Nazia Karsan

Acid-sensing ion channel 1: a novel therapeutic target for migraine with aura.

Migraine with aura is a severe debilitating neurological disorder with few relatively specific therapeutic options.

Calcitonin gene-related peptide and migraine

PURPOSE OF REVIEW Migraine is a common, complex disorder of the brain with significant morbidity. As the pathophysiology of the disorder has become better appreciated, the role of neuropeptides has been explored. Calcitonin gene-related peptide (CGRP) has emerged as a promising therapeutic target. RECENT FINDINGS CGRP is widely distributed in the nervous system, particularly at anatomical areas thought to be involved with migraine, including the trigeminovascular nociceptive system. In studies, CGRP has been shown to be released during severe migraine attacks, and effective triptan treatment of an attack normalizes these levels. CGRP administration triggers migraine in patients and CGRP receptor antagonists can abort migraine. Moreover, recent data demonstrate that CGRP mechanism blockade either by small molecule receptor antagonists or by monoclonal antibodies can have a preventive effect in migraine. SUMMARY This article highlights the evidence behind the role of CGRP in migraine and the state of CGRP-based mechanism treatment development. We present a summary of the evidence base behind CGRP in migraine pathophysiology and the novel CGRP mechanism drugs and their potential future contribution to migraine management in our clinical practice.

CGRP mechanism antagonists and migraine management.

Migraine is a complex disorder of the brain that is common and highly disabling. As understanding of the neural pathways has advanced, and it has become clear that the vascular hypothesis does not explain the disorder, new therapeutic avenues have arisen. One such target is calcitonin gene-related peptide (CGRP)-based mechanisms. CGRP is found within the trigeminovascular nociceptive system widely from the trigeminal ganglion to second-order and third-order neurons and in regulatory areas in the brainstem. Studies have shown CGRP is released during severe migraine attacks and the reversal of the attack with effective triptan treatment normalizes those levels. CGRP administration triggers migraine in patients, and CGRP receptor antagonists have been shown to abort migraine. Here, we review the current state of CGRP mechanism antagonist therapy as its research and development is increasing in migraine therapeutics. We discuss several recent trials, highlighting the evidence base behind these novel drugs, and their potential future contribution to migraine management.

Targeted Acid-Sensing Ion Channel Therapies for Migraine

Acid-sensing ion channels (ASICs) are a family of ion channels, consisting of four members; ASIC1 to 4. These channels are sensitive to changes in pH and are expressed throughout the central and peripheral nervous systems—including brain, spinal cord, and sensory ganglia. They have been implicated in a number of neurological conditions such as stroke and cerebral ischemia, traumatic brain injury, and epilepsy, and more recently in migraine. Their expression within areas of interest in the brain in migraine, such as the hypothalamus and PAG, their demonstrated involvement in preclinical models of meningeal afferent signaling, and their role in cortical spreading depression (the electrophysiological correlate of migraine aura), has enhanced research interest into these channels as potential therapeutic targets in migraine. Migraine is a disorder with a paucity of both acute and preventive therapies available, in which at best 50% of patients respond to available medications, and these medications often have intolerable side effects. There is therefore a great need for therapeutic development for this disabling condition. This review will summarize the understanding of the structure and CNS expression of ASICs, the mechanisms for their potential role in nociception, recent work in migraine, and areas for future research and drug development.

1557 Alterations in cerebral blood flow during the postdrome phase of a migraine attack captured with arterial spin labelled (asl) mri

Background Symptoms patients experience in the premonitory and postdromal phase of migraine are broadly similar. The postdrome of a migraine attack, however, is poorly characterised and largely unexplored in literature. No functional imaging study has evaluated the postdrome phase in depth. Aim To study the alterations in cerebral blood flow during the postdrome phase of a migraine attack using arterial spin labelled (ASL) MRI in nitroglycerin-induced migraine attacks. Method Sixteen subjects completed three study visits in the study. ASL MRI scans over the course of triggered migraine attacks were analysed (SPM 12, www.fil.ion.ac.uk/spm). Results Significant alterations were detected in rCBF over the superior frontal gyrus, medial frontal gyrus, middle frontal gyrus, putamen, superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, thalamus, hypothalamus, midbrain, posterior cingulate, anterior cingulate, claustrum (p<0.001) in the postdrome phase compared to premonitory phase Conclusion The brain processes involved in the premonitory phase and postdrome phase are different. The symptoms experienced by subjects in the postdrome are associated with a near global reduction in cerebral blood flow.

Flunarizine in migraine-related headache prevention: results from 200 patients treated in the UK

For over 20 years, as a group we have been using flunarizine in primary headache disorders. Flunarizine is widely used in Europe, but not licensed in the UK. In September 2014, the National Institute for Clinical Excellence published supportive guidelines for flunarizine use in migraine, based on randomized controlled evidence that it is as effective as propranolol and topiramate in adults.

PO067 Nitroglycerin triggering as a human migraine model in clinical research

Studying human migraine has challenges; namely capturing spontaneous attacks. Exogenous triggering has been developed, with substances such as nitroglycerin (NTG), to overcome some of these challenges and enable attacks to be studied in a predictable and reproducible fashion. We aimed to study NTG triggering of migraine attacks, with a view to phenotyping these compared to spontaneous attacks and imaging them using functional MRI. Subjects were screened and recruited following a migraine history and informed consent (n=49). Each subject was exposed to a 0.5 mcg/kg/min over 20 min NTG infusion. The phenotype of migraine symptomatology following triggering was documented. The association between baseline migraine diagnosis (episodic vs. chronic) and effectiveness of NTG triggering migraine headache was analysed using the Chi-squared test. p<0.05 was considered significant. The monthly baseline headache frequency ranged from 0–22 days (median=8). Migraine headache was successfully triggered in 40 subjects (82%). There was a trend towards a statistically significant association (p=0.061) between effective triggering and chronic migraine versus episodic. All 9 subjects who did not trigger a headache had episodic migraine with monthly headache days ranging from 0–10. NTG is an effective migraine trigger. Successful triggering may be related to a threshold effect, associated with baseline headache frequency.

PO068 The similarities between spontaneous and nitroglycerin-triggered premonitory symptoms in migraineurs

Human models of migraine are required to understand the neurobiology of this disabling condition. Nitroglycerin (NTG) effectively triggers migraine headache in 60%–70% of migraineurs, and has also been shown to trigger premonitory symptomatology. We aimed to study the triggering of premonitory symptomatology with NTG, comparing the phenotype of triggered attacks to spontaneous attacks. Migraineurs who reported spontaneous premonitory symptoms were recruited following informed consent (n=49). A detailed migraine history was taken from each subject at screening. NTG (0.5 mcg/kg/min over 20 min) was administered intravenously to each subject. The phenotype of premonitory symptoms where present (n=47) following triggering was recorded for each subject. Statistical analyses were performed to assess the correlation between common spontaneous and triggered symptoms using the Chi-squared test. p<0.05 was considered significant. Analyses were performed for fatigue, concentration difficulty, irritability, neck stiffness and yawning. Triggered premonitory symptomatology was similar to spontaneous symptomatology, with a statistically significantly increased likelihood of reporting most of the common symptoms following triggering if reported in spontaneous attacks (fatigue, neck stiffness, irritability and yawning). There was a trend towards significance for concentration difficulty (p=0.053). The similarities between spontaneous and triggered attacks suggest that NTG triggering is an effective model to study human migraine.

PO066 Alterations in attention, fatigue and alertness associated with the premonitory and postdrome stages of triggered migraine attacks

Despite increasing awareness that non-painful symptoms can manifest at any time during a migraine attack, there is little quantitative evidence to support the severity of such symptoms. We aimed to understand the differences in fatigue (Daily Fatigue Impact Scale- DFIS), attention (Sustained Attention to Response Task- SART) and alertness (Karolinska Sleepiness Scale- KSS) at baseline and during the premonitory and postdrome stages of nitroglycerin-triggered migraine attacks, using validated psychological tests. Baseline (symptom free) scores for all tests for each subject (n=16) were collected prior to any drug administration. The same tests were conducted in the premonitory (n=7) or postdrome (n=9) phases of triggered attacks, following display of symptoms after nitroglycerin infusion and when appropriate, after effective headache treatment. Statistical analyses were performed using the paired t-test. p<0.05 was considered significant. There were statistically significant increases in scores on the KSS and DFIS in the premonitory and postdrome stages compared to baseline. No statistically significant differences in SART scores in either phase were observed compared to baseline. Despite a small sample size, we have demonstrated notable changes in alertness and fatigue in the premonitory and postdrome stages of a migraine attack. This is an area that warrants increased clinical and research attention.

Premonitory-like symptomatology in migraine

Citing this paper Please note that where the full-text provided on Kings Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publishers definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publishers website for any subsequent corrections.