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1.  Features of migraine aura in teenagers 
Complex migraine aura in teenagers can be complicated to diagnose. The aim of this study was to present detailed features of migraine aura in teenage migraineurs.
This cross-sectional study was conducted in the period from 2008 till 2013. A total number of 40 teenage migraineurs (20 females and 20 males) met criteria for this study. The patients were interviewed using a specially designed questionnaire for collecting data about migraine aura features. Main outcome measures were frequency of visual, somatosensory and higher cortical dysfunction (HCD) symptoms in teenage migraineurs population during the aura, and also within each individual.
Visual aura was reported in every attack, followed by somatosensory (60%) and dysphasic (36.4%) aura. Scintillating scotoma and blurry vision were mostly reported and predominant visual symptoms. The most common somatosensory symptom was numbness in hand. HCD were reported by 22 (55%) patients. Slowed speech was mostly reported symptom of HCD, followed by dyslexia, déjà vu phenomenon, color dysgnosia, and dyspraxia. In patients with HCD, aura frequency per year (6.18 ± 3.17 vs. 3.33 ± 2.03, p = 0.003) and prevalence of somatosensory symptoms (77.3% vs. 38.9%, p = 0.014) were significantly higher than in patients without HCD.
Aura symptoms vary to a great extent in complexity in teenage migraineurs. Consequently, results obtained in this study provide useful information for clinicians when faced with unusual migraine aura.
PMCID: PMC4273684  PMID: 25496701
Migraine aura; Higher cortical dysfunction; Teenagers
2.  The global burden of headache in children and adolescents – developing a questionnaire and methodology for a global study 
Burden of headache has been assessed in adults in countries worldwide, and is high, but data for children and adolescents are sparse. The objectives of this study were o develop a questionnaire and methodology for the global estimation of burden of headache in children and adolescents, to test these in use and to present preliminary data.
We designed structured questionnaires for mediated-group self-administration in schools by children aged 6-11 years and adolescents aged 12-17 years. In two pilot studies, we offered the questionnaires to pupils in Vienna and Istanbul. We performed face-to-face interviews in a randomly selected subsample of 199 pupils to validate the headache diagnostic questions.
Data were collected from 1,202 pupils (mean 13.9 ± 2.4 years; 621 female, 581 male). The participation rate was 81.1% in Istanbul, 67.2% in Vienna. The questionnaire proved acceptable: ≤5% of participants disagreed partially or totally with its length, comprehensibility or simplicity. The sensitivity, specificity, positive and negative predictive values ranged between 0.71 and 0.76 for migraine and between 0.61 and 0.85 for tension-type headache (TTH). Cronbach’s alpha was 0.83. The 1-year prevalence of headache was 89.3%, of migraine 39.3% and of TTH 37.9%. The prevalence of headache on ≥15 days/month was 4.5%. One fifth (20.7%) of pupils with headache lost ≥1 day of school during the preceding 4 weeks and nearly half (48.8%) reported ≥1 day when they could not do activities they had wanted to. The vast majority of pupils with headache experienced difficulties in coping with headache and in concentrating during headache. Quality of life was poorer in pupils with headache than in those without.
These pilot studies demonstrate the usefulness of the questionnaires and feasibility of the methodology for assessing the global burden of headache in children and adolescents, and predict substantial impact of headache in these age groups.
PMCID: PMC4273720  PMID: 25496532
Migraine; Tension-type headache; Burden of headache; Quality of life; Global campaign against headache
3.  Theory-based analysis of clinical efficacy of triptans using receptor occupancy 
Triptans, serotonin 5-HT1B/1D receptor agonists, exert their action by targeting serotonin 5-HT1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans.
To evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUCcp) and the areas under the time curves for Ф1B and Ф1D (AUCФ1B and AUCФ1D). Moreover, parameters expressing drug transfer and binding rates (A cp , A Ф 1B , A Ф 1D ) were calculated.
Our calculations showed that Фmax1B and Фmax1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUCcp, AUCΦ1B, AUCΦ1D, and A cp  · AUCcp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and A Φ 1B  · AUCΦ1B or A Φ 1D  · AUCΦ1D that was not affected by the drug and the form of administration.
These results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.
PMCID: PMC4273730  PMID: 25488888
Triptans; Serotonin 5-HT1B/1D receptor agonists; Receptor occupancy; Migraine
4.  Magnetic suppression of perceptual accuracy is not reduced in episodic migraine without aura 
Altered cortical excitability is thought to be part of migraine pathophysiology. Reduced magnetic suppression of perceptual accuracy (MSPA) has been found in episodic migraine with aura and in chronic migraine, and has been interpreted as reduced inhibition of the occipital cortex in these migraine subtypes. Results are less clear for episodic migraine without aura. In the present study we compared MSPA between 24 healthy controls and 22 interictally measured episodic migraine patients without aura. In addition, we investigated test-retest reliability in 33 subjects (24 controls, 9 migraine).
Visual accuracy was assessed by letter recognition and modulated by transcranial magnetic stimulation delivered to the occipital cortex at different intervals to the letter presentation (40, 100 and 190 ms). The results confirm suppression of visual accuracy at the 100 ms interval (p < 0.001), but there were no significant group differences (percentage of correctly recognized letters, control: 36.1 ± 36.2; migraine: 44.0 ± 32.3, p = 0.44). Controls and migraine patients were pooled for assessment of test-retest reliability (n = 33). Levels of suppression at 100 ms were similar at test (percentage of correctly recognized letters: 42.3 ± 32.6) and retest (41.9 ± 33.8, p = 0.90) and test-retest correlations were good (r = 0.82, p < 0.001).
The results demonstrate that occipital cortex inhibition as assessed with MSPA is not reduced in episodic migraine without aura. This suggests a larger role of occipital cortex excitability in episodic migraine with aura and in chronic migraine compared to episodic migraine without aura. Test-retest reliability of MSPA was good.
PMCID: PMC4273691  PMID: 25471445
Magnetic suppression of perceptual accuracy; Transcranial magnetic stimulation; Migraine; Cortical excitability; Test-retest reliability
5.  The relationship between headache and religious attendance (the Nord-Trøndelag health study- HUNT) 
Religious belief can be used as a pain coping strategy. Our purpose was to evaluate the relationship between headache and religious activity using prospective data from a large population-based study.
This longitudinal cohort study used data from two consecutive surveys in the Nord-Trøndelag Health Survey (HUNT 2 and 3) performed in 1995–1997; and 2006–2008. Among the 51,383 participants aged ≥ 20 years who answered headache questions at baseline, 41,766 were eligible approximately 11 years later. Of these, 25,177 (60%) completed the question in HUNT 3 regarding religious activity. Frequent religious attendees (fRA) (used as a marker of stronger religious belief than average) were defined as those who had been to church/prayer house at least once monthly during the last six months.
In the multivariate analyses, adjusting for known potential confounders, individuals with headache 1–14 days/month in HUNT 2 were more likely to be fRA 11 years later than headache-free individuals. Migraine at baseline predisposed more strongly to fRA at follow-up (OR = 1.25; 95% CI 1.19-1.40) than did non-migrainous headache (OR = 1.13; 95% 1.04-1.23). The odds of being fRA was 48% increased (OR 1.48; 95% 1.19-1.83) among those with migraine 7–14 days/month at baseline compared to subjects without headache. In contrast, headache status at baseline did not influence the odds of being frequent visitors of concerts, cinema and/or theatre at follow-up 11 years later.
In this prospective study, headache, in particular migraine, at baseline slightly increased the odds of being fRA 11 years later.
PMCID: PMC3880847  PMID: 24386923
Epidemiology; Religion; Spirituality; Headache; Migraine
6.  Acknowledgements to referees 2013 
Contributing reviewers
The quality of The Journal of Headache and Pain depends on the qualified and regular collaboration of renowned scientists, who devoted their time to constructively review the submitted articles.
We are indebted to the following experts who reviewed papers that completed the peer-reviewing process within 2013.
PMCID: PMC3904204  PMID: 24472416
7.  Gender differences of cognitive function in migraine patients: evidence from event-related potentials using the oddball paradigm 
Migraine shows gender-specific incidence and has a higher prevalence in females. Gender plays an important role in the prevalence of migraine, but few studies have investigated the effect of gender on the cognitive functions of migraine patients. This study investigated gender differences in the cognitive function of migraine patients without aura.
We recruited 29 migraine patients (15 females; mean age 25.4 y) during the interictal period and 28 healthy age-matched participants (14 females; mean age 24.8 y). We used an auditory oddball paradigm to analyze target processing using event-related potentials.
We investigated the N2 and P3 components. The P3 amplitude was decreased in patients compared with the control, and this reduction was not modulated by gender. These results of the P3 provided a new evidence for the dysfunction of cognitive function in migraine patients. The N2 amplitude was larger for male than female migraine patients, and this gender effect was not found in the control group.
These results of the P3 provided a new evidence for the dysfunction of cognitive function in migraine patients. And those of N2 may explain that male patients have the super-sensitivity of cerebral function relevant to the early target-selection and response preparation. Our findings emphasize the importance of considering gender when researching the cognitive function of migraine patients.
PMCID: PMC3904684  PMID: 24467625
Migraine; ERPs; P3; N2; Gender difference
9.  Diagnosis, prevalence estimation and burden measurement in population surveys of headache: presenting the HARDSHIP questionnaire 
The global burden of headache is very large, but knowledge of it is far from complete and needs still to be gathered. Published population-based studies have used variable methodology, which has influenced findings and made comparisons difficult. The Global Campaign against Headache is undertaking initiatives to improve and standardize methods in use for cross-sectional studies. One requirement is for a survey instrument with proven cross-cultural validity. This report describes the development of such an instrument. Two of the authors developed the initial version, which was used with adaptations in population-based studies in China, Ethiopia, India, Nepal, Pakistan, Russia, Saudi Arabia, Zambia and 10 countries in the European Union. The resultant evolution of this instrument was reviewed by an expert consensus group drawn from all world regions. The final output was the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, designed for application by trained lay interviewers. HARDSHIP is a modular instrument incorporating demographic enquiry, diagnostic questions based on ICHD-3 beta criteria, and enquiries into each of the following as components of headache-attributed burden: symptom burden; health-care utilization; disability and productive time losses; impact on education, career and earnings; perception of control; interictal burden; overall individual burden; effects on relationships and family dynamics; effects on others, including household partner and children; quality of life; wellbeing; obesity as a comorbidity. HARDSHIP already has demonstrated validity and acceptability in multiple languages and cultures. Modules may be included or not, and others (eg, on additional comorbidities) added, according to the purpose of the study and resources (especially time) available.
PMCID: PMC3906903  PMID: 24400999
Epidemiology; Burden of headache; Methodology; Diagnostic instrument; Global Campaign against Headache
10.  The methodology of population surveys of headache prevalence, burden and cost: Principles and recommendations from the Global Campaign against Headache 
The global burden of headache is very large, but knowledge of it is far from complete and needs still to be gathered. Published population-based studies have used variable methodology, which has influenced findings and made comparisons difficult. Among the initiatives of the Global Campaign against Headache to improve and standardize methods in use for cross-sectional studies, the most important is the production of consensus-based methodological guidelines. This report describes the development of detailed principles and recommendations. For this purpose we brought together an expert consensus group to include experience and competence in headache epidemiology and/or epidemiology in general and drawn from all six WHO world regions. The recommendations presented are for anyone, of whatever background, with interests in designing, performing, understanding or assessing studies that measure or describe the burden of headache in populations. While aimed principally at researchers whose main interests are in the field of headache, they should also be useful, at least in parts, to those who are expert in public health or epidemiology and wish to extend their interest into the field of headache disorders. Most of all, these recommendations seek to encourage collaborations between specialists in headache disorders and epidemiologists. The focus is on migraine, tension-type headache and medication-overuse headache, but they are not intended to be exclusive to these. The burdens arising from secondary headaches are, in the majority of cases, more correctly attributed to the underlying disorders. Nevertheless, the principles outlined here are relevant for epidemiological studies on secondary headaches, provided that adequate definitions can be not only given but also applied in questionnaires or other survey instruments.
PMCID: PMC3907133  PMID: 24467862
Burden of headache; Epidemiology; Guidelines; Methodology; Global Campaign against Headache
11.  Release of CGRP from mouse brainstem slices indicates central inhibitory effect of triptans and kynurenate 
CGRP is contained in a substantial proportion of unmyelinated trigeminal neurons innervating intracranial tissues. Previously, we have described a hemisected rodent scull preparation and later the intact trigeminal ganglion to measure stimulated CGRP release from trigeminal afferents.
Here, we establish a preparation for examining CGRP release from central trigeminal terminals using single fresh slices of the mouse medullary brainstem.
Basal and stimulated amount of CGRP substantially exceeded the detection level. Experiments were designed as matched pairs of at least six brainstem slices per animal. Stimulation with high potassium induced calcium-dependent and reversible CGRP release. Capsaicin stimulation of TRPV1 provoked concentration-dependent CGRP release. The anti-migraine drug naratriptan did not inhibit capsaicin-induced CGRP release from peripheral terminals but inhibited the release from brainstem slices. The glutamate antagonist kynurenate showed a similar pattern of site-specific inhibition of CGRP release.
As observed earlier for other drugs used in the treatment of migraine this indicates that the central terminals in the spinal trigeminal nucleus may be the main site of action. The preparation allows evaluating the trigeminal brainstem as a pharmacological site of action.
PMCID: PMC3922191  PMID: 24506953
Headache; Migraine; Neuropeptide; Nociception; 5-HT receptor
12.  Hemicrania continua: towards a new classification? 
Hemicrania continua (HC) was described and coined in 1984 by Sjaastad and Spierings. Later cases, carrying this appellation, should conform to the original description. The proposed classification criteria (ICHD 3rd edition beta version) for HC focus e.g. on localized, autonomic and “vascular” features. Such features do, however, not belong to the core symptomatology of HC and should accordingly be removed. The genuine, original HC will then re-appear.The headache that the new criteria refer to, has in an unfair and unjustified manner been given the designation HC. A revision of the proposed criteria seems mandatory.
PMCID: PMC3936800  PMID: 24524413
Hemicrania continua; Headache classification
13.  Should we educate about the risks of medication overuse headache? 
Medication-overuse headache (MOH) is caused by the regular use of medications to treat headache. There has been a lack of research into awareness of MOH. We distributed an electronic survey to undergraduate students and their contacts via social networking sites. Analgesic use, awareness of MOH, perceived change in behaviour following educational intervention about the risks of MOH and preferred terminology for MOH was evaluated.
485 respondents completed the questionnaire (41% having received healthcare training). 77% were unaware of the possibility of MOH resulting from regular analgesic use for headache. Following education about MOH, 80% stated they would reduce analgesic consumption or seek medical advice. 83% indicated that over the counter analgesia should carry a warning of MOH. The preferred terminology for MOH was painkiller-induced headache.
This study highlights the lack of awareness of MOH. Improved education about MOH and informative packaging of analgesics, highlighting the risks in preferred lay terminology (i.e. painkiller-induced headache), may reduce this iatrogenic morbidity and warrants further evaluation.
PMCID: PMC3942071  PMID: 24524380
Medication-overuse headache; Analgesia; Headache; Prevention; Education
14.  A common cause of sudden and thunderclap headaches: reversible cerebral vasoconstriction syndrome 
Thunderclap headache (TCH) is a sudden headache (SH) with accepted criteria of severe intensity and onset to peak within one minute. It is a well-known presentation for subarachnoid hemorrhage (SAH) but most patients with TCH or SH run a benign course without identifiable causes. Reversible cerebral vasoconstriction syndrome (RCVS), a recently recognized syndrome characterized by recurrent TCH attacks, has been proposed to account for most of these patients.
We recruited consecutive patients presenting with SH at our headache clinic. Computed tomography and/or magnetic resonance imaging with angiography were performed to exclude structural causes and to identify vasoconstriction. Catheter angiography and lumbar puncture were performed with patients consent. Reversibility of vasoconstriction was confirmed by follow-up study.
From July 2010 to June 2013, 31 patients with SH were recruited. Twenty-four (72.7%) of these SH patients exhibited headache fulfilling the TCH criteria. The diagnosis of RCVS was confirmed in 14 (45.2%) of patients with SH and 11 (45.8%) of patients with TCH. Other diagnoses were as follows: primary headaches (SH: 41.9%, TCH: 45.8%) and other secondary causes (SH: 12.9%, TCH: 8.3%). Compared with non-RCVS patients, patients with RCVS were older (50.8 ± 9.3 years vs. 40.8 ± 10.0 years, P = 0.006) and less likely to experience short headache duration of < 1 hour (23.1% vs. 78.6%, P = 0.007). Patients with RCVS were more likely to cite bathing (42.9% vs. 0%, P = 0.004) and less likely to cite exertion (0% vs. 29.4%, P = 0.048) as headache triggers.
Reversible cerebral vasoconstriction syndrome is a common cause of SH and TCH. Considering the potential mortality and morbidity of RCVS, systemic examination of cerebral vessels should be performed in these patients.
PMCID: PMC3973996  PMID: 24580731
Bath-related thunderclap headache; Orgasmic headache; Primary cough headache; Primary exertional headache; Primary headache associated with sexual activity; Reversible cerebral vasoconstriction syndrome; Sentinel headache; Sudden headache; Subarachnoid hemorrhage; Thunderclap headache
15.  Hemicrania continua- building on experience and clinical science 
This is a reply letter to Letter to the ‘Editor Hemicrania continua: towards a new classification?’ Fabio Antonaci and Ottar Sjaastad The Journal of Headache and Pain Citation: 2014, 15:8.
PMCID: PMC3974119  PMID: 24524422
16.  Erythema associated with pain and warmth on face and ears: a variant of erythermalgia or red ear syndrome? 
Erythermalgia is a rare cutaneous disorder characterized by attacking of erythema, pain and increased temperature, which primarily involves the extremities and may infrequently extend to the neck, face, ears and even the scrotum. We reported an 18-year-old woman who presented with 3 years history of sole involvement of attacking erythema, pain and warmth over her face and ears without any other associations. The frequency and severity of the flares progressed gradually during the course. Cutaneous examination revealed erythema, increased temperature and tenderness on the face and ears during the flare. The symptoms could be relieved rapidly by cooling. Dermatoscope showed that vessels inside the erythema were more dilated during the episode than after application of ice. The lesion is considered a rare variant of erythermalgia with sole involvement of face and ears. The symptoms had mild response to oral antihistamines, topical steroids and tacrolimus, but had excellent response to the combinative therapy of aspirin and paroxetins.
PMCID: PMC3976166  PMID: 24670221
Erythermalgia; Erythromelalgia; Ear; Face; Pain; Treatment; Variant
17.  The evolution of headache from childhood to adulthood: a review of the literature 
Headache is one of the most common disorders in childhood, with an estimated 75% of children reporting significant headache by the age of 15 years. Pediatric migraine is the most frequent recurrent headache disorder, occurring in up to 28% of older teenagers. Headaches rank third among the illness-related causes of school absenteeism and result in substantial psychosocial impairment among pediatric patients.
The aim of this study was to clarify the evolution of the clinical features of primary headache in the transition from childhood to adulthood through a review of relevant data available in the PubMed and Google Scholar databases for the period 1988 to July 2013.
The search strategy identified 15 published articles which were considered eligible for inclusion in the analysis (i.e. relevant to the investigation of pediatric headache outcome). All were carried out after the publication of the first version of the International Classification of Headache Disorders (ICHD-I).
The availability of data on the evolution of primary headaches over a period of time is important from both a clinical and a public health perspective. The identification of prognostic factors of the evolution of headache (remission or evolution into another headache form) over time should be an objective of future headache research for the development of prevention strategies. Given that headache is a major factor contributing to school absenteeism and poorer quality of life not only in childhood but also in adolescence, understanding the natural history and the management of the different headache forms is vital for our future.
PMCID: PMC3995299  PMID: 24641507
Migraine; Tension-type headache; Cluster headache; Childhood; Adolescence; Evolution
18.  Activation of CB2 receptors as a potential therapeutic target for migraine: evaluation in an animal model 
Experimental animal models of migraine have suggested the existence of interactions between the endocannabinoid system and pain mediation in migraine. Extensive evidence has demonstrated a role for the cannabinoid-1 (CB1) receptor in antinociception. However, recent research suggests that also CB2 receptors, especially located outside the central nervous system, play a role in the perception of pain. Systemic administration of nitroglycerin (NTG) consistently induces spontaneous-like headache attacks in migraneurs; in the rat, systemic NTG induces a condition of hyperalgesia, probably through the activation of cerebral/spinal structures involved in nociceptive transmission. In this study we evaluated the role of CB2 receptors in two animal models of pain that may be relevant for migraine: the tail flick test and the formalin test performed during NTG-induced hyperalgesia.
The study was performed in male Sprague-Dawley rats pre-treated with NTG (10 mg/kg, i.p.) or vehicle (4 hours before) and treated with the CB2 agonist AM1241 o dimethylsulfoxide (DMSO) 60 minutes before both the tail flick test and the formalin test.
AM1241 showed a significant analgesic effect in baseline conditions in both tests. Furthermore, when administered 3 hours after NTG administration, AM1241 at both doses significantly reduced the total number of flinches/shakes during phase II of the test.
These findings suggest that the pharmacological manipulation of the CB2 receptor may represent a potential therapeutic tool for the treatment of migraine.
PMCID: PMC3995520  PMID: 24636539
Migraine; Nitroglycerin; Hyperalgesia; CB2 agonist
19.  Headstrong intervention for pediatric migraine headache: a randomized clinical trial 
The purpose of this study was to evaluate the efficacy of a self-guided CD-ROM program (“Headstrong”) containing cognitive-behavioral self-management strategies versus an educational CD-ROM program for treating headaches, headache-related disability, and quality of life.
Participants were 35 children ages 7–12 years with migraine recruited from one university medical center and two children’s hospital headache clinics. Participants were randomly assigned to complete the Headstrong or educational control CD-ROM program over a 4-week period. Data on headache frequency, duration, and severity, migraine-related disability, and quality of life (QOL) were obtained at baseline, post-intervention, and 3-months post-intervention.
At post-intervention, Headstrong resulted in lower severity (on a 10-point scale) than the control group by child report (5.06 ± 1.50 SD vs. 6.25 ± 1.92 SD, p = 0.03, ES = 0.7). At 3-months post-intervention, parents reported less migraine-related disability (on the PedMIDAS) in the Headstrong group compared to the control group (1.36 ± 2.06 SD vs. 5.18 ± 6.40 SD; p = 0.04, ES = 0.8). There were no other group differences at post treatment or at 3-months post-intervention.
When compared to an educational control, Headstrong resulted in lower pain severity at post-treatment and less migraine-related disability at 3-months post-intervention, by child and parent report respectively. Headache frequency and quality of life did not change more for Headstrong versus control. Additional research is needed on the Headstrong Program to increase its efficacy and to test it with a larger sample recruited from multiple centers simultaneously.
PMCID: PMC3996073  PMID: 24580721
Headache; Children; Migraine; Behavioral treatments; E-health; CD-ROM; Child; Migraine headaches; Cognitive-behavioral treatment
20.  Ophthalmoplegia starting with a headache circumscribed in a line-shaped area: a subtype of ophthalmoplegic migraine? 
Recurrent painful ophthalmoplegic neuropathy (RPON), formerly named ophthalmoplegic migraine (OM), is a rare condition characterized by the association of unilateral headaches and the ipsilateral oculomotor nerve palsy. The third cranial nerve is most commonly involved in the recurrent attacks. But it is still debated whether a migraine or an oculomotor neuropathy may be the primary cause of this disorder. Here, we report an elder patient who had a recurrent ophthalmoplegia starting with an unilateral headache circumscribed in an area shaped in a line linking the posterior-parietal region and the ipsilateral eye. And the headache had couple of features similar to that of migraine, such as past history of recurrent migraine attacks, accompaniments of nausea, vomiting, and phonophobia, response to flunarizine and sodium valproate. We may herein report a subtype of OM but not a RPON. This case report indicates that OM may exist as an entity and some OM may be wrongly grouped under the category of RPON in the current international headache classification.
PMCID: PMC3996493  PMID: 24739597
Recurrent painful ophthalmoplegic neuropathy; Ophthalmoplegic migraine; Migraine; Epicrania fugax; Neuralgia
21.  Cuneus and fusiform cortices thickness is reduced in trigeminal neuralgia 
Chronic pain disorders are presumed to induce changes in brain grey and white matters. Few studies have focused CNS alterations in trigeminal neuralgia (TN).
The aim of this study was to explore changes in white matter microstructure in TN subjects using diffusion tensor images (DTI) with tract-based spatial statistics (TBSS); and cortical thickness changes with surface based morphometry. Twenty-four patients with classical TN (37-67 y-o) and 24 healthy controls, matched for age and sex, were included in the study.
Comparing patients with controls, no diffusivity abnormalities of brain white matter were detected. However, a significant reduction in cortical thickness was observed at the left cuneus and left fusiform cortex in the patients group. The thickness of the fusiform cortex correlated negatively with the carbamazepine dose (p = 0.023).
Since the cuneus and the fusiform gyrus have been related to the multisensory integration area and cognitive processing, as well as the retrieval of shock perception conveyed by Aδ fibers, our results support the role of these areas in TN pathogenesis. Whether such changes occurs as an epiphenomenon secondary to daily stimulation or represent a structural predisposition to TN in the light of peripheral vascular compression is a matter of future studies.
PMCID: PMC3997919  PMID: 24661349
Trigeminal neuralgia; MRI; Brain; Cortical thickness analysis; White matter; Diffusion tensor imaging
22.  Galeata: chronic migraine independently considered in a medieval headache classification 
Chronic migraine is a quite recent concept. However, there are descriptions suggestive of episodic migraine since the beginning of scientific medicine. We aim to review main headache classifications during Classical antiquity and compared them with that proposed in the 11th century by Constantine the African in his Liber Pantegni, one of the most influential texts in medieval medicine.
We have carried out a descriptive review of Henricum Petrum's Latin edition, year 1539.
Headache classifications proposed by Aretaeus of Cappadocia, Galen of Pergamun and Alexander of Tralles, all of them classifying headaches into three main types, considered an entity (called Heterocrania or Hemicrania), comparable to contemporary episodic migraine.
In ninth book of Liber Pantegni, headaches were also classified into three types and one of them, Galeata, consisted on a chronic pain of mild intensity with occasional superimposed exacerbations.
In Liber Pantegni we have firstly identified, as a separate entity, a headache comparable to that we currently define as chronic migraine: Galeata.
PMCID: PMC3998035  PMID: 24655582
Chronic migraine; Constantine the African; Galeata; Headache classifications
23.  Interferon beta-associated recurrence of painful trigeminal neuropathy attributed to a multiple sclerosis plaque 
We report the case of a 49-year-old woman with painful trigeminal neuropathy in the right maxillary division attributed to a multiple sclerosis plaque as the presenting symptom of multiple sclerosis. The patient was initially treated with intravenous corticosteroids and was pain free on pregabalin for six months. She was then started on an immunomodulatory treatment and coinciding with the up-titration of interferon beta-1a, she experienced recurrence of painful trigeminal neuropathy as well as weekly migraine attacks. Worsening of primary headache disorders by interferon treatment has been previously reported. Our case suggests that treatment with interferon beta may also exacerbate symptomatic trigeminal neuralgia in multiple sclerosis.
PMCID: PMC4005472  PMID: 24742132
Trigeminal neuralgia; Multiple sclerosis; Interferon
24.  Comparison of the vasodilator responses of isolated human and rat middle meningeal arteries to migraine related compounds 
Migraine attacks occur spontaneously in those who suffer from the condition, but migraine-like attacks can also be induced artificially by a number of substances. Previously published evidence makes the meninges a likely source of migraine related pain. This article investigates the effect of several vasodilators on meningeal arteries in order to find a connection between the effect of a substance on a meningeal vessel and its ability to artificially induce migraine.
A myograph setup was used to test the vasodilator properties of the substances acetylcholine (ACh), sodium nitroprusside (SNP), sildenafil, prostaglandin E2 (PGE2), pituitary adenylate cyclase activating peptide-38 (PACAP-38), calcitonin gene-related peptide (CGRP) and NaCl buffer on meningeal arteries from human and rat. An unpaired t-test was used to statistically compare the mean Emax(%) at the highest concentration of each substance to the Emax(%) of NaCl buffer.
In the human experiments, all substances except PACAP-38 had an Emax (%) higher than the NaCl buffer, but the difference was only significant for SNP and CGRP. For the human samples, clinically tested antimigraine compounds (sumatriptan, telcagepant) were applied to the isolated arteries, and both induced a significant decrease of the effect of exogenously administrated CGRP. In experiments on rat middle meningeal arteries, pre-contracted with PGF2α, similar tendencies were seen. When the pre-contraction was switched to K+ in a separate series of experiments, CGRP and sildenafil significantly relaxed the arteries.
Still no definite answer can be given as to why pain is experienced during an attack of migraine. No clear correlation was found between the efficacy of a substance as a meningeal artery vasodilator in human and the ability to artificially induce migraine or the mechanism of action. Vasodilatation could be an essential trigger, but only in conjunction with other unknown factors. The vasculature of the meninges likely contributes to the propagation of the migrainal cascade of symptoms, but more research is needed before any conclusions can be drawn about the nature of this contribution.
PMCID: PMC4011837  PMID: 24754925
Vasodilation; Middle meningeal artery; Migraine; CGRP
25.  The impact of depression and ghrelin on body weight in migraineurs 
Comorbidity of migraine with anxiety and depression may play a role in the link between migraine and obesity. We examined the moderating and mediating roles of ghrelin in the relationship between depression (and anxiety) and body weight in newly diagnosed migraineurs.
Participants were 63 newly diagnosed migraine patients (using the ICHD-II criteria) and 42 healthy volunteers. Body mass index (BMI) was calculated by measuring height and weight. Ghrelin was assessed at fasting. Depression was assessed with the Hamilton Depression scale, and anxiety with the Hamilton Anxiety scale.
The data did not support the mediating role of ghrelin in the relationship between depression (or anxiety) and BMI for either the migraine or the control group. The interaction between ghrelin and depression as well as anxiety was significant for the migraine group, but not for the control group. Depressed (or anxious) migraineurs had a positive association between ghrelin and BMI, whereas for the non-depressed (or non-anxious) migraineurs this association was negative.
Depression and anxiety moderated the effect of ghrelin on BMI for migraineurs. Management of anxiety and depression might be regarded as part of migraine treatment.
PMCID: PMC4016645  PMID: 24762133
Body weight; Ghrelin; Migraine; Psychiatric comorbidity; Depression; Anxiety

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