consent.
Conclusion
This report endorses the feasibility of undertaking a rigorous randomized clinical trial of CST for migraine using a standardized CST protocol and an innovative control protocol developed for the study. Subjects are able and willing to complete detailed headache diaries during an 8-week baseline period, with few dropouts during the study period, indicating the acceptability of both interventions.
Trial Registration
ClinicalTrials.gov NCT00665236
doi:10.1186/1472-6882-8-28
PMCID: PMC2442042  PMID: 18541041
6.  One-year prevalence and the impact of migraine and tension-type headache in Turkey: a nationwide home-based study in adults 
The Journal of Headache and Pain  2012;13(2):147-157.
Several studies have shown that the prevalence of migraine and tension-type headache (TTH) varied between different geographical regions. Therefore, there is a need of a nationwide prevalence study for headache in our country, located between Asia and Europe. This nationwide study was designed to estimate the 1-year prevalence of migraine and TTH and analyse the clinical features, the impact as well as the demographic and socio-economic characteristics of the participant households in Turkey. We planned to investigate 6,000 representative households in 21 cities of Turkey; and a total of 5,323 households (response rate of 89%) aged between 18 and 65 years were examined for headache by 33 trained physicians at home on the basis of the diagnostic criteria of the second edition of the International Classification of Headache Disorders (ICHD-II). The electronically registered questionnaire was based on the headache features, the associated symptoms, demographic and socio-economic situation and history. Of 5,323 participants (48.8% women; mean age 35.9 ± 12 years) 44.6% reported recurrent headaches during the last 1 year and 871 were diagnosed with migraine at a prevalence rate of 16.4% (8.5% in men and 24.6% in women), whereas only 270 were diagnosed with TTH at a prevalence rate of 5.1% (5.7% in men and 4.5% in women). The 1-year prevalence of probable migraine was 12.4% and probable TTH was 9.5% additionally. The rate of migraine with aura among migraineurs was 21.5%. The prevalence of migraine was highest among 35–40-year-old women while there were no differences in age groups among men and in TTH overall. More than 2/3 of migraineurs had ever consulted a physician whereas only 1/3 of patients with TTH had ever consulted a physician. For women, the migraine prevalence was higher among the ones with a lower income, while among men, it did not show any change by income. Migraine prevalence was lower in those with a lower educational status compared to those with a high educational status. Chronic daily headache was present in 3.3% and the prevalence of medication overuse headache was 2.1% in our population. There was an important impact of migraine with a monthly frequency of 5.9 ± 6, and an attack duration of 35.1 ± 72 h, but only 4.9% were on prophylactic treatment. The one-year prevalence of migraine estimated as 16.4% was similar or even higher than world-wide reported migraine prevalence figures and identical to a previous nation-wide study conducted in 1998, whereas the TTH prevalence was much lower using the same methodology with the ICHD-II criteria.
Electronic supplementary material
The online version of this article (doi:10.1007/s10194-011-0414-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s10194-011-0414-5
PMCID: PMC3274583  PMID: 22246025
Prevalence of migraine; Prevalence of tension-type headache; Migraine; Tension-type headache; Headache
7.  One-year prevalence and the impact of migraine and tension-type headache in Turkey: a nationwide home-based study in adults 
The Journal of Headache and Pain  2012;13(2):147-157.
Several studies have shown that the prevalence of migraine and tension-type headache (TTH) varied between different geographical regions. Therefore, there is a need of a nationwide prevalence study for headache in our country, located between Asia and Europe. This nationwide study was designed to estimate the 1-year prevalence of migraine and TTH and analyse the clinical features, the impact as well as the demographic and socio-economic characteristics of the participant households in Turkey. We planned to investigate 6,000 representative households in 21 cities of Turkey; and a total of 5,323 households (response rate of 89%) aged between 18 and 65 years were examined for headache by 33 trained physicians at home on the basis of the diagnostic criteria of the second edition of the International Classification of Headache Disorders (ICHD-II). The electronically registered questionnaire was based on the headache features, the associated symptoms, demographic and socio-economic situation and history. Of 5,323 participants (48.8% women; mean age 35.9 ± 12 years) 44.6% reported recurrent headaches during the last 1 year and 871 were diagnosed with migraine at a prevalence rate of 16.4% (8.5% in men and 24.6% in women), whereas only 270 were diagnosed with TTH at a prevalence rate of 5.1% (5.7% in men and 4.5% in women). The 1-year prevalence of probable migraine was 12.4% and probable TTH was 9.5% additionally. The rate of migraine with aura among migraineurs was 21.5%. The prevalence of migraine was highest among 35–40-year-old women while there were no differences in age groups among men and in TTH overall. More than 2/3 of migraineurs had ever consulted a physician whereas only 1/3 of patients with TTH had ever consulted a physician. For women, the migraine prevalence was higher among the ones with a lower income, while among men, it did not show any change by income. Migraine prevalence was lower in those with a lower educational status compared to those with a high educational status. Chronic daily headache was present in 3.3% and the prevalence of medication overuse headache was 2.1% in our population. There was an important impact of migraine with a monthly frequency of 5.9 ± 6, and an attack duration of 35.1 ± 72 h, but only 4.9% were on prophylactic treatment. The one-year prevalence of migraine estimated as 16.4% was similar or even higher than world-wide reported migraine prevalence figures and identical to a previous nation-wide study conducted in 1998, whereas the TTH prevalence was much lower using the same methodology with the ICHD-II criteria.
Electronic supplementary material
The online version of this article (doi:10.1007/s10194-011-0414-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s10194-011-0414-5
PMCID: PMC3274583  PMID: 22246025
Prevalence of migraine; Prevalence of tension-type headache; Migraine; Tension-type headache; Headache
8.  Clinical and prognostic subforms of new daily-persistent headache 
Neurology  2010;74(17):1358-1364.
Background: According to the International Classification of Headache Disorders (ICHD)–2, primary daily headaches unremitting from onset are classified as new daily-persistent headache (NDPH) only if migraine features are absent. When migraine features are present, classification is problematic.
Methods: We developed a revised NDPH definition not excluding migraine features (NDPH-R), and applied it to consecutive patients seen at the Montefiore Headache Center. We divided this group into patients meeting ICHD-2 criteria (NDPH-ICHD) and those with too many migraine features for ICHD-2 (NDPH-mf). We compared clinical and demographic features in these groups, identifying 3 prognostic subgroups: persisting, remitting, and relapsing-remitting. Remitting and relapsing-remitting patients were combined into a nonpersisting group.
Results: Of 71 NDPH-R patients, 31 (43.7%) also met NDPH-ICHD-2 criteria. The NDPH-mf and the NDPH-ICHD-2 groups were similar in most clinical features though the NDPH-mf group was younger, included more women, and had a higher frequency of depression. The groups were similar in the prevalence of allodynia, triptan responsiveness, and prognosis. NDPH-R prognostic subforms were also very similar, although the persisting subform was more likely to be of white race, to have anxiety or depression, and to have a younger onset age.
Conclusions: Current International Classification of Headache Disorders (ICHD)–2 criteria exclude the majority of patients with primary headache unremitting from onset. The proposed criteria for revised new daily-persistent headache definition not excluding migraine features (NDPH-R) classify these patients into a relatively homogeneous group based on demographics, clinical features, and prognosis. Both new daily-persistent headache with too many migraine features for ICHD-2 and new daily-persistent headache meeting ICHD-2 criteria include patients in equal proportions that fall into the persisting, remitting, and relapsing-remitting subgroups. Our criteria for NDPH-R should be considered for inclusion in ICHD-3.
doi:10.1212/WNL.0b013e3181dad5de
PMCID: PMC3462554  PMID: 20421580
9.  Grey zones in the diagnosis of adult migraine without aura based on the International Classification of Headache Disorders-III beta: Exploring the covariates of possible migraine without aura 
An update to the International Classification of Headache Disorders is being developed, which may alter the diagnosis of disorders such as migraine headaches. Patients often report some, but not all, of the criteria for migraine without aura (MWoA), leading to several ‘grey zones’ that include patients who are not formally diagnosed with MWoA. The authors of this article assessed, in a total of 1365 patients diagnosed with MWoA, these ‘grey zones’ and possible implications for the update to the International Classification of Headache Disorders.
BACKGROUND:
Exploring clinical characteristics and migraine covariates may be useful in the diagnosis of migraine without aura.
OBJECTIVE:
To evaluate the diagnostic value of the International Classification of Headache Disorders (ICHD)-III beta-based diagnosis of migraine without aura; to explore the covariates of possible migraine without aura using an analysis of grey zones in this area; and, finally, to make suggestions for the final version of the ICHD-III.
METHODS:
A total of 1365 patients (mean [± SD] age 38.5±10.4 years, 82.8% female) diagnosed with migraine without aura according to the criteria of the ICHD-III beta were included in the present tertiary care-based retrospective study. Patients meeting all of the criteria of the ICHD-III beta were classified as having full migraine without aura, while those who did not meet one, two or ≥3 of the diagnostic criteria were classified as zones I, II and III, respectively. The diagnostic value of the clinical characteristics and covariates of migraine were determined.
RESULTS:
Full migraine without aura was evident in 25.7% of the migraineurs. A higher likelihood of zone I classification was shown for an attack lasting 4 h to 72 h (OR 1.560; P=0.002), with pulsating quality (OR 4.096; P<0.001), concomitant nausea/vomiting (OR 2.300; P<0.001) and photophobia/phonophobia (OR 4.865; P<0.001). The first-rank determinants for full migraine without aura were sleep irregularities (OR 1.596; P=0.005) and periodic vomiting (OR 1.464; P=0.026). However, even if not mentioned in ICHD-III beta, the authors determined that motion sickness, abdominal pain or infantile colic attacks in childhood, associated dizziness and osmophobia have important diagnostic value.
CONCLUSIONS:
In cases that do not fulfill all of the diagnostic criteria although they are largely consistent with the characteristics of migraine in clinical terms, the authors believe that a history of infantile colic; periodic vomiting (but not periodic vomiting syndrome); recurrent abdominal pain; the presence of motion sickness or vertigo, dizziness or osmophobia accompanying the pain; and comorbid atopic disorder are characteristics that should to be discussed and considered as additional diagnostic criteria (covariates) in the preparation of the final version of ICHD-III.
PMCID: PMC4325894  PMID: 25493966
Covariates; Diagnostic criteria; Grey zones; ICHD-III; Migraine without aura
10.  Selectivity in Genetic Association with Sub-classified Migraine in Women 
PLoS Genetics  2014;10(5):e1004366.
Migraine can be sub-classified not only according to presence of migraine aura (MA) or absence of migraine aura (MO), but also by additional features accompanying migraine attacks, e.g. photophobia, phonophobia, nausea, etc. all of which are formally recognized by the International Classification of Headache Disorders. It remains unclear how aura status and the other migraine features may be related to underlying migraine pathophysiology. Recent genome-wide association studies (GWAS) have identified 12 independent loci at which single nucleotide polymorphisms (SNPs) are associated with migraine. Using a likelihood framework, we explored the selective association of these SNPs with migraine, sub-classified according to aura status and the other features in a large population-based cohort of women including 3,003 active migraineurs and 18,108 free of migraine. Five loci met stringent significance for association with migraine, among which four were selective for sub-classified migraine, including rs11172113 (LRP1) for MO. The number of loci associated with migraine increased to 11 at suggestive significance thresholds, including five additional selective associations for MO but none for MA. No two SNPs showed similar patterns of selective association with migraine characteristics. At one extreme, SNPs rs6790925 (near TGFBR2) and rs2274316 (MEF2D) were not associated with migraine overall, MA, or MO but were selective for migraine sub-classified by the presence of one or more of the additional migraine features. In contrast, SNP rs7577262 (TRPM8) was associated with migraine overall and showed little or no selectivity for any of the migraine characteristics. The results emphasize the multivalent nature of migraine pathophysiology and suggest that a complete understanding of the genetic influence on migraine may benefit from analyses that stratify migraine according to both aura status and the additional diagnostic features used for clinical characterization of migraine.
Author Summary
Migraine is among the most common and debilitating neurological disorders. Diagnostic criteria for migraine recognize a variety of symptoms including a primary dichotomous classification for the presence or absence of aura, typically a visual disturbance phenomenon, as well as others such as sensitivity to light or sound, and nausea, etc. We explored whether any of 12 recently discovered genetic variants associated with common migraine might have selective association for migraine sub-classified by aura status or nine additional migraine features in a population of middle-aged women including 3,003 migraineurs and 18,180 non-migraineurs. Five of the 12 genetic variants met the most stringent significance criterion for association with migraine, among which four had selective association with sub-classified migraine, including one that was selective for migraine without aura. At suggestive significance, all of the remaining genetic variants were selective for sub-classifications of migraine although no two variants showed the same pattern of selectivity. The selectivity patterns suggest very different contributions to migraine pathophysiology among the 12 loci and their implicated genes. Further, the results suggest that future discovery efforts for new migraine susceptibility loci would benefit by considering associations with sub-classified migraine toward the ultimate goals of more specific diagnosis and personalized treatment.
doi:10.1371/journal.pgen.1004366
PMCID: PMC4031047  PMID: 24852292
11.  Migraine may be a risk factor for the development of complex regional pain syndrome 
The aim was to assess the relative frequency of migraine and the headache characteristics of complex regional pain syndrome (CRPS) sufferers. CRPS and migraine are chronic, often disabling pain syndromes. Recent studies suggest that headache is associated with the development of CRPS. Consecutive adults fulfilling International Association for the Study of Pain criteria for CRPS at a pain clinic were included. Demographics, medical history, and pain characteristics were obtained. Headache diagnoses were made using International Classification of Headache Disorders, 2nd edn criteria. Migraine and pain characteristics were compared in those with migraine with those without. ANOVA with Tukey post hoc tests was used to determine the significance of continuous variables and Fisher’s exact or χ2 tests for categorical variables. The expected prevalence of migraine and chronic daily headache (CDH) was calculated based on age- and gender-stratified general population estimates. Standardized morbidity ratios (SMR) were calculated by dividing the observed prevalence of migraine by the expected prevalence from the general population. The sample consisted of 124 CRPS participants. The mean age was 45.5 ± 12.0 years. Age-and gender-adjusted SMRs showed that those with CRPS were 3.6 times more likely to have migraine and nearly twice as likely to have CDH as the general population. Aura was reported in 59.7% (74/124) of participants. Of those CRPS sufferers with migraine, 61.2% (41/67) reported the onset of severe headaches before the onset of CRPS symptoms Mean age of onset of CRPS was earlier in those with migraine (34.9 ± 11.1 years) and CDH (32.5 ± 13.4 years) compared with those with no headaches (46.8 ± 14.9 years) and those with tension-type headache (TTH) (39.9 ± 9.9 years), P < 0.05. More extremities were affected by CRPS in participants with migraine (median of four extremities) compared with the combined group of those CRPS sufferers with no headaches or TTH (median 2.0 extremities), P < 0.05. The presence of static, dynamic and deep joint mechanoallodynia together was reported by more CRPS participants with migraine (72.2%) than those with no headaches or TTH (46.2%), P ≤ 0.05. Migraine may be a risk factor for CRPS and the presence of migraine may be associated with a more severe form of CRPS. Specifically: (i) migraine occurs in a greater percentage of CRPS sufferers than expected in the general population; (ii) the onset of CRPS is reported earlier in those with migraine than in those without; and (iii) CRPS symptoms are present in more extremities in those CRPS sufferers with migraine compared with those without. In addition, as we also found that the presence of aura is reported in a higher percentage of those CRPS sufferers with migraine than reported in migraineurs in the general population, further evaluation of the cardiovascular risk profile of CRPS sufferers is warranted.
doi:10.1111/j.1468-2982.2009.01916.x
PMCID: PMC3979276  PMID: 19614690
Migraine; chronic daily headache; complex regional pain syndrome; allodynia; aura
12.  Effect of preventive (β blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial 
Objective To determine if the addition of preventive drug treatment (β blocker), brief behavioural migraine management, or their combination improves the outcome of optimised acute treatment in the management of frequent migraine.
Design Randomised placebo controlled trial over 16 months from July 2001 to November 2005.
Setting Two outpatient sites in Ohio, USA.
Participants 232 adults (mean age 38 years; 79% female) with diagnosis of migraine with or without aura according to International Headache Society classification of headache disorders criteria, who recorded at least three migraines with disability per 30 days (mean 5.5 migraines/30 days), during an optimised run-in of acute treatment.
Interventions Addition of one of four preventive treatments to optimised acute treatment: β blocker (n=53), matched placebo (n=55), behavioural migraine management plus placebo (n=55), or behavioural migraine management plus β blocker (n=69).
Main outcome measure The primary outcome was change in migraines/30 days; secondary outcomes included change in migraine days/30 days and change in migraine specific quality of life scores.
Results Mixed model analysis showed statistically significant (P≤0.05) differences in outcomes among the four added treatments for both the primary outcome (migraines/30 days) and the two secondary outcomes (change in migraine days/30 days and change in migraine specific quality of life scores). The addition of combined β blocker and behavioural migraine management (−3.3 migraines/30 days, 95% confidence interval −3.2 to −3.5), but not the addition of β blocker alone (−2.1 migraines/30 days, −1.9 to −2.2) or behavioural migraine management alone (−2.2 migraines migraines/30 days, −2.0 to −2.4), improved outcomes compared with optimised acute treatment alone (−2.1 migraines/30 days, −1.9 to −2.2). For a clinically significant (≥50% reduction) in migraines/30 days, the number needed to treat for optimised acute treatment plus combined β blocker and behavioural migraine management was 3.1 compared with optimised acute treatment alone, 2.6 compared with optimised acute treatment plus β blocker, and 3.1 compared with optimised acute treatment plus behavioural migraine management. Results were consistent for the two secondary outcomes, and at both month 10 (the primary endpoint) and month 16.
Conclusion The addition of combined β blocker plus behavioural migraine management, but not the addition of β blocker alone or behavioural migraine management alone, improved outcomes of optimised acute treatment. Combined β blocker treatment and behavioural migraine management may improve outcomes in the treatment of frequent migraine.
Trial registration Clinical trials NCT00910689.
doi:10.1136/bmj.c4871
PMCID: PMC2947621  PMID: 20880898
13.  Anatomical Alterations of the Visual Motion Processing Network in Migraine with and without Aura 
PLoS Medicine  2006;3(10):e402.
Background
Patients suffering from migraine with aura (MWA) and migraine without aura (MWoA) show abnormalities in visual motion perception during and between attacks. Whether this represents the consequences of structural changes in motion-processing networks in migraineurs is unknown. Moreover, the diagnosis of migraine relies on patient's history, and finding differences in the brain of migraineurs might help to contribute to basic research aimed at better understanding the pathophysiology of migraine.
Methods and Findings
To investigate a common potential anatomical basis for these disturbances, we used high-resolution cortical thickness measurement and diffusion tensor imaging (DTI) to examine the motion-processing network in 24 migraine patients (12 with MWA and 12 MWoA) and 15 age-matched healthy controls (HCs). We found increased cortical thickness of motion-processing visual areas MT+ and V3A in migraineurs compared to HCs. Cortical thickness increases were accompanied by abnormalities of the subjacent white matter. In addition, DTI revealed that migraineurs have alterations in superior colliculus and the lateral geniculate nucleus, which are also involved in visual processing.
Conclusions
A structural abnormality in the network of motion-processing areas could account for, or be the result of, the cortical hyperexcitability observed in migraineurs. The finding in patients with both MWA and MWoA of thickness abnormalities in area V3A, previously described as a source in spreading changes involved in visual aura, raises the question as to whether a “silent” cortical spreading depression develops as well in MWoA. In addition, these experimental data may provide clinicians and researchers with a noninvasively acquirable migraine biomarker.
A structural abnormality in the network of motion-processing areas could account for, or be the result of, the cortical hyperexcitability seen in people who have migraine.
Editors' Summary
Background.
Migraine is a disabling brain disorder that affects more than one in ten people during their lifetimes. It is characterized by severe, recurrent headaches, often accompanied by nausea, vomiting, and light sensitivity. In some migraineurs (people who have migraines), the headaches are preceded by neurological disturbances known as “aura.” These usually affect vision, causing illusions of flashing lights, zig-zag lines, or blind spots. There are many triggers for migraine attacks—including some foods, stress, and bright lights—and every migraineur has to learn what triggers his or her attacks. There is no cure for migraine, although over-the-counter painkillers can ease the symptoms and doctors can prescribe stronger remedies or drugs to reduce the frequency of attacks. Exactly what causes migraine is unclear but scientists think that, for some reason, the brains of migraineurs are hyperexcitable. That is, some nerve cells in their brains overreact when they receive electrical messages from the body. This triggers a local disturbance of brain function called “cortical spreading depression,” which, in turn, causes aura, headache, and the other symptoms of migraine.
Why Was This Study Done?
Researchers need to know more about what causes migraine to find better treatments. One clue comes from the observation that motion perception is abnormal in migraineurs, even between attacks—they can be very sensitive to visually induced motion sickness, for example. Another clue is that aura are usually visual. So could brain regions that process visual information be abnormal in people who have migraines? In this study, the researchers investigated the structure of the motion processing parts of the brain in people who have migraine with aura, in people who have migraine without aura, and in unaffected individuals to see whether there were any differences that might help them understand migraine.
What Did the Researchers Do and Find?
The researchers used two forms of magnetic resonance imaging—a noninvasive way to produce pictures of internal organs—to examine the brains of migraineurs (when they weren't having a migraine) and healthy controls. They concentrated on two brain regions involved in motion processing known as the MT+ and V3A areas and first measured the cortical thickness of these areas—the cortex is the wrinkled layer of gray matter on the outside of the brain that processes information sent from the body. They found that the cortical thickness was increased in both of these areas in migraineurs when compared to healthy controls. There was no difference in cortical thickness between migraineurs who had aura and those who did not, but the area of cortical thickening in V3A corresponded to the source of cortical spreading depression previously identified in a person who had migraine with aura. The researchers also found differences between the white matter (the part of the brain that transfers information between different regions of the gray matter) immediately below the V3A and MT+ areas in the migraineurs and the controls but again not between the two groups of migraineurs.
What Do These Findings Mean?
This study provides new information about migraine. First, it identifies structural changes in the brains of people who have migraines. Until now, it has been thought that abnormal brain function causes migraine but that migraineurs have a normal brain structure. The observed structural differences might either account for or be caused by the hyperexcitability that triggers migraines. Because migraine runs in families, examining the brains of children of migraineurs as they grow up might indicate which of these options is correct, although it is possible that abnormalities in brain areas not examined here actually trigger migraines. Second, the study addresses a controversial question about migraine: Is migraine with aura the same as migraine without aura? The similar brain changes in both types of migraine suggest that they are one disorder. Third, the abnormalities in areas MT+ and V3A could help to explain why migraineurs have problems with visual processing even in between attacks. Finally, this study suggests that it might be possible to develop a noninvasive test to help doctors diagnose migraine.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030402.
The MedlinePlus encyclopedia has several pages on migraine
The US National Institute of Neurological Disorders and Stroke offers patient information on migraine and other headaches
The NHS Direct Online contains patient information on migraine from the UK National Health Service
MAGNUM provides information from The US National Migraine Association
The Migraine Trust is a UK charity that supports research and provides support for patients
The Migraine Aura Foundation is a site about aura that includes a section on art and aura
doi:10.1371/journal.pmed.0030402
PMCID: PMC1609120  PMID: 17048979
14.  Diagnostic criteria for CADASIL in the International Classification of Headache Disorders (ICHD-II): are they appropriate? 
The Journal of Headache and Pain  2010;11(3):181-186.
We reviewed the characteristics of headache in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), to verify the appropriateness of the International Classification of Headache Disorders, second edition (ICHD-II) criteria. Available data were found through Medline/PubMed using the keyword “cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)”. The search was restricted to studies published in English in the years between 1993 and 2008. We excluded studies that did not report original data on CADASIL and information regarding the presence of headache. We found 34 studies reporting data on 749 patients overall; 387 (51.7%) patients had headache. According to the authors’ definition, 356 (92%) patients were reported as having migraine and 31 (8%) as having headache. Of the 356 patients who were defined as migraineurs, 125 (35.1%) had migraine with aura, 7 (2%) migraine without aura, 156 (43.8%) unspecified migraine and 68 (19.1%) had more than one type of migraine. Among the 31 patients reported as suffering from headache, the headache was not further detailed in 18 (58.1%) patients; it was defined as chronic in 6 (19.3%), as resembling migraine with aura in 4 (12.9%), as resembling migraine without aura in 2 (6.5%) and as tension type in 1 (3.2%) patient. In patients with CADASIL, the headache was usually referred to as migraine and mostly as migraine with aura. However, this referral is formally incorrect since the diagnostic criteria for any type of migraine in the ICHD-II require that the disturbance is not attributed to another disorder. For this reason, we suggest updating the ICHD-II in relation to CADASIL. Our suggestion is to insert a new category referred to as Headache attributed to genetic disorder including Headache attributed to CADASIL.
doi:10.1007/s10194-010-0203-6
PMCID: PMC3451909  PMID: 20224942
Migraine; Headache; CADASIL; International Classification of Headache Disorders
15.  Headache associated with moyamoya disease: a case story and literature review 
Headache associated with moyamoya disease (HAMD) is common in moyamoya disease. However, the characteristics and classification of HAMD are largely unknown. We present a case of a 39-year-old woman with HAMD. To characterize and classify the features of this syndrome, the patient was asked to complete a 4-month diagnostic headache diary. There was a total of 15 ictal days. All episodes were without aura. The headache was more commonly pressing (10/15), mild to moderate in severity (14/15), unchanged by physical activity (11/15), and associated with photophobia (10/15). The International Headache Society Classification was utilized to determine that eight episodes met criteria for probable migraine without aura, while seven episodes met criteria for probable frequent episodic tension-type headache. We identified four other case reports of HAMD with partial descriptions of the characteristics. When combined with our patient, the median age was 34 years old (range 6–49, SD 16). Four were female, while the patient with cluster headache was male. The median time from headache onset to diagnosis with moyamoya disease was 9.5 months (range 0–192, SD 88.0). Headaches were described as migraine with aura in two of five cases, hemiplegic migraine in one of five, and cluster headache in one of five. The highest intensity was described as severe in three of three cases, in which headache intensity was reported. Meanwhile, nausea, vomiting, and photophobia were present in two of three cases, where these features were reported, while nausea without vomiting was seen in one of three cases. In all five cases, patients had other neurological symptoms, such as paresis, seizures, visual disturbances, dysarthria, allodynia, ptosis, and unilateral restless leg syndrome. In conclusion, HAMD can present as migraine without aura. It can be the first presenting symptom of moyamoya disease. The headache features are not diagnostic; hence, early neurovascular imaging should be considered in patients with new onset, refractory migraine-like headache, especially in the setting of other neurological symptoms to exclude underlying moyamoya disease. Further reports using headache diaries are needed to better characterize HAMD as well as to determine whether headache with tension-type features is also part of this condition.
doi:10.1007/s10194-009-0181-8
PMCID: PMC3452187  PMID: 20012551
Moyamoya; Headache; Migraine; Cluster; Diagnosis
16.  The relation of sexual function to migraine-related disability, depression and anxiety in patients with migraine 
Background
Depression and anxiety are two phenomena that affect quality of life as well as sexual function. Depression and anxiety levels are reported to be high in migraine sufferers. We aimed to understand whether sexual function in women with migraine was associated to migraine-related disability and frequency of migraine attacks, and whether this relationship was modulated by depressive and anxiety symptoms.
Methods
As migraine is more commonly seen in females, a total of 50 women with migraine were included. The diagnosis of migraine with or without aura was confirmed by two specialists in Neurology, according to the second edition of International Headache Society (IHS) International Classification of Headache Disorders (ICHD-II) in 2004. Migraine disability assessment scale score, female sexual function index scores, Beck depression inventory score and Beck anxiety inventory scores.
Results
Mean MIDAS score was 19.3 ± 12.8, and mean number of migraine attacks per month were 4.3 ± 2.7. Mean Female Sexual Function Index score was 20.9 ± 5.9 and 90% of patients had sexual dysfunction. Sexual dysfunction was not related to MIDAS score or frequency and severity of attacks. No relationship between sexual function and anxiety was found, whereas severity of depressive symptoms was closely related to sexual function. Depressive symptoms affected all dimensions of sexual function, except for pain.
Conclusion
Sexual dysfunction seemed to be very common in our patients with migraine, while not related to migraine related disability, frequency of attacks and migraine severity or anxiety. The most important factor that predicted sexual function was depression, which was also independent of disease severity and migraine related disability. While future larger scale studies are needed to clarify the exact relationship, depressive and sexual problems should be properly addressed in all patients with migraine, regardless of disease severity or disability.
doi:10.1186/1129-2377-15-32
PMCID: PMC4046390  PMID: 24884652
Migraine; Sexual dysfunction; Migraine related disability; Depression; Anxiety
17.  Comparison of oxidative stress among migraineurs, tension-type headache subjects, and a control group 
Background:
A primary headache, particularly migraine, is associated with oxidative stress during the attack. However, data regarding the interictal state in migraineurs and in those with tension-type headache (TTH) is limited.
Objectives:
(1) To assess the oxidative stress in migraineurs and TTH subjects in between the episodes and (2) to see if there is a difference in the degree of oxidative stress in the different subtypes of migraine and TTH.
Materials and Methods:
Fifty migraineurs, 50 patients with TTH, and 50 control subjects were included in this study after screening for the exclusion criteria. Diagnosis of headache was made according to the International Classification of Headache Disorders (ICHD)-2 criteria. A venous blood sample was collected from the antecubital vein at least 3 days after the last attack of headache. The sample was centrifuged immediately and the plasma was stored at –70°C. The ferric reducing activity of plasma (FRAP) and the malondialdehyde (MDA) levels were assessed using colorimetric methods. Statistical analysis was done with the help of SPSS for Windows, v 11.0. One way ANOVA with post hoc Tukey test, independent sample t test, univariate regression, and multivariate regression analysis were done as indicated.
Results:
Migraineurs had higher values of MDA and FRAP than the subjects in the other two groups (P<0.001). No difference was observed between the TTH group and the control group. FRAP levels were significantly higher in subjects who had mixed migraine (migraine with aura and without aura) as compared to those with only migraine without aura (mean difference 196.1; 95% CI = 27.3 to 364.9; P = 0.01). Similarly, oxidative stress was significantly higher in patients with episodic TTH as compared to those with chronic TTH (FRAP t = 3.16; P = 0.003 and MDA t = 2.75; P = 0.008).
Conclusions:
This study suggests that oxidative stress continues even between headache episodes in migraineurs but not in those with TTH. This could probably be consequent to the different pathophysiological mechanisms of TTH and migraine.
doi:10.4103/0972-2327.56316
PMCID: PMC2824933  PMID: 20174497
Migraine; tension type headache; oxidative stress; ferric reducing activity of plasma; malondialdehyde
18.  Migraine: is it related to hormonal disturbances or stress? 
Background
Common neurological syndrome (migraine without aura) is more common among women than men. Migraine is among the top 20 causes of disability. Menstruation is known to be a powerful trigger for migraine, and so is stress, but the presentation of headache is similar in both. Also, women are more vulnerable to stress as well as migraine, and this makes a complex relationship of menstruation, stress, and migraine.
Objective
This study was done to understand the association of hormonal fluctuation in menstruation and stress with common migraine.
Materials and methods
A cross-sectional comparative study was conducted in 40 young adult females, of whom 20 participants were cases of migraine without aura (18–35 years old), and the remaining 20 participants were age-matched controls. The study was done in Maulana Azad Medical College, New Delhi. Study participants were selected on the basis of International Headache Society (ICHD-IIA1.1) (2004) classification. Study participants with neurological disorders, chronic diseases, and disease suggestive of any hormonal disturbances were excluded. Clinically diagnosed migraine cases were asked to maintain a headache diary and to fill in the Depression Anxiety Stress Scales questionnaire. Biochemical assessment of hormonal status for thyroid-stimulating hormone, triiodothyronine, thyroxine, estrogen, follicle-stimulating hormone, luteinizing hormone, and prolactin was also done on the second day of their menstrual cycle. We used the Mann–Whitney U test to compare hormonal levels and the χ2 test to compare anxiety- or depression-related stress among the migraine and nonmigraine groups.
Results
Significantly higher values of prolactin were observed in cases (mean ± standard deviation, 152.7 mIU/L±30.5) compared to controls (76.1 mIU/L±8.7), with a P-value <0.001. There was no statistically significant difference observed in levels of thyroid-stimulating hormone (P=0.081), estrogen (P=0.086), luteinizing hormone (P=0.091), or follicle-stimulating hormone (P=0.478). Also, anxiety with stress or depression with stress was significantly higher among the migraine group than the controls (P=0.002). Odds of any stress in migraine were higher in the migraine group than in the nonmigraine group (odds ratio 12, 95% confidence interval 2.7–53.33).
Conclusion
Migraine, particularly without aura, in women is mainly associated with stress-related anxiety or depression, and are more susceptible to stress in the premenstrual period.
Video abstract
doi:10.2147/IJWH.S62922
PMCID: PMC4216045  PMID: 25368535
migraine; menstruation; stress
19.  Association of benign recurrent vertigo and migraine in 208 patients 
The aim of this study was to determine the association of benign recurrent vertigo (BRV) and migraine, using standardized questionnaire-based interview of 208 patients with BRV recruited through a University Neurotology clinic. Of 208 patients with BRV, 180 (87%) met the International Classification of Headache Disorders 2004 criteria for migraine: 112 migraine with aura (62%) and 68 without aura (38%). Twenty-eight (13%) did not meet criteria for migraine. Among patients with migraine, 70% experienced headache, one or more auras, photophobia, or auditory symptoms with some or all of their vertigo attacks, meeting the criteria for definite migrainous vertigo. Thirty per cent never experienced migraine symptoms concurrent with vertigo attacks. These met criteria for probable migrainous vertigo. Among patients without migraine, 21% experienced either photophobia or auditory symptoms with some or all of their vertigo attacks; 79% experienced only isolated vertigo. The age of onset and duration of vertigo attacks did not differ significantly between patients with (34 ± 1.2 years) and patients without migraine (31 ± 3.0 years). In patients with migraine, the age of onset of migraine headache preceded the onset of vertigo attacks by an average of 14 years and aura preceded vertigo by 8 years. The most frequent duration of vertigo attacks was between 1 h and 1 day. Benign recurrent vertigo is highly associated with migraine, but a high proportion of patients with BRV and migraine never have migraine symptoms during their vertigo attacks. Other features such as age of onset and duration of vertigo are similar between patients with or without migraine.
doi:10.1111/j.1468-2982.2008.01770.x
PMCID: PMC2820365  PMID: 19170697
20.  Cranial autonomic symptoms in pediatric migraine are the rule, not the exception 
Neurology  2013;81(5):431-436.
Objective:
The presence of cranial autonomic symptoms often leads to a misdiagnosis of “sinus headache” in adult migraineurs, leading to unnecessary treatments and delaying appropriate migraine therapy. In this study, we examined the frequency of cranial autonomic symptoms in pediatric/adolescent patients with migraine.
Methods:
This cross-sectional study included all pediatric and adolescent patients with migraine evaluated by a single investigator at 4 different sites over the course of the study period.
Results:
Of 125 pediatric migraineurs, 62% had at least one cranial autonomic symptom based on current International Classification of Headache Disorders, second edition (ICHD-II) criteria, and 70% based on proposed ICHD-III criteria. The majority had more than one cranial autonomic symptom and the symptoms tended to be bilateral. Age, sex, laterality of headache, presence of aura, and whether migraine was episodic vs chronic did not influence the likelihood of having cranial autonomic symptoms.
Conclusions:
In pediatric/adolescent migraine, the presence of cranial autonomic symptoms appears to be the rule rather than the exception. Clinicians should be careful to consider migraine when evaluating a child with headache and associated ocular or nasal symptoms so as to avoid giving a misdiagnosis of sinus headache.
doi:10.1212/WNL.0b013e31829d872a
PMCID: PMC3776532  PMID: 23897870
21.  Short-term diagnostic stability of probable headache disorders based on the International Classification of Headache Disorders, 3rd edition beta version, in first-visit patients: a multicenter follow-up study 
Background
A “Probable headache disorder” is diagnosed when a patient’s headache fulfills all but one criterion of a headache disorder in the 3rd beta edition of the International Classification of Headache Disorder (ICHD-3β). We investigated diagnostic changes in probable headache disorders in first-visit patients after at least 3 months of follow-up.
Methods
This was a longitudinal study using a prospective headache registry from nine headache clinics of referral hospitals. The diagnostic change of probable headache disorders at baseline was assessed at least 3 months after the initial visit using ICHD-3β.
Results
Of 216 patients with probable headache disorders at baseline, the initial probable diagnosis remained unchanged for 162 (75.0 %) patients, while it progressed to a definite diagnosis within the same headache subtype for 45 (20.8 %) by fulfilling the criteria during a median follow-up period of 6.5 months. Significant difference on the proportions of constant diagnosis was not found between headache subtypes (P < 0.935): 75.9 % for probable migraine, 73.7 % for probable tension-type headache (TTH), and 76.0 % for probable other primary headache disorders (OPHD). Among patients with headache recurrence, the proportion of constant diagnosis was higher for probable migraine than for probable TTH plus probable OPHD (59.2 vs. 23.1 %; P < 0.001). The proportions of constant diagnosis did not significantly differ by follow-up duration (>3 and ≤ 6 months vs. > 6 and ≤ 10 months) in probable migraine, probable TTH, and probable OPHD, respectively.
Conclusions
In this study, a probable headache diagnosis, based on ICHD-3β, remained in approximately three-quarters of the outpatients; however, diagnostic stability could differ by headache recurrence and subtype. Probable headache management might have to consider these differences.
doi:10.1186/s10194-016-0605-1
PMCID: PMC4759261  PMID: 26892842
Headache; Migraine; Tension-type headache; Tracking; Stability; Probable diagnosis
22.  Transcutaneous supraorbital neurostimulation in “de novo” patients with migraine without aura: the first Italian experience 
Background
Transcutaneous supraorbital neurostimulation (tSNS) has been recently found superior to sham stimulation for episodic migraine prevention in a randomized trial. We evaluated both the safety and efficacy of a brief period of tSNS in a group of patients with migraine without aura (MwoA).
Methods
We enrolled 24 consecutive patients with MwoA experiencing a low frequency of attacks, which had never taken migraine preventive drugs in the course of their life. Patients performed a high frequency tSNS and were considered “compliant” if they used the tSNS for ≥ 2/3 of the total time expected. For this reason, four patients were excluded from the final statistical analysis. Primary outcome measures were the reduction migraine attacks and migraine days per month (p < 0.05). Furthermore, we evaluated the percentage of patients having at least 50 % reduction of monthly migraine attacks and migraine days. Secondary outcome measures were the reduction of headache severity during migraine attacks and HIT-6 (Headache Impact Test) rating as well as in monthly intake of rescue medication (p < 0.05). Finally, compliance and satisfaction to treatment and potential adverse effects related to tSNS have been evaluated.
Results
Between run-in and second month of tSNS treatment, both primary and secondary endpoints were met. Indeed, we observed a statistically significant decrease in the frequency of migraine attacks (p < 0.001) and migraine days (p < 0.001) per month. We also demonstrated at least 50 % reduction of monthly migraine attacks and migraine days in respectively 81 and 75 % of patients. Furthermore, a statistically significant reduction in average of pain intensity during migraine attacks (p = 0.002) and HIT-6 rating (p < 0.001) and intake of rescue medication (p < 0.001) has been shown. All patients showed good compliance levels and no relevant adverse events.
Conclusion
In patients experiencing a low frequency of attacks, significant improvements in multiple migraine severity parameters were observed following a brief period of high frequency tSNS. Therefore, tSNS may be considered a valid option for the preventive treatment of migraine attacks in patients who cannot or are not willing to take daily medications, or in whom low migraine frequency and/or intensity would not require pharmacological preventive therapies.
doi:10.1186/s10194-015-0551-3
PMCID: PMC4510103  PMID: 26197977
Migraine; Transcutaneous supraorbital neurostimulation; tSNS; Therapy; Cefaly
23.  Chronic Migraine – New Treatment Options 
Mædica  2014;9(4):401-404.
Chronic migraine (CM) is defined as headache occurring more than fifteen days/month for at least three consecutive months, with headache having the clinical features of migraine without aura for at least eight days per month.
Recently, new treatment options became available in chronic migraine patients.
Topiramate is effective in chronic migraine, in the presence or absence of medication overuse, and/or other migraine prophylaxis.
Efficacy of onabotulinumtoxin A as a preventive treatment of chronic migraine has been shown in the PREEMPT studies.
Occipital nerve stimulation (ONS) is an invasive treatment for refractory chronic headaches. ONS has encouraging results in refractory chronic migraine patients in commercially funded, multi-centre randomized trials.
PMCID: PMC4316889  PMID: 25705314
chronic migraine; topiramate; onabotulimumtoxin A; occipital nerve stimulation
24.  Visual migraine aura with or without headache: association with right to left shunt and assessment following transcutaneous closure 
Video abstract
Video
Background
Right to left shunting, usually caused by a patent foramen ovale (PFO), is associated with migraine and visual aura. It is unknown if patients who present with visual aura without headache behave similarly to those experiencing typical migraine headache with aura. The purpose of this study was to assess the prevalence of right to left shunting in patients who present with migraine aura without headache and evaluate the response to PFO closure.
Methods
The records of patients referred to the Interventional Cardiology program at the University of California at Los Angeles for suspected intracardiac right to left shunt were reviewed. Individuals with visual auras with or without migraine headaches were divided into three groups: group A (aura + migraine), migraine aura during or within 60 minutes of headache; group B (migraine aura unrelated to headache), migraine aura and headache temporally unrelated; and group C (migraine aura only), isolated migraine visual aura without a history of headaches. The presence of right to left shunt was assessed using transcranial Doppler with an agitated saline test. PFO closure was performed in 80 patients. Residual headache and migraine visual aura were assessed 3 and 12 months after the procedure. The control group consisted of 200 patients referred for diagnostic cardiac catheterization.
Results
Of 590 referred patients, 225 had migraine visual aura with or without headache. The prevalence of right to left shunt was similar (P = 0.66) in groups B (21/29, 72%) and C (14/21, 67%). Group A patients had a higher prevalence of right to left shunt (168/175, 96%) due to selection bias. The prevalence of right to left shunt in the control group was significantly (P < 0.0001) lower (36/200, 18%) than in groups A, B, and C. At 12 months after PFO closure, visual aura was resolved in 52%, 75%, and 80% of patients in groups A, B, and C, respectively (difference not statistically significant).
Conclusion
There is an increased prevalence of PFO among patients with migraine aura without headache. The closure of PFO correlates with improvement of the visual aura, suggesting a causative association between the presence of PFO and both visual aura and migraine headaches. Ophthalmologists should be aware of the association of right to left shunts with visual aura.
doi:10.2147/OPTH.S30999
PMCID: PMC3413347  PMID: 22888208
visual aura without headache; right to left shunt; patent foramen ovale
25.  European headache federation consensus on technical investigation for primary headache disorders 
The diagnosis of primary headache disorders is clinical and based on the diagnostic criteria of the International Headache Society (ICHD-3-beta). However several brain conditions may mimic primary headache disorders and laboratory investigation may be needed. This necessity occurs when the treating physician doubts for the primary origin of headache. Features that represent a warning for a possible underlying disorder causing the headache are new onset headache, change in previously stable headache pattern, headache that abruptly reaches the peak level, headache that changes with posture, headache awakening the patient, or precipitated by physical activity or Valsalva manoeuvre, first onset of headache ≥50 years of age, neurological symptoms or signs, trauma, fever, seizures, history of malignancy, history of HIV or active infections, and prior history of stroke or intracranial bleeding. All national headache societies and the European Headache Alliance invited to review and comment the consensus before the final draft. The consensus recommends brain MRI for the case of migraine with aura that persists on one side or in brainstem aura. Persistent aura without infarction and migrainous infarction require brain MRI, MRA and MRV. Brain MRI with detailed study of the pituitary area and cavernous sinus, is recommended for all TACs. For primary cough headache, exercise headache, headache associated with sexual activity, thunderclap headache and hypnic headache apart from brain MRI additional tests may be required. Because there is little and no good evidence the committee constructed a consensus based on the opinion of experts, and should be treated as imperfect.
doi:10.1186/s10194-016-0596-y
PMCID: PMC4747925  PMID: 26857820
Primary headache disorders; Migraine; Tension-type headache; TACs; Consensus; Diagnostic tests; Brain MRI

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