Cephalalgia

Migraine is a neurological disease involving recurrent attacks of moderate-to-severe and disabling head pain. Worsening of pain with routine physical activity during attacks is a principal migraine symptom; however, the frequency, individual consistency, and correlates of this symptom are unknown. Given the potential of this symptom to undermine participation in daily physical activity, an effective migraine prevention strategy, further research is warranted. This study is the first to prospectively evaluate (a) frequency and individual consistency of physical activity-related pain worsening during migraine attacks, and (b) potential correlates, including other migraine symptoms, anthropometric characteristics, psychological symptoms, and daily physical activity.

Participants were women (n = 132) aged 18–50 years with neurologist-confirmed migraine and overweight/obesity seeking weight loss treatment in the Women’s Health and Migraine trial. At baseline, participants used a smartphone diary to record migraine attack occurrence, severity, and symptoms for 28 days. Participants also completed questionnaires and 7 days of objective physical activity monitoring before and after diary completion, respectively. Patterning of the effect of physical activity on pain was summarized within-subject by calculating the proportion (%) of attacks in which physical activity worsened, improved, or had no effect on pain.

Participants reported 5.5 ± 2.8 (mean ± standard deviation) migraine attacks over 28 days. The intraclass correlation (coefficient = 0.71) indicated high consistency in participants’ reports of activity-related pain worsening or not. On average, activity worsened pain in 34.8 ± 35.6% of attacks, had no effect on pain in 61.8 ± 34.6% of attacks and improved pain in 3.4 ± 12.7% of attacks. Few participants (9.8%) reported activity-related pain worsening in all attacks. A higher percentage of attacks where physical activity worsened pain demonstrated small-sized correlations with more severe nausea, photophobia, phonophobia, and allodynia (r = 0.18 – 0.22, p < 0.05). Pain worsening due to physical activity was not related to psychological symptoms or total daily physical activity.

There is large variability in the effect of physical activity on pain during migraine attacks that can be accounted for by individual differences. For a minority of participants, physical activity consistently contributed to pain worsening. More frequent physical activity-related pain worsening was related to greater severity of other migraine symptoms and pain sensitivity, which supports the validity of this diagnostic feature.

ClinicalTrials.govIdentifier: NCT01197196

According to the neurovascular theory of migraine, activation of the trigeminovascular system contributes to the development of migraine. This study examined the effects of chronic intraperitoneal ghrelin (150 µg/kg) treatment on the development of chronic migraine induced by intermittent injection of nitroglycerin 10 mg/kg.

Baseline and post-drug (2 h following nitroglycerin injection) mechanical and thermal sensitivity were assessed by von Frey hair and tail immersion tests, respectively on days 1, 3, 5, 7, 9 and 11. Moreover, we investigated the effect of ghrelin treatment on nitroglycerin-induced aversive behavior by using a two-chamber conditioned place aversion paradigm. At the end of behavioral testing, on day 11, animals were sacrificed and plasma concentration of calcitonin gene-related peptide was measured using a rat-specific enzyme-linked immunosorbent assay kit. Also, real time polymerase chain reaction was used to quantify mRNA expression of calcitonin gene-related peptide and transient receptor potential vanilloid 1 in the trigeminal ganglion.

Our results indicated that nitroglycerin activated the trigeminovascular system, which was reflected by mechanical and thermal hypersensitivity and elevation of mRNA expression of calcitonin gene-related peptide and transient receptor potential vanilloid-1, as migraine markers, and plasma calcitonin gene-related peptide levels. Moreover, chronic nitroglycerin injection induced conditioned place aversion and body weight loss. Nevertheless, ghrelin modulated nitroglycerin-triggered changes in transient receptor potential vanilloid-1 and calcitonin gene-related peptide expression, and mitigated nitroglycerin-induced hyperalgesia.

These results provide the first convincing evidence that ghrelin has a modulating effect on central sensitization induced by chronic intermittent nitroglycerin, and its antinociceptive effect may be related to a reduction of these factors in the trigeminal ganglion.

To investigate the intranetwork resting state fMRI connectivity within the Salience Network of chronic migraine with and without medication overuse headache.

We compared 351 pairs of intranetwork connectivity in chronic migraine (n = 13) and chronic migraine with medication overuse headache (n = 16) compared to matched controls, and between each chronic migraine subgroup.

Compared to controls, 17 pairs of intranetwork connections in chronic migraine and 27 pairs in chronic migraine with medication overuse headache were decreased. When comparing chronic migraine with medication overuse headache versus chronic migraine, connectivity between bilateral extended amygdala, and between paracingulate to right ventral tegmental area/substantia nigra were decreased in chronic migraine (chronic migraine < chronic migraine with medication overuse headache). Connectivity between left dorsolateral prefrontal cortex to bilateral ventral striatum/pallidum, to bilateral dorsal anterior cingulate cortex; left anterior prefrontal cortex to contralateral orbitofrontal insula; and left ventral striatum/pallidum to ipsilateral supplementary motor area (SMA)/preSMA were decreased in chronic migraine with medication overuse headache (chronic migraine with medication overuse headache < chronic migraine).

Both chronic migraine subgroups had shared intranetwork connectivity abnormality, however, each subgroup had unique pattern of disruption within the salience network. The results suggest that the aberrant assignment of salience to external and internal stimuli plays an important role in chronic migraine and chronic migraine with medication overuse headache interictally, mostly involving mesolimbic pathways (especially bilateral extended amygdala) in chronic migraine, and prefrontal-subcortical limbic pathways in chronic migraine with medication overuse headache.

In children and adolescents, the prevalence rate of migraine with aura is 1.6%. Few studies concerning migraine with aura features in paediatric population have been reported.

The aim of our study was to investigate clinical features of aura in a retrospective cohort of children with migraine with aura. Furthermore, we studied whether the International Classification of Headache Disorder (ICHD) 3 beta version criteria could efficiently detect migraine with aura in a paediatric population.

We included 164 patients who experienced aura associated with headache (mean age 9.92 ± 2.64 years). When the ICHD-II criteria were used, a final diagnosis of migraine with typical aura was obtained in 15.3% of patients, probable migraine with typical aura in 13.4%, and typical aura with headache in 61.8%, while in in 9.5% of patients the diagnosis was undetermined. According to ICHD-3 beta, we diagnosed migraine with typical aura in 77.7% of patients, probable migraine with typical aura in 13.4%, and an undetermined diagnosis in 9.5% (less than two attacks).

Aura features did not depend on age and were similar to those of adults. However, the headache could be difficult to classify if headache duration was considered. In this view, the ICHD-3 beta offers the advantage of not considering headache features, including pain duration, for the diagnosis of migraine with typical aura, thus making this diagnosis easier in children and adolescents.

Sarcoma family kinase activity is associated with multiple diseases including ischemia and cancer; however, its role in the mechanism of migraine aura has been less well characterised. This study aims to investigate whether sarcoma family kinase is required for cortical spreading depression.

Cortical spreading depression was induced by topical application of K⁺ to the cerebral cortex and was monitored using electrophysiology in rats, and intrinsic optical signal in mouse brain slices. Drugs were perfused into the contralateral cerebral ventricle for pharmacological manipulations in rats. Western blot analysis was used for detecting the level of phosphorylated, and total, sarcoma family kinase in the ipsilateral cortex of rats.

The data demonstrate that a single cortical spreading depression in rats induced ipsilateral cortical sarcoma family kinase phosphorylation at the Y416 site. Deactivation of sarcoma family kinase by its inhibitor (3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-dpyrimidin-4-amine) suppressed the elevated enzyme activity and cortical susceptibility to cortical spreading depression. Interestingly, the inhibitory effect of the N-methyl-D-aspartate receptor antagonist NVP-AAM077 on cortical spreading depression was reversed by the sarcoma family kinase activator pYEEI (EPQY(PO₃H₂)EEEIPIYL), suggesting a link between this enzyme and N-methyl-D-aspartate receptors. Similarly, after deactivation of sarcoma family kinase, a reduction of sarcoma family kinase phosphorylation and cortical susceptibility to cortical spreading depression was observed with NVP-AAM077.

We conclude that activation of sarcoma family kinase is required for cortical spreading depression, and this process is regulated by recruiting N-methyl-D-aspartate receptors. This study provides novel insight for sarcoma family kinase function in the mechanism of migraine aura.

Results from studies on diabetes and migraine risk are conflicting, which may be due to methodological limitations. Prospective studies with long follow-up could increase our understanding of the relationship between the two diseases.

We performed a cohort study including the whole Norwegian population alive on 01.01.2004, using prescriptions registered in the Norwegian prescription database to identify individuals developing type 1 diabetes, type 2 diabetes and migraine during follow-up (10 years). We used Cox proportional hazards regression to estimate rate ratios with corresponding 95% confidence intervals for the effect of diabetes on migraine risk, adjusting for age, sex, and educational level.

We identified 7,883 type 1 diabetes patients and 93,600 type 2 patients during the study period. Type 1 diabetes was significantly associated with a subsequent decreased migraine risk during follow-up in the age- and sex-adjusted analyses (0.74; 0.61–0.89). Type 2 diabetes was also associated with a significantly lower migraine risk (0.89; 0.83–0.95). Further adjustment for educational level yielded similar results for both diabetes.

Both type 1 and type 2 diabetes were significantly associated with a decreased risk of migraine. This suggests that diabetes or diabetes treatment may have a protective effect on the development of migraine.

To determine the red flags for serious organic causes of headache in children, to analyze if the management of headache in the Pediatric Emergency Department is appropriate, and whether the follow-up may limit repeated visits to the Emergency Department.

All the patients ≤ 18 years referred to our pediatric Emergency Department for non-traumatic headache over 5 years were retrospectively reviewed. The patients followed up by the Pediatric Headache Centre were also screened. Statistical analysis was undertaken using the Chi-squared test or Fisher’s exact test and multivariate analysis; significance at p < 0.05.

1833 patients (54.6% males) accessed our Emergency Department 2086 times; 62.1% had primary headache, 30.0% had secondary headache, 7.8% received inconsistent diagnosis. Among those with secondary headache, 24 (1.1% of total visits) were diagnosed with serious disorders. The clinical red flags for “serious headache” were: Cranial nerves palsy, strabismus, and drowsiness. One hundred and eighty four patients (8.8 %) underwent neuroimaging (rate of pathological findings: 7.1 %); 37.2 % of the patients received analgesic therapy. One hundred and fifteen patients (6.2 %) returned within three months; 24 of these were referred to the Headache Centre, with only one accessing the Emergency Department again.

The vast majority of headaches referred to the Pediatric Emergency Department are benign, and primary forms prevail. “Serious headache” is rare and shows typical clinical features and abnormal neurologic evaluation; specific clinical red flags, along with suggestive personal history, should lead the pediatrician to prescribe only appropriate neuroimaging. Pain relief is still insufficient in the Pediatric Emergency Department despite appropriate guidelines. Last, the collaboration with the Headache Centre is crucial to limit repeated visits.

Chronic migraine has a well-documented association with increased insulin resistance and metabolic syndrome. The hypothalamus may play a role in the progression of insulin resistance in chronic migraine through the regulation of orexigenic peptides such as neuropeptide Y. Insulin resistance may lead to increased risk of future type 2 diabetes mellitus in patients with chronic migraine, which is more likely to occur if other pathogenetic defects of type 2 diabetes mellitus, such as impaired pancreatic β-cell functions and defects in intestinal glucagon-like peptide-1 secretion after meals. We studied the relationship of fasting neuropeptide Y with insulin resistance, β-cell function, and glucagon-like peptide-1 secretion in non-obese female chronic migraine patients. We also aimed to investigate glucose-stimulated insulin and glucagon-like peptide-1 secretions as early pathogenetic mechanisms responsible for the development of carbohydrate intolerance.

In this cross-sectional controlled study, 83 non-obese female migraine patients of reproductive age categorized as having episodic migraine or chronic migraine were included. The control group consisted of 36 healthy females. We studied glucose-stimulated insulin and glucagon-like peptide-1 secretion during a 75 g oral glucose tolerance test. We investigated the relationship of neuropeptide Y levels with insulin resistance and β-cell insulin secretion functions.

Fasting glucose levels were significantly higher in migraine patients. Plasma glucose and insulin levels during the oral glucose tolerance test were otherwise similar in chronic migraine, episodic migraine and controls. Patients with chronic migraine were more insulin resistant than episodic migraine or controls (p = 0.048). Glucagon-like peptide-1 levels both at fasting and two hours after glucose intake were similar in chronic migraine, episodic migraine, and controls. Neuropeptide Y levels were higher in migraineurs. In chronic migraine, neuropeptide Y was positively correlated with fasting glucagon-like peptide-1 levels (r = 0.57, p = 0.04), but there was no correlation with insulin resistance (r = 0.49, p = 0.09) or β-cell function (r = 0.50, p = 0.07).

Non-obese premenopausal female patients with chronic migraine have higher insulin resistance, but normal β-cell function is to compensate for the increased insulin demand during fasting and after glucose intake. Increased fasting neuropeptide Y levels in migraine may be a factor leading to increased insulin resistance by specific alterations in energy intake and activation of the sympathoadrenal system.

Although there is a great wealth of knowledge about the neurobiological processes underlying migraine and its accompanying symptoms, the mechanisms by which an attack starts remain elusive, and the disease remains undertreated. Although the vast majority of literature focuses on the involvement of the trigeminovascular systems and higher systems it innervates, such as thalamic and hypothalamic nuclei, several lines of evidence implicate the cerebellum in the pathophysiology of migraine.

In this review, we aim to summarize potential cerebellar involvement seen from different perspectives including the results from imaging studies, cerebellar connectivity to migraine-related brain structures, comorbidity with disorders implying cerebellar dysfunction, similarities in triggers precipitating both such disorders, and migraine and cerebellar expression of migraine-related genes and neuropeptides. We aim to inspire an increase in interest for future research on the subject.

It is hoped that future studies can provide an answer as to how the cerebellum may be involved and whether treatment options specifically targeting the cerebellum could provide alleviation of this disorder.

Of the multiple etiologies identified for symptomatic cluster headache, vascular origin is common; however, there are no known reports of arteriovenous (AV) fistulas. Here we report a case with typical presentation of cluster headache, which might be associated with middle meningeal AV fistulas.

The subject is a 49-year-old man with a 7-year history of episodic left-side cluster headache, consistent with the criteria in the International Classification of Headache Disorders, 3rd edition, beta version (ICHD-3β). Magnetic resonance angiography (MRA) demonstrated dural arteriovenous fistulas at the left posterior fossa, which is supplied mainly by the left middle meningeal artery. After endovascular balloon-assisted embolization, his symptoms have disappeared without relapse for 1.5 years.

We suggest that middle meningeal arteriovenous fistulas should be considered as a potential differential diagnosis of secondary cluster headache, even when the initial clinical manifestations and treatment response are typical for primary cluster headache.