Henrik Winther Schytz

Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-diagnosed and under-treated. To support clinical decision-making, we convened a European panel of experts to develop a ten-step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-term follow-up.

Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man. Pituitary adenylate cyclase activating peptide-38 (PACAP38) is a strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers. We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients. Twelve healthy subjects and 12 migraine patients were examined in two separate studies. All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a randomized, double-blind crossover study design. Headache was scored on a verbal rating scale (VRS) during hospital (0-2 h) and post-hospital (2-12 h) phases. Mean blood flow velocity in the middle cerebral artery (V(MCA)) by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) by high resolution ultrasonography were recorded during hospital phase in migraineurs. PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients. Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo (P = 0.016). Most of attacks (6 out of 7) occurred during the post-hospital phase [mean time 6 h (range 2-11)]. Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase. In the hospital phase, the area under the curve (AUC) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects (P = 0.005) and tended to be larger in migraineurs (P = 0.066). In the post-hospital phase, the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects (P = 0.005) and migraine patients (P = 0.013). In migraine patients, PACAP38 caused a peak decrease of 16.1% in V(MCA) and a 37.5% increase in STA diameter at 20 min after start of infusion. In conclusion, PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients. In migraine sufferers, PACAP38 caused delayed migraine-like attacks. The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38.

Near-infrared spectroscopy (NIRS) is susceptible to signal artifacts caused by relative motion between NIRS optical fibers and the scalp. These artifacts can be very damaging to the utility of functional NIRS, particularly in challenging subject groups where motion can be unavoidable. A number of approaches to the removal of motion artifacts from NIRS data have been suggested. In this paper we systematically compare the utility of a variety of published NIRS motion correction techniques using a simulated functional activation signal added to 20 real NIRS data sets which contain motion artifacts. Principle component analysis, spline interpolation, wavelet analysis and Kalman filtering approaches are compared to one another and to standard approaches using the accuracy of the recovered, simulated hemodynamic response function. Each of the four motion correction techniques we tested yields a significant reduction in the mean-squared error and significant increase in the contrast-to-noise ratio of the recovered HRF when compared to no correction and compared to a process of rejecting motion-contaminated trials. Spline interpolation produces the largest average reduction in mean-squared error (55 %) while wavelet analysis produces the highest average increase in contrast-to-noise ratio (39 %). On the basis of this analysis, we recommend the routine application of motion correction techniques (particularly spline interpolation or wavelet analysis) to minimize the impact of motion artifacts on functional NIRS data.

A minority of headache patients have a secondary headache disorder. The medical literature presents and promotes red flags to increase the likelihood of identifying a secondary etiology. In this review, we aim to discuss the incidence and prevalence of secondary headaches as well as the data on sensitivity, specificity, and predictive value of red flags for secondary headaches. We review the following red flags: (1) systemic symptoms including fever; (2) neoplasm history; (3) neurologic deficit (including decreased consciousness); (4) sudden or abrupt onset; (5) older age (onset after 65 years); (6) pattern change or recent onset of new headache; (7) positional headache; (8) precipitated by sneezing, coughing, or exercise; (9) papilledema; (10) progressive headache and atypical presentations; (11) pregnancy or puerperium; (12) painful eye with autonomic features; (13) posttraumatic onset of headache; (14) pathology of the immune system such as HIV; (15) painkiller overuse or new drug at onset of headache. Using the systematic SNNOOP10 list to screen new headache patients will presumably increase the likelihood of detecting a secondary cause. The lack of prospective epidemiologic studies on red flags and the low incidence of many secondary headaches leave many questions unanswered and call for large prospective studies. A validated screening tool could reduce unneeded neuroimaging and costs.

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide are structurally and functionally closely related but show differences in migraine-inducing properties. Mechanisms responsible for the difference in migraine induction are unknown. Here, for the first time, we present a head-to-head comparison study of the immediate and long-lasting observations of the migraine-inducing, arterial, physiological and biochemical responses comparing PACAP38 and vasoactive intestinal polypeptide. In a double-blind crossover study 24 female migraine patients without aura were randomly allocated to intravenous infusion of PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We recorded incidence of migraine during and after infusion (0-24 h). Magnetic resonance angiography of selected extra- and intracranial arteries, blood samples (plasma PACAP38 and vasoactive intestinal polypeptide and serum tryptase), and vital signs (blood pressure, heart rate, respiratory frequency, and end-tidal pressure of CO2) was recorded before and up to 5 h after infusion. Twenty-two patients [mean age 24 years (range 19-36)] completed the study on both days. Sixteen patients (73%) reported migraine-like attacks after PACAP38 and four after vasoactive intestinal polypeptide (18%) infusion (P = 0.002). Three of four patients, who reported migraine-like attacks after vasoactive intestinal polypeptide, also reported attacks after PACAP38. Both peptides induced marked dilatation of the extracranial (P < 0.05), but not intracranial arteries (P > 0.05). PACAP38-induced vasodilatation was longer lasting (>2 h), whereas vasoactive intestinal polypeptide-induced dilatation was normalized after 2 h. We recorded elevated plasma PACAP38 at 1 h after the start of PACAP38 infusion only in those patients who later reported migraine attacks. Blood levels of vasoactive intestinal polypeptide and tryptase were unchanged after PACAP38 infusion. In conclusion, PACAP38-induced migraine was associated with sustained dilatation of extracranial arteries and elevated plasma PACAP38 before onset of migraine-like attacks. PACAP38 has a much higher affinity for the PAC1 receptor and we therefore suggest that migraine induction by PACAP38 may be because of activation of the PAC1 receptor, which may be a future anti-migraine drug target.