Erenumab and galcanezumab in chronic migraine prevention: effects after treatment termination.

BACKGROUND: Monoclonal antibodies (mAbs) targeting the CGRP pathway are safe and efficacious therapies for the prevention of migraine. In this study we assessed the effects of discontinuation of preventive erenumab and galcanezumab treatment in patients with chronic migraine. METHODS: This retrospective pooled analysis included completers of the open-label extension study phase for the preventive treatment of chronic migraine with galcanezumab (NCT02614261; 9 months) and erenumab (NCT02174861; 12 months) in a single headache center. We compare migraine data until week 12 after open-label treatment completion, when patients did not have any pharmacological preventive medication, to study baseline values of the double-blind trial period, and to the last 4 weeks of the open-label extension. The assessment included changes in monthly migraine days, headache hours, days with severe headache and acute headache medication use. RESULTS: Data from 16 patients after galcanezumab (n = 9) and erenumab (n = 7) open-label treatment completion were analyzed. The mean number of monthly migraine days was 18.38 ± 3.74 at baseline, and 12.19 ± 4.53 in the last 4 weeks of the open-label extension (p < 0.001). Monthly migraine days remained significantly reduced compared to baseline during the entire 12-week observation period after open-label termination (p = 0.002), with a reduction of 5.38 ± 4.92 in weeks 1-4 (p = 0.001), 4.75 ± 4.15 in weeks 5-8 (p = 0.001), and 3.93 ± 5.45 in weeks 9-12 (p = 0.014). There was no significant difference in monthly migraine days between the 12 weeks after open-label termination and the last 4 weeks of the open-label phase (p = 0.228). All other analyses revealed numerical improvement through week 12 in comparison to baseline. CONCLUSIONS: In this small, self-selected cohort, the results indicate a therapeutic effect of monoclonal antibodies targeting the CRGP pathway in chronic migraine prevention after treatment termination up to 12 weeks.

CGRP Monoclonal Antibodies for the Preventative Treatment of Migraine.

PURPOSE OF REVIEW: CGRP is a key neuropeptide in migraine pathophysiology. The blockade of the CGRP pathway at the side of the CGRP receptor of the CGRP peptide leads to the interruption of trigeminal nerve system-mediated headache syndromes such as migraine. Monoclonal antibodies (mAbs) targeting the CGRP pathway have been developed and are currently under investigation for episodic (EM) and chronic migraine (CM) prevention. Here, we report data from these clinical trials. RECENT FINDINGS: Placebo-controlled, randomized double-blind phase studies of CGRP mAbs in episodic and chronic migraine have shown that the specific blockade of the peptide or the CGRP receptor are both powerful mechanisms to reduce migraine frequency. Along with the reduction of acute migraine-specific medication intake, early onset of efficacy of mAbs has been demonstrated. Most common adverse events are injection sider reactions. Depending on the mAb, the administration mode is a monthly or even less frequently s.c. or I.V. formulation. Phase II studies in EM and CM demonstrate that CGRP mAbs are effective anti-migraine preventatives with a beneficial adverse event profile. Further detailed results from larger phase III clinical trials are expected soon.

The safety and efficacy of the 5-HT 1F receptor agonist lasmiditan in the acute treatment of migraine.

INTRODUCTION: Migraine is among the most disabling disorders worldwide, with a significant therapeutic need. Triptans are drugs of choice in the acute attack treatment, but they are contraindicated in patients with vascular conditions due to their potential vasoconstrictive properties. Further limitations include side effects, inconsistency in therapeutic action and possible non-response. Lasmiditan, a highly selective 5-HT1F receptor agonist, is a novel acute anti-migraine substance devoid of vasoconstriction. Areas covered: This article reviews the clinical efficacy and safety of oral and intravenous lasmiditan as a possible acute migraine treatment. We analyze all currently available results in Phase I to III studies. Expert opinion: Lasmiditan is a promising acute migraine therapy, in particular for patients at cardiovascular risk. Phase II and the first Phase III clinical trials show a significant better headache response in comparison to placebo. The efficacy of lasmiditan proves that vasoconstriction is not essential for acute migraine therapy and thereby points, in addition to a well-established trigeminal contribution, to central neuronal mechanisms in migraine pathophysiology. Lasmiditan penetrates the blood-brain barrier and CNS associated adverse events are common, but mostly in mild to moderate severity. The results of long-term Phase III studies will determine if these adverse events represent a limitation in clinical practice.

Structural Gray Matter Alterations in Chronic Migraine: Implications for a Progressive Disease?

OBJECTIVE: To identify possible gray matter alterations in patients with chronic migraine using voxel-based morphometry (VBM). BACKGROUND: VBM studies demonstrate structural alterations of gray matter (GM) in episodic migraine (EM) patients. Some of these alterations correlate with disease duration and headache frequency. We assessed GM alterations in chronic migraine (CM) and EM to evaluate the concept of migraine as a progressive disorder of the brain. METHODS: Individually age and sex-matched subjects with CM or EM (both without aura) and healthy controls (n = 21 per group) underwent magnetic resonance imaging-based VBM. RESULTS: We found an increase of GM volume (GMV) in amygdala and putamen, in CM compared to controls. GMV of EM compared to controls did not differ statistically significantly. Headache frequency in all migraineurs (EM and CM) correlated positively with GMV in putamen, frontal and temporal gyrus and negatively in left cuneus. CONCLUSION: CM is associated with structural changes in brain regions involved in pain processing but also in affective and cognitive aspects of pain. Some GM alterations are correlated with headache frequency assessed in EM and CM. The findings support the assumption that chronic pain alters brain plasticity. GMV increase may reflect a remodeling of the central nervous system due to repetitive headache attacks leading to chronic sensitization and a continuous ictal-like state of the brain in chronic migraineurs.

No microstructural white matter alterations in chronic and episodic migraineurs: a case-control diffusion tensor magnetic resonance imaging study.

BACKGROUND: In patients with episodic migraine (EM), diffusion tensor imaging (DTI) revealed microstructural white matter alterations in various brain regions related to pain processing. Some of these changes were correlated with migraine duration and attack frequency, suggesting that migraine is a progressive disease with proceeding structural alterations of the brain. This study aimed to identify possible microstructural white matter alterations in patients with chronic migraine (CM) using DTI. We hypothesized that alterations in DTI are more pronounced in patients with CM compared with EM. METHODS: Individually, age- and sex-matched subjects with CM without aura, EM without aura, and healthy controls (n = 21 per group) underwent conventional head magnetic resonance imaging and DTI imaging in a 3T MRI scanner and were included in analysis. DTI data were analyzed using a tract-based spatial statistics approach. Fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity were compared between subjects with CM and EM, CM and controls, EM and controls, as well as between all subjects with migraine (EM + CM) and controls. RESULTS: In chronic migraineurs (mean age 49 ± 7.5 years), we did not find any statistically significant difference (P < .05, threshold-free cluster enhancement corrected for multiple comparison) in DTI-derived parameters in comparison with episodic migraineurs (FA: P > .245) and healthy controls (FA: P > .099). In contrast to previous DTI studies, we did not find alterations in DTI-derived indices in subjects with EM compared with healthy controls (FA: P > .486). CONCLUSIONS: No microstructural white matter changes could be observed in middle-aged chronic and episodic migraineurs using DTI. CM does not seem to be a risk factor for progressive microstructural changes in DTI.

The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine.

More than 20 years have passed without the launch of a new substance class for acute migraine therapy. Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile. New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who cannot tolerate triptans for attack treatment. Lasmiditan is a novel highly specific 5-HT1F receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay. In both phase II randomized, placebo-controlled trials in acute migraine the primary endpoint was met. For the intravenous formulation a clear dose-dependent effect on headaches could be determined. Lasmiditan tablets in doses of 50-400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms. This substance is chemically clearly different from other antimigraine drugs, which is also reflected by its dose-dependent adverse event profile chiefly including dizziness, vertigo, paresthesia and fatigue. Adverse events are usually linked to the central nervous system. Future phase III clinical trials with an active triptan comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans. They will also determine whether lasmiditan will become available to the migraine patient.

Corticosteroids alter CGRP and melatonin release in cluster headache episodes.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is a marker of trigeminal activation in acute cluster headache (CH). Melatonin production is altered in CH patients and may reflect hypothalamic dysfunction. We assessed the effects of short-term CH prevention with corticosteroids on CGRP and melatonin release in a prospective observational cohort study hypothesizing that corticosteroids influence the interictal activity of both systems indicated by the change of these biomarkers. METHODS: Episodic CH subjects (n = 9) in the bout and controls with multiple sclerosis (n = 6) received 1000 mg/d methylprednisolone (MPD) i.v. for three days followed by oral tapering with prednisone. We determined CGRP plasma levels in external jugular vein blood outside an attack and 6-sulfatoxymelatonin (aMT6s) - the stable metabolite of melatonin - in 12-hour day- and nighttime urine collection prior to and several times after MPD therapy and again when CH subjects were outside the bout in complete remission. CH patients recorded the frequency of attacks. RESULTS: In parallel to the reduction of headache frequency, administration of corticosteroids resulted in significantly decreased CGRP plasma levels and increased nocturnal aMT6s urine excretion in CH subjects. No significant changes were observed in controls. CONCLUSION: Corticosteroids alter CGRP plasma and aMT6s urine levels in a cluster bout. These changes may indicate an effect of corticosteroids on trigeminal activation and hypothalamic dysfunction.

Clinical and psychopathological definition of the interictal dysphoric disorder of epilepsy.

PURPOSE: Different authors suggested the occurrence of a pleomorphic affective syndrome in patients with epilepsy named interictal dysphoric disorder (IDD). We sought to investigate whether IDD occurs only in patients with epilepsy and to validate IDD features against DSM-IV criteria. METHODS: Consecutive patients with a diagnosis of epilepsy (E) or migraine (M) have been assessed using the BDI, MDQ, and the Interictal Dysphoric Disorder Inventory (IDDI), a questionnaire specifically created to evaluate IDD symptoms. Diagnosis of current and lifetime DSM-IV Axis I disorders was established using the MINI Plus version 5.0.0. RESULTS: A total of 229 patients (E = 117; M = 112) were evaluated. Females were significantly more represented in the migraine group (E = 46.5% vs. M = 73.3% p = 0.009), but there was no difference in age, duration of the disease, or education level. Patients with epilepsy were more likely to screen positively at MDQ (E = 17% vs. M = 5.3% p = 0.006) and to have a diagnosis of bipolar disorder (E = 14.5% vs. M = 4.5% p = 0.013) as compared to migraine patients. There was no between-groups difference in IDD prevalence (E = 17%; M = 18.7%) and IDDI total scores (E = 4.1 +/- 2.0 vs. M = 3.8 +/- 2.0). Validation of IDD against DSM-IV categories showed current major depression being the foremost diagnostic category correlated with IDD in both epilepsy (OR = 0.32-0.12-0.88, p = 0.028) and migraine (OR = 0.10, 95% CI = 0.02-0.49, p = 0.004) samples. Current anxiety disorder correlated with IDD only in migraine patients (OR = 0.19, 95% CI = 0.05-0.77, p = 0.02). CONCLUSION: IDD represents a homogenous construct that can be diagnosed in a relevant proportion of patients but it is not typical only of epilepsy, occurring in other central nervous system disorders such as migraine.

Increased serotonin transporter availability in the brainstem of migraineurs.

For decades, serotonin has been speculated to play a major role in migraine pathophysiology. The central serotonergic system is located in the raphe nuclei and the adjacent reticular formation in the brainstem. Recently, radioligands targeting the brain serotonin transport protein (SERT) have been developed. We used the highly specific SERT-radioligand (123)I-ADAM [2-((2-((dimethylamino) methyl)phenyl)thio)-5-iodophenylamine] to test the hypothesis of the mesopontine serotonergic system being involved in the pathophysiology of migraine. Nineteen migraine patients and 10 healthy, age- and sex-matched controls were enrolled. The neuroimaging study was performed interictally during the pain-free interval. Single Photon Emission Computed Tomography (SPECT)-images were coregistered with MRI-scans. Region of interest (ROI)-analysis revealed a highly significant increase of (123)I-ADAM uptake in the mesopontine brainstem of migraineurs (p < 0.001). In contrast, (123)IADAM uptake in the thalamus did not differ significantly between migraineurs and controls. Our study demonstrates for the first time a significant increase of brainstem SERT-availability in migraineurs, suggesting a dysregulation of the brainstem serotonergic system. It remains to be elucidated whether the altered SERT-availability is causally related to migraine pathophysiology or whether it reflects secondary pathophysiological mechanisms.

Habituation of the visually evoked potential and its vascular response: implications for neurovascular coupling in the healthy adult.

In the human, visually evoked potentials (VEP) and cerebral oxygenation changes, as measured by near-infrared spectroscopy (NIRS), are assessed to elucidate the relation between electrophysiological and vascular responses to a checkerboard stimulus reversing at 3 Hz. Habituation of either response is analysed on two time scales. Within the 1-min stimulation period we find a decrease in P100N135-component amplitude, closely coupled to a decrease in the amplitude of the oxygenation parameters (concentration changes in oxygenated and deoxygenated haemoglobin, [oxy-Hb] and [deoxy-Hb]). The N75P100-component amplitude exhibits a different behaviour along the 1-min stimulation period. An initial increase is overridden by an overall decrease, the latter not reaching statistical significance. The analysis across the 13 successive stimulation blocks separated by resting periods of equal duration yields a trend for an decrease in the VEP-components' amplitude, not reflected in the vascular response. When calculating a ratio between the amplitude of the P100N135-component and the concentration changes in the haemoglobins a "coupling index" of a 0.2 microM decrease in [deoxy-Hb] and an increase of 0.6 microM in [oxy-Hb] is found per 1 microV increase in VEP-component amplitude. The ratio is the same irrespective of its assessment from the difference stimulation/ rest or from the habituation effect, i.e., the difference between the amplitudes at the beginning and towards the end of the stimulation period. Although supporting the notion that the coupling between neuronal activation and the vascular response exhibits linear aspects, our findings cannot be taken as a proof of such a linearity across all brain regions and activation types. On the contrary, tentatively calculating a coupling index for the data assessed in the visual system, we intend to stress the necessity to assess both neuronal and vascular response to allow for a comparison between different systems and conditions in whom neurovascular coupling is expected to be altered (Miller et al, 2001; Mechelli et al, 2001).