Outside Of Attacks Research Articles

Recurrent Painful Ophthalmoplegic Neuropathy: Migraine, Neuralgia, or Something Else?

Recurrent painful ophthalmoplegic neuropathy (RPON) is a very rare disease characterized by recurrent attacks (at least two) of unilateral headache associated with ipsilateral ophthalmoplegia due to paresis of one or more cranial motor nerves, not due to any orbital, parasellar, or posterior fossa lesions. The differential diagnoses for this condition are broad. In addition to disability during an acute attack, this disease could also cause a permanent neurologic deficit. The understanding of RPON pathogenesis has changed over time, leading to a change in the classification of this disorder between editions of the International Classification of Headache Disorders, in which the condition was moved from the chapter on migraine to the chapter on cranial neuralgias and central causes of facial pain. There is no consensus on the pathogenesis of RPON. It is possible that multiple pathogenic mechanisms underlie various clinical forms of the disease. A depiction of pathologic analyses of patients with radiologically confirmed changes in the affected nerves during and outside of attacks would significantly contribute to knowledge of its pathogenesis. Brain imaging should be performed in each patient during an acute RPON attack and at a regular schedule between attacks. Further case reports and case series are required before further conclusions can be made regarding RPON pathogenesis and proposals for treatment options.

Plasma Glucose Levels Increase During Spontaneous Attacks of Migraine With and Without Aura.

To investigate plasma glucose changes during the ictal state of migraine compared to the interictal state. Previous studies suggest abnormal glucose metabolism in migraine patients during and outside of attacks. It is not known if plasma glucose levels change during spontaneous migraine attacks. Plasma glucose levels were measured during and outside of spontaneous migraine attacks with and without aura. Plasma glucose values were corrected for diurnal variation of plasma glucose by subtracting the difference between the moving average (intervals of 2 hours) and overall mean from the plasma glucose values. This was a sub-study of a larger study conducted at Rigshospitalet Glostrup in the Capital Region of Denmark. Thirty-one patients (24 F, 7 M, 13 with aura, 18 without aura) were included in the study. Mean time from attack onset to blood sampling was 7.6hours. Mean pain at the time of investigation was 6 on a 0-10 verbal rating scale. Plasma glucose was higher ictally compared to the interictal phase (interictal mean: 88.63mg/dL, SD 11.70mg/dL; ictal mean: 98.83mg/dL, SD 13.16mg/dL, difference 10.20mg/dL, 95% CI=[4.30; 16.10]), P=.0014). The ictal increase was highest in patients investigated early during attacks and decreased linearly with time from onset of migraine (-1.57mg/dL/hour from onset of attack, P=.020). The attack-related increase in blood glucose was not affected by pain intensity or presence of aura symptoms. We demonstrated higher plasma glucose values during spontaneous migraine attacks, independent of the presence of aura symptoms and not related to pain intensity, peaking in the early phase of attacks. Additional studies are necessary to confirm our findings and explore the possible underlying mechanisms.

Association Between Sumatriptan Treatment During a Migraine Attack and Central 5-HT1B Receptor Binding

Triptans, the most efficient acute treatment for migraine attacks, are 5-HT1B/1D receptor agonists, but their precise mechanism of action is not completely understood. The extent to which triptans enter the central nervous system and bind to 5-HT1B receptors in the brain is unknown. To determine the occupancy of sumatriptan to central 5-HT1B receptors, and to investigate changes in brain serotonin levels during migraine attacks. This study of 8 patients in Denmark used a within-participant design and was conducted from April 20, 2015, to December 5, 2016. Participants were otherwise healthy patients with untreated episodic migraine without aura, aged between 18 and 65 years, and recruited from the general community. Data analysis was performed from January 2017 to April 2018. All participants underwent positron emission tomographic scans after injection of [11C]AZ10419369, a specific 5-HT1B receptor radiotracer. All participants were scanned 3 times: (1) during an experimentally induced migraine attack, (2) after a subcutaneous injection of 6-mg subcutaneous sumatriptan, and (3) on a migraine attack-free day. Scans 1 and 2 were conducted on the same study day. Each scan lasted for 90 minutes. The primary outcome was the nondisplaceable binding potential of [11C]AZ10419369 across 7 brain regions involved in pain modulation. The binding potential reflects receptor density, and changes in binding potential reflects displacement of the radiotracer. The occupancy of sumatriptan was estimated from the 2 scans before and after sumatriptan administration. Eight patients with migraine were included in the study; of these participants, 7 (87%) were women. The mean (SD) age of participants on study day 1 was 29.5 (9.2) years and on study day 2 was 30.0 (8.9) years. Sumatriptan was associated with statistically significantly reduced 5-HT1B receptor binding across pain-modulating regions (mean [SD] binding potential, 1.20 [0.20] vs 1.02 [0.22]; P = .001), corresponding to a mean (SD) drug occupancy rate of 16.0% (5.3%). Furthermore, during migraine attacks, as compared with outside of attacks, 5-HT1B receptor binding was statistically significantly associated with reduced in pain-modulating regions (mean [SD] binding potential, 1.36 [0.22] vs 1.20 [0.20]; P = .02). Treatment with sumatriptan during migraine attacks appeared to be associated with a decrease in 5-HT1B receptor binding, a finding that is most likely associated with the binding of sumatriptan to central 5-HT1B receptors, but the contribution of ongoing cerebral serotonin release to the lower binding cannot be excluded; the migraine attack-associated decrease in binding could indicate that migraine attacks are associated with increases in endogenous serotonin.

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

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. 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. No differences of functional connectivity were found between patients and controls. 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.

EHMTI-0372. No abnormalities of intrinsic brain connectivity during the interictal phase of migraine with aura

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 (fMRI) is a powerful technique for evaluating resting-state functional connectivity, i.e. coherence of brain activity across cerebral areas.

Gastric stasis in migraineurs: Etiology, characteristics, and clinical and therapeutic implications

Migraine is a disabling neurological disorder often complicated by gastrointestinal conditions such as gastric stasis. The association between migraine and gastric stasis has received very little attention in the literature, but the existing evidence suggests that they may share a common etiology. Patients with migraine and those with gastric stasis exhibit abnormal autonomic nervous system function. Furthermore, empirical studies demonstrate that migraineurs experience significant delays in gastric emptying, both during and outside of attacks, when compared to non-migrainous controls. More research is needed to establish the relationship between gastric stasis and migraine burden and to determine the impact of gastric stasis on migraine treatment.

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.

No increase of calcitonin gene–related peptide in jugular blood during migraine

Increased calcitonin gene-related peptide (CGRP) in external jugular venous blood during migraine attack is one of the most cited findings in the headache literature. The finding has not been convincingly reproduced and is based on comparison with historic control subjects. The validity of this finding is important for the understanding of migraine. We therefore investigated the issue using an intrapatient comparison design and two different CGRP assays. We sampled blood from the external jugular and cubital vein during, as well as outside of, an attack of migraine without aura. We succeeded in 17 patients, whereas only cubital fossa blood could be sampled in an additional 4 patients. CGRP was measured with the same assay as most previous studies (assay I) and furthermore with a more sensitive and validated assay (assay II). For assay I, mean CGRP concentration in external jugular venous blood during attack was 17.18 pmol/L compared with 15.88 pmol/L outside of attack. Mean difference was 1.81 pmol/L (95% confidence interval [CI]: -2.88, 6.41; p = 0.44). In peripheral blood during attack, CGRP was 16.86 pmol/L compared with 17.57 pmol/L outside of attack. Mean difference was -0.79 pmol/L (95% CI: -4.64, 3.06; p = 0.69). For assay II, external jugular venous blood concentration of CGRP during attack was 32.59 pmol/L compared with 30.59 pmol/L outside of attack; mean difference was 2.00 pmol/L (standard error, 2.39; 95% CI: -3.07, 7.07; p = 0.416). In peripheral blood during attack, CGRP was 33.37 pmol/L compared with 31.84 pmol/L outside of attack; mean difference was 1.53 pmol/L (standard error, 1.90; 95% CI: -2.46, 5.51; p = 0.431). Thus, no difference between CGRP level in external jugular or cubital fossa blood during and outside of attack was found. No difference was found between external jugular and peripheral venous blood. Thus, previous findings of increased CGRP level in external jugular or cubital fossa venous blood could not be confirmed. Our finding strongly suggests that CGRP is not increased in jugular venous blood during migraine without aura. CGRP cannot be used as a biomarker to validate human or animal models of migraine.

Evidence for increased plasma levels of calcitonin gene-related peptide in migraine outside of attacks

Although calcitonin gene-related peptide (CGRP) has been shown to be elevated in jugular venous blood of adult migraineurs during acute migraine attacks, it remains unknown whether CGRP is increased outside of attacks in jugular or cubital venous blood. The aim of the present study was to compare interictal plasma levels of CGRP in adult migraine patients and in healthy controls. Twenty patients with a diagnosis of migraine with or without aura and 20 healthy controls were included. In blood from the cubital vein, CGRP levels were significantly higher in patients (75±8 pmol/l (mean±SEM)) than in controls (49±3 pmol/l) ( P=0.005). The subgroup of patients suffering exclusively from migraine without aura ( n=14) also had significantly higher levels of CGRP (82±10 pmol/l) than controls ( n=20; 49±3 pmol/l) ( P=0.001). The findings could not be explained by confounding factors such as age, sex or use of contraceptive pills. We therefore conclude that CGRP is increased in cubital venous blood of migraineurs outside of attack. It is hypothesized that this finding may reflect a long-lasting or permanent abnormal neurogenic vascular control in patients with migraine.