Imaging the brain and vascular reactions to headache treatments: a systematic review.

BACKGROUND: Neuroimaging studies have made an important contribution to our understanding of headache pathophysiology. This systematic review aims to provide a comprehensive overview and critical appraisal of mechanisms of actions of headache treatments and potential biomarkers of treatment response disclosed by imaging studies. MAIN BODY: We performed a systematic literature search on PubMed and Embase databases for imaging studies investigating central and vascular effects of pharmacological and non-pharmacological treatments used to abort and prevent headache attacks. Sixty-three studies were included in the final qualitative analysis. Of these, 54 investigated migraine patients, 4 cluster headache patients and 5 patients with medication overuse headache. Most studies used functional magnetic resonance imaging (MRI) (n = 33) or molecular imaging (n = 14). Eleven studies employed structural MRI and a few used arterial spin labeling (n = 3), magnetic resonance spectroscopy (n = 3) or magnetic resonance angiography (n = 2). Different imaging modalities were combined in eight studies. Despite of the variety of imaging approaches and results, some findings were consistent. This systematic review suggests that triptans may cross the blood-brain barrier to some extent, though perhaps not sufficiently to alter the intracranial cerebral blood flow. Acupuncture in migraine, neuromodulation in migraine and cluster headache patients, and medication withdrawal in patients with medication overuse headache could promote headache improvement by reverting headache-affected pain processing brain areas. Yet, there is currently no clear evidence for where each treatment acts, and no firm imaging predictors of efficacy. This is mainly due to a scarcity of studies and heterogeneous treatment schemes, study designs, subjects, and imaging techniques. In addition, most studies used small sample sizes and inadequate statistical approaches, which precludes generalizable conclusions. CONCLUSION: Several aspects of headache treatments remain to be elucidated using imaging approaches, such as how pharmacological preventive therapies work, whether treatment-related brain changes may influence therapy effectiveness, and imaging biomarkers of clinical response. In the future, well-designed studies with homogeneous study populations, adequate sample sizes and statistical approaches are needed.

Extreme ecchymoses in a migraine patient using concomitant treatment with calcitonin gene-related peptide receptor antibodies and fish oil supplements: a case report.

BACKGROUND: Erenumab, a monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor, is registered for migraine prevention. Compared to other conventional migraine prevention medicines (i.e. topiramate, betablockers and amitriptyline) erenumab has better tolerability. Impaired hemostasis has not been reported previously. Here, we report the first case of an increased tendency to bruise in a migraine patient treated with erenumab. CASE PRESENTATION: A 41-year old female migraine patient was treated with erenumab for 12 months, which led to a significant reduction of headache and migraine days. Three months after treatment start, she experienced increased tendency to bruise leading to extreme ecchymosis after 4 months treatment. Platelet counts and aggregation, thromboelastography, activated partial thromboplastin time (APTT) and international normalized ratio (INR) were all normal. Thorough interview revealed intake of fish oil supplements for many years prior to treatment. The increased tendency to bruise subsided after discontinuation of fish oil supplements. CONCLUSION: The combination of fish oil supplements and erenumab may cause increased tendency to bruise. Erenumab has no effect on the platelets per se but may cause impaired wound healing by suppression of CGRP. Thus, small and unnoticeable bruises may be aggravated instead in patients with tendency to bruise caused by for instance fish oil supplements.

Future prophylactic treatments in migraine: Beyond anti-CGRP monoclonal antibodies and gepants.

Migraine is ranked as a leading cause of years lived with disability among all neurological disorders. Therapies targeting the calcitonin gene-related peptide (CGRP) signaling pathway, including monoclonal antibodies against the receptor or ligand and small molecule CGRP receptor antagonists (gepants), are today approved for migraine prophylaxis with additional compounds expected to be introduced to the market soon. In this review, we consider other putative prophylactic migraine drugs in development, including compounds targeting G-protein coupled receptors, glutamate, ion channels, and neuromodulatory devices. Emergence of these new interventions could complement our current treatment armamentarium for migraine management.

Intact blood-brain barrier during spontaneous attacks of migraine without aura: a 3T DCE-MRI study.

BACKGROUND AND PURPOSE: The integrity of the blood-brain barrier (BBB) has been questioned in migraine, but BBB permeability has never been investigated during spontaneous migraine attacks. In the present study, BBB permeability during spontaneous attacks of migraine without aura was investigated compared to an interictal state. METHODS: Seventy-four patients suffering from migraine without aura were recruited to participate in this cross-sectional dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) study. The patients were instructed to report at the hospital for DCE-MRI scan during and outside of a spontaneous migraine attack. The primary end-point was a difference in the BBB permeability (ml/100 g/min) between the attack and the headache-free days. The permeability was assessed in five different regions of interest (ROIs) located in the anterior, middle and posterior cerebral area, brain stem, posterior pons and whole brain. The paired samples t test was used to compare Ki (permeability) values between the attack and headache-free days. RESULTS: Nineteen patients completed the study. Median time from onset of migraine attack to scan was 6.5 h (range 4.0-15.5 h). No change in the mean BBB permeability (ml/100 g/min) was found between the attack and the headache-free days in any of the measured ROIs. No relationship between the pain side or intensity and BBB permeability was found in 15 patients with unilateral pain during the examined attack. CONCLUSIONS: It was demonstrated that the BBB permeability during spontaneous migraine attacks without aura was unchanged.

Prevalence of migraine in persons with the 3243A>G mutation in mitochondrial DNA.

BACKGROUND AND PURPOSE: Over the last three decades mitochondrial dysfunction has been postulated to be a potential mechanism in migraine pathogenesis. The lifetime prevalence of migraine in persons carrying the 3243A>G mutation in mitochondrial DNA was investigated. METHODS: In this cross-sectional study, 57 mDNA 3243A>G mutation carriers between May 2012 and October 2014 were included. As a control group, a population-based cohort from our epidemiological studies on migraine in Danes was used. History of headache and migraine was obtained by telephone interview, based on a validated semi-structured questionnaire, performed by trained physicians. RESULTS: The prevalence of migraine is significantly higher in persons carrying the 3243A>G mutation than in controls (58% vs. 18%; P < 0.001). This applies for both subforms of migraine, migraine without aura (47% vs. 12%; P < 0.001) and migraine with aura (18% vs. 6%; P < 0.001), and in females (58% vs. 24%; P < 0.001) and males (58% vs. 12%; P < 0.001) for any migraine. CONCLUSIONS: A high prevalence of migraine in persons with the mDNA 3243A>G mutation was found. This finding suggests a clinical association between a monogenetically inherited disorder of mitochondrial dysfunction and susceptibility to migraine. Mitochondrial DNA aberrations may contribute to the pathogenesis of migraine.

[Influence of sociohygienic factors on the shaping of the nutritional status in children and teenagers].

There was revealed the structure of deteriorations in the nutritional status of schoolchildren in the city: the most of students has normal nutritional status, but there was noted the high prevalence of excessive body weight and obesity among children and teenagers. Risk factors for development of deteriorations of the nutrition state were detected as follows: irrational food regimen, qualitative compartment offood, factors of educational environment, lifestyle. The main role in system of control of the nutritional status in children is referred to the correction of socio-hygienic factors which prove to be the priority ones in the shaping of the nutritional status in students. As the main condition determining the nutrition state of the up-to-date schoolchildren and the quality of their life in the whole the social cultural level of children and adolescents must be regarded as a result of the hygienic education and training in fundamentals of healthy lifestyle. Priority protective factors of the gain in the part of schoolchildren with normal nutritional status (optimalfood regimen, optimal dietary habits, sufficient level of physical activity) laidfrom the child age in conditions of the family, sufficient level of the physical activity and the implementation of the other element of hygienically expedient day regimen served as the base for the elaboration of the system of the control of nutritional status. Algorithm of the control of the nutritional status in the students of educational institutions includes the creation of healthcare educational environment, optimization of nutrition and physical activity, the shaping of the culture of healthy lifestyle, health-improving measures for children with disorders of nutritional status and their psychological pedagogical supports at the stage of the correction of the nutritional status, improvement of the medical service for the early detection of deviations of nutritional status with the estimation of the efficiency of the system ofpreventive and health-improving measures.

No abnormalities of intrinsic brain connectivity in the interictal phase of migraine with aura.

BACKGROUND AND PURPOSE: Functional neuroimaging studies have shown hyperresponsiveness of cortical areas to visual stimuli in migraine patients with aura outside of attacks. This may be a key feature in the initiation of aura episodes and possibly also migraine headache attacks. It is unknown if cortical dysfunction is present at rest, i.e. in the absence of any external stimuli. Functional magnetic resonance imaging is a powerful technique for evaluating resting state functional connectivity, i.e. coherence of brain activity across cerebral areas. The objective of this study was to investigate resting-state functional brain connectivity in migraineurs with aura outside of attacks using functional magnetic resonance imaging. METHODS: Forty patients suffering from migraine with visual aura and 40 individually age and gender matched healthy controls with no history or family history of migraine were investigated. Following advanced denoising, the data were analyzed both in a hypothesis-driven fashion, testing for abnormalities involving 27 different brain areas of potential relevance to migraine with aura including the cortical visual areas, the amygdala and peri-aqueductal grey matter, and in a data-driven exploratory fashion (dual regression) in order to reveal any possible between-group differences of resting state networks. Age, gender, attack frequency and disease duration were included as nuisance variables. RESULTS: No differences of functional connectivity were found between patients and controls. CONCLUSIONS: The previously reported increased cortical hyperresponsivity in the interictal phase of migraine with aura is unlikely to be caused by abnormalities of intrinsic brain connectivity. The interictal migraine aura brain may be abnormally functioning only during exposure to external stimuli.

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.

Habituation of evoked responses is greater in patients with familial hemiplegic migraine than in controls: a contrast with the common forms of migraine.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare, dominantly inherited subtype of migraine with transient hemiplegia during the aura phase. Mutations in at least three different genes can produce the FHM phenotype. The mutated FHM genes code for ion transport proteins that animal and cellular studies have associated with disturbed ion homeostasis, altered cellular excitability, neurotransmitter release, and decreased threshold for cortical spreading depression. The common forms of migraine are characterized interictally by a habituation deficit of cortical and subcortical evoked responses that has been attributed to neuronal dysexcitability. FHM and the common forms of migraine are thought to belong to a spectrum of migraine phenotypes with similar pathophysiology, and we therefore examined whether an abnormal habituation pattern would also be found in FHM patients. METHODS: In a group of genotyped FHM patients (five FHM-1, four FHM-2), we measured habituation of visual evoked potentials (VEP), auditory evoked potentials including intensity dependence (IDAP), the nociception-specific blink reflex (nsBR) and compared the results to a group of healthy volunteers (HV). RESULTS: FHM patients had a more pronounced habituation during VEP (P=0.025) and nsBR recordings (P=0.023) than HV. There was no difference for IDAP, but the slope tended to be steeper in FHM. CONCLUSION: Contrary to the common forms of migraine, FHM patients are not characterized by a deficient, but rather by an increased habituation in cortical/brain stem evoked activities. These results suggest differences between FHM and the common forms of migraine, as far as central neuronal processing is concerned.

[The characteristics of morphofunctional status of rural schoolchildren].

The authors made a complex evaluation of the physical development of 7-16-year-old rural schoolchildren from a large administrative territorial entity and developed age-gender-related standards, by using the percentile technique. There were significant morphofunctional differences between the urban and rural schoolchildren at the present stage of a secular trend, which determines the necessity of developing the physical development standards for rural children and adolescents in order to correctly interpret the data on their health status.

1st Post-European Headache Federation Meeting: a review of the latest developments presented at the 2020 European Headache Federation Congress. / I Reunión Post-European Headache Federation: revisión de las novedades presentadas en el Congreso de la European Headache Federation de 2020.

INTRODUCTION: After the European Headache Federation (EHF) Congress, renowned Spanish neurologists specialised in migraine presented the most significant latest developments in research in this field at the Post-EHF Meeting. DEVELOPMENT: The main data presented concerning the treatment of chronic and episodic migraine were addressed, with attention paid more specifically to those related to preventive treatments and real-life experience in the management of the disease. An important review was carried out of the new therapeutic targets and the possibilities they offer in terms of understanding the pathophysiology of migraine and its treatment. An update was also presented of the latest developments in the treatment of migraine with fremanezumab, a monoclonal antibody recently authorised by the European Medicines Agency. Participants were also given an update on the latest developments in basic research on the pathology, as well as an overview of the symptoms of migraine and COVID-19. Finally, the repercussions of migraine in terms of its burden on the care and economic resources of the health system were addressed, along with its impact on society. CONCLUSIONS: The meeting summarised the content presented at the 14th EHF Congress, which took place in late June/early July 2020.

TITLE: I Reunión Post-European Headache Federation: revisión de las novedades presentadas en el Congreso de la European Headache Federation de 2020.Introducción. Tras la celebración del congreso de la European Headache Federation (EHF), reconocidos neurólogos españoles expertos en el tratamiento de la migraña expusieron en la Reunión Post-EHF las principales novedades presentadas en el congreso y relacionadas con ese ámbito. Desarrollo. Se abordan los principales datos presentados relacionados con el tratamiento de la migraña crónica y episódica; concretamente, los relacionados con los tratamientos preventivos y la experiencia en vida real en el manejo de la enfermedad. Se hizo una importante revisión de las nuevas dianas terapéuticas y las posibilidades que ofrecen en cuanto al conocimiento de la fisiopatología de la migraña y su tratamiento. Asimismo, se hizo una actualización de las novedades presentadas en el tratamiento de la migraña con fremanezumab, anticuerpo monoclonal recientemente autorizado por la Agencia Europea de Medicamentos. Se hizo una actualización de las novedades en investigación básica en la patología, así como una relación de los síntomas de migraña y COVID-19. Finalmente, se abordaron las implicaciones de la migraña en la carga sanitaria asistencial y económica, y su impacto en la sociedad. Conclusiones. En la reunión se hizo un resumen del contenido presentado en el 14 Congreso de la EHF, que tuvo lugar a finales de junio y principios de julio de 2020.

Prostaglandin I2 (epoprostenol) triggers migraine-like attacks in migraineurs.

Prostacyclin [prostaglandin I(2) (PGI(2))] activates and sensitizes meningeal sensory afferents. In healthy subjects PGI(2) triggers headache in healthy subjects. However, the migraine-eliciting effect of PGI(2) has not been systematically studied in patients with migraine. We hypothesized that intravenous infusion of the stable prostacyclin analogue epoprostenol would trigger migraine-like attacks in migraineurs. We infused 10 ng kg(-1) min(-1) PGI(2) or placebo over 25 min in 12 migraineurs without aura in a controlled, double-blind, cross-over study and recorded headache intensity and associated symptoms, velocity in the middle cerebral artery (V(MCA)) and diameter in the superficial temporal artery. In the period 0-14 h, 12 subjects reported headache on PGI(2) day compared with three subjects on placebo day (P = 0.004), and six subjects fulfilled the criteria for an experimentally induced migraine-like attack compared with two subjects on placebo (P = 0.219). During infusion and post-infusion phases the AUC under the headache curve on PGI(2) was significantly larger than on placebo (P < 0.05). There was a significant V(MCA) decrease (P = 0.015) and superficial temporal artery diameter increase (P < 0.001) on PGI(2) compared with placebo. In conclusion, PGI(2) may trigger a migraine-like attack in migraine sufferers. We suggest sensitization of perivascular nociceptors and arterial dilation as the mode of action of PGI(2)-induced headache and migraine-like attacks.

Carbachol induces headache, but not migraine-like attacks, in patients with migraine without aura.

Carbachol induces headache in healthy subjects, but the migraine eliciting effect of carbachol has not previously been studied. We hypothesized that the cholinomimetic agonist carbachol would induce headache and migraine-like attacks in migraineurs. Carbachol (3 µg/kg) or placebo was randomly infused into 18 patients with migraine without aura in a double-blind crossover study. Headache was scored on a verbal rating scale from 0 to 10. Velocity in the middle cerebral artery (V(MCA)) and diameter of the superficial temporal artery (STA) were recorded. Fifteen patients experienced headache after carbachol compared with eight after placebo (P = 0.039). There was no difference in incidence of migraine-like attacks after carbachol (n = 8) compared with placebo (n = 6) (P = 0.687). Carbachol caused a decrease in V(MCA) (P = 0.044), but no change in STA (P = 0.089) compared with placebo. The study demonstrated that carbachol provocation is not a good model for experimental migraine.

Matrix metalloproteinases during and outside of migraine attacks without aura.

To test the hypothesis that permeability of the blood-brain barrier (BBB) is altered during migraine attack due to enhanced activation of matrix metalloproteinases (MMPs), we investigated MMP-3, MMP-9 and tissue inhibitor of metalloproteases (TIMP)-1 in the external jugular vein during and outside of migraine attacks in 21 patients with migraine without aura. In addition, we measured plasma levels of several other proteins including MMP-7, -8, -10 and TIMP-2. We used Rules-Based Medicine multi-analyte profiling and protein array technologies to study plasma concentration of MMPs. There was no difference in MMP-9 and TIMP-1 levels between ictal and interictal periods. We found significantly decreased plasma levels of MMP-3 in the external jugular (P = 0.002) and cubital (P = 0.008) vein during attacks compared with outside of attacks. We found no correlation of ictal or interictal MMP-3, MMP-9 and TIMP-1 to migraine duration and frequency analysed in 21 patients (P > 0.05). There was no difference between ictal and interictal plasma levels of MMP-7, -8, -10 and TIMP-2 (P > 0.05). Our data suggest that plasma MMP-9 cannot be used as a biomarker of BBB disruption in migraine without aura. Decreased MMP-3 levels are an interesting and unexpected finding warranting further investigation.

Intact neurovascular coupling during executive function in migraine without aura: interictal near-infrared spectroscopy study.

An altered neurovascular coupling has been proposed in migraine. We aimed to investigate neurovascular coupling during a mental task interictally in patients with migraine without aura (MO) by near-infrared spectroscopy (NIRS). Twelve migraineurs and 12 healthy controls were included. Using NIRS, we recorded the magnitude and latency of cortical changes in oxyhaemoglobin (HbO(2)) and deoxyhaemoglobin (Hb) during the colour-word matching Stroop test via 16 channels covering the forehead. We found no differences in the magnitude of responses between migraineurs and healthy subjects in the incongruent Stroop task subtracted by the neutral Stroop task on either side of the frontal cortex for HbO(2) (left, P = 0.984; right, P = 0.406) or Hb (left, P = 0.689; right, P = 0.406) values. No differences in error rate (P = 0.611) or reaction time (P = 0.936) were found between healthy subjects and MO patients for incongruent tasks. The present study suggests that vascular reactivity and oxygen supply during a mental task in patients with MO are intact interictally.

Finding new drug targets for the treatment of migraine attacks.

No new preventive drugs specific to migraine have appeared for the last 20 years and existing acute therapies need improvement. Unfortunately, no animal models can predict the efficacy of new therapies for migraine. Because migraine attacks are fully reversible and can be aborted by therapy, the headache- or migraine-provoking property of naturally occurring signalling molecules can be tested in a human model. This model has predicted efficacy of nitric oxide synthase inhibition and calcitonin gene-related peptide receptor blockade. The pharmaceutical industry should pay more attention to human models, although methods are different from normal target validation.

Prostaglandin E2(PGE2) induces headache in healthy subjects.

The role of prostanoids in nociception is well established. The headache-eliciting effects of prostaglandin E(2) (PGE(2)) and its possible mechanisms have previously not been systematically studied in man. We hypothesized that infusion of PGE(2) might induce headache and vasodilation of cranial vessels. PGE(2) (0.40 microg kg(-1) min(-1)) or saline was infused for 25 min into 11 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (V(MCA)) by transcranial Doppler and diameter of the superficial temporal artery (STA) by high-resolution ultrasonography. All 11 subjects reported headache on the PGE(2) day and no subjects reported headache on the placebo day (P = 0.001). During the immediate phase (0-30 min) (P = 0.005) and the postinfusion phase (30-90 min) (P = 0.005), the area under the curve for headache score was significantly larger on the PGE(2) day compared with the placebo day. PGE(2) caused dilatation of the STA (23.5%; 95% CI 14.0, 37.8) and the MCA (8.3%; 95% CI 4.0, 12.6). We suggest that PGE(2) induces headache by activation and sensitization of cranial perivascular sensory afferents.

The cholinomimetic agent carbachol induces headache in healthy subjects.

The parasympathetic nervous system is likely to be involved in migraine pathogenesis. We hypothesized that the cholinomimetic agonist carbachol would induce headache and vasodilation of cephalic and radial arteries. Carbachol (3 microg/kg) or placebo was randomly infused into 12 healthy subjects in a double-blind crossover study. Headache was scored on a verbal rating scale from 0-10. Velocity in the middle cerebral artery (V(MCA)) and diameter of the superficial temporal artery (STA) and radial artery (RA) were recorded. Nine participants developed headache after carbachol compared with three after placebo. The area under the curve for headache was increased after carbachol compared with placebo both during infusion (0-30 min) (P = 0.042) and in the postinfusion period (30-90 min) (P = 0.027). Carbachol infusion caused a drop in V(MCA) (P = 0.003) and an increase in STA diameter (P = 0.006), but no increase in the RA diameter (P = 0.200). In conclusion, the study demonstrated that carbachol caused headache and dilation of cephalic arteries in healthy subjects.

Changes in cerebral blood flow after acetazolamide: an experimental study comparing near-infrared spectroscopy and SPECT.

BACKGROUND AND PURPOSE: It is important to find a reliable and bedside method, which can estimate the cerebral blood flow (CBF) of patients in clinical settings. Estimation of CBF by calculating a blood flow index (BFI) using continuous wave near-infrared spectroscopy (CW-NIRS) and indocyanine green (ICG) as an i.v. tracer has been proposed to be a feasible and promising method. To validate if the BFI method can detect relative changes in CBF we compared data with the established method (133)Xenon single photon emission computer tomography ((133)Xe-SPECT). METHODS: Ten healthy subjects were investigated before and after a bolus of acetazolamide. NIRS data were obtained using a multi source detector separation configuration in order to assess a corrected BFI (BFI(corr)) value, which attempts to eliminate contamination of skin blood flow. RESULTS: Data obtained showed no significant correlation between CBF changes measured by (133)Xe-SPECT and BFI(corr) (0.133, P = 0.732). After acetazolamide, a 49% increase in CBF was detected using the (133)Xe-SPECT method, whereas no changes in any ICG variables were observed after acetazolamide. CONCLUSION: The study shows that it is not possible to obtain reliable BFI data, which reflect changes in CBF after acetazolamide infusion, using the CW-NIRS and ICG method.

Familial hemiplegic migraine type 1 shows no hypersensitivity to nitric oxide.

Familial hemiplegic migraine type 1 (FHM-1) is a dominantly inherited subtype of migraine with aura and transient hemiplegia associated with mutations in the CACNA1A gene. FHM-1 shares many phenotypical similarities with common types of migraine, indicating common neurobiological pathways. Experimental studies have established that activation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that CACNA1A mutations in patients with FHM-1 are associated with hypersensitivity to NO-cGMP pathway. We included eight FHM-1 patients with R583Q and C1369Y mutations and nine healthy controls, who received intravenous infusions of 0.5 microg kg(-1) min(-1) glyceryl trinitrate (GTN) over 20 min. We recorded: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (V(meanMCA)) by transcranial Doppler; diameter of the superficial temporal artery (STA) by Dermascan. One patient reported migraine without aura 5 h after start of the GTN infusion. No aura was reported. The AUC(headache) in the immediate phase was more pronounced in patients than in controls (P = 0.01). In the 14 h following GTN infusion, there was no difference in the AUC(headache) between patients and controls (P = 0.17). We found no difference in the AUC(VmeanMCA) (P = 0.12) or AUC(STA) (P = 0.71) between FHM-1 patients and controls. None of the control persons reported migraine-like headache. FHM-1 patients do not show hypersensitivity of the NO-cGMP pathway, as characteristically seen in migraine patients with and without aura. This indicates that the pathophysiological pathways underlying migraine headache in FHM-1 may be different from the common types of migraine.