Six-month therapy of CGRP monoclonal antibodies in real-world clinical practice: an interim analysis of efficacy and safety data

Introduction. Migraine is one of the most common disabling neurological disorders. Recently developed monoclonal antibodies to calcitonin gene-related peptide (CGRP) or its receptor are the first targeted medication for preventive therapy of both episodic and chronic migraine. They have been thoroughly investigated in clinical trials; however, there is little data from real-world clinical practice available to date. The aim of this study is to assess the efficacy and safety of 6 months of treatment with erenumab in real-world clinical practice and investigate the effect of the drug on the patients’ sensitivity to medicines for migraine headaches relief and patient satisfaction after treatment.Materials and methods. Our observational cohort prospective study included patients in our Headache Clinic prescribed monoclonal antibodies blocking the CGRP-receptor – erenumab. During the investigation, we evaluated the previous preventive therapy and its efficacy, the number of days with migraine per month, adverse events occurring during the erenumab treatment, depression and anxiety (HADS), migraine disability (MIDAS), the presence of allodynia (ACS-12) and improved response to acute therapy after treatment. A total of 42 patients participated in the study: 6 men, 36 women, the average age was 43.9 ± 12.2. Of them, 38 patients (90%) had chronic migraine. Thirty-two patients (76%) had previously been prescribed preventive therapy, which proved ineffective, and 10 patients (24%) had not once received any type of migraine prevention.Results. Among our patients, we identified 11 patients with resistant migraine and one patient with refractory migraine. During the study, two patients dropped out due to adverse events (constipation). Thirty patients continued the administration of erenumab 70 mg for at least six months. The average number of migraine days per month before treatment was 22.8, and after six months of treatment, it dropped to 7.3. Twenty-nine patients (72.5%) also noted that the response to acute headache treatment improved after the therapy.Conclusion. The results of our study are consistent with the international experience of using erenumab and confirm its effectiveness for migraine preventive therapy, including difficult-to-treat migraine cases. However, further studies with more participants and evaluation of predictors of successful monoclonal antibody therapy are still needed.

Sleep disturbance management in patients with trigeminal autonomic cephalalgias

Trigeminal autonomic cephalalgias (TACs) are rare but are the most intense primary headaches that severely limit patients’ ability to work and be socially active. This article reviews the modern classification of TACs, based on the International Classification of Headache Disorders-3, and the key differences between TAC types, as well as the pathophysiological mechanisms – the role of the trigeminovascular system, autonomic nervous system, hypothalamus and vagus nerve – and their relation to circadian rhythms. The sleep disturbances that can occur in patients with TACs, exacerbating the course of the disease, and the role of melatonin, hypothalamus and suprachiasmatic nucleus in these conditions are also discussed. In addition, current therapies for cluster headache are described, which include acute therapy and prophylactic therapy, with recommendations regarding the timing of prophylactic therapy discontinuation. The review also includes the available data on melatonin as well as new therapies such as CGRP monoclonal antibodies and neuromodulation, which includes the two most promising techniques: non-invasive vagus nerve stimulation and sphenopalatine ganglion microstimulation. Furthermore, the authors present the clinical case of a patient with chronic cluster headache, which was significantly reduced in frequency and intensity when melatonin was added to the therapy.

GP.1 Changes in ischemic stroke presentations and associated workflow during the first wave of the COVID-19 pandemic: A population study

Background: Pandemics may promote hospital avoidance among patients with emergencies, and added precautions may exacerbate treatment delays. Methods: We used linked administrative data and data from the Quality Improvement and Clinical Research Alberta Stroke Program – a registry capturing stroke-related data on the entire Albertan population(4.3 million) – to identify all patients hospitalized with stroke in the pre-pandemic(01/01/2016-27/02/2020) and COVID-19 pandemic(28/02/2020-30/08/2020) periods. We examined changes in stroke presentation rates and use of thrombolysis and endovascular therapy(EVT), adjusted for age, sex, comorbidities, and pre-admission care needs; and in workflow, stroke severity(National Institutes of Health Stroke Scale/NIHSS), and in-hospital outcomes. Results: We analyzed 19,531 patients with ischemic stroke pre-pandemic versus 2,255 during the pandemic. Hospitalizations/presentations dropped(weekly adjusted-incidence-rate-ratio[aIRR]:0.48,95%CI:0.46-0.50), as did population-level incidence of thrombolysis(aIRR:0.49,0.44-0.56) or EVT(aIRR:0.59,0.49-0.69). However, proportions of presenting patients receiving thrombolysis/EVT did not decline (thrombolysis:11.7% pre-pandemic vs 13.1% during-pandemic, aOR:1.02,0.75-1.38). For out-of-hospital strokes, onset-to-door times were prolonged(adjusted-coefficient:37.0-minutes, 95%CI:16.5-57.5), and EVT recipients experienced greater door-to-reperfusion delays(adjusted-coefficient:18.7-minutes,1.45-36.0). NIHSS scores and in-hospital mortality did not differ. Conclusions: The first COVID-19 wave was associated with a halving of presentations and acute therapy utilization for ischemic stroke at a population level, and greater pre-/in-hospital treatment delays. Our data can inform public health messaging and stroke care in future pandemic waves.

CSF Findings in Acute NMDAR and LGI1 Antibody–Associated Autoimmune Encephalitis

Background and ObjectivesCSF in antibody-defined autoimmune encephalitis (AE) subtypes shows subtype-dependent degrees of inflammation ranging from rare and often mild to frequent and often robust. AEs with NMDA receptor antibodies (NMDAR-E) and leucine-rich glioma-inactivated protein 1 antibodies (LGI1-E) represent opposite ends of this spectrum: NMDAR-E with typically frequent/robust and LGI1-E with rare/mild CSF inflammation. For a more in-depth analysis, we characterized CSF findings in acute, therapy-naive NMDAR-E and LGI1-E in a multicentric, retrospective, cross-sectional setting.MethodsEighty-two patients with NMDAR-E and 36 patients with LGI1-E from the GErman NEtwork for Research of AuToimmune Encephalitis (GENERATE) with lumbar puncture within 90 days of onset and before immunotherapy were included. CSF parameters comprised leukocytes, oligoclonal bands (OCBs), and CSF/serum ratios for albumin, immunoglobulin G (IgG), A (IgA), and M (IgM), the latter 3 converted to Z scores according to Reiber formulas. The MRZ reaction was tested in 14 patients with NMDAR-E and 6 patients with LGI1-E, respectively.ResultsCSF was abnormal in 94% of NMDAR-E but only in 36% of LGI1-E patients. Robust quantitative intrathecal immunoglobulin synthesis (IIS, IgG > IgM >> IgA) was characteristic for NMDAR-E, but absent in LGI-E. In NMDAR-E, CSF leukocytes were higher when IIS was present or more pronounced. In addition, in NMDAR-E, CSF leukocytes were lower and IIS occurred less often and if so to a lesser degree at older age. Patients with NMDAR-E with severe functional impairment more often had positive OCBs. In CSF obtained later than 3 weeks of onset, leukocytes were lower. In parallel, the correlation of leukocytes with IIS disappeared as IIS was partially independent of disease duration. The MRZ reaction was positive in 5 (36%) patients with NMDAR-E. All these associations were completely absent in LGI1-E. Here, younger patients showed more blood-CSF barrier dysfunction. In LGI1-E, but not in NMDAR-E, the blood-CSF barrier was more dysfunctional when CSF leukocytes were higher.DiscussionNMDAR-E and LGI-E differ in their typical extent of CSF inflammation. In addition, the patterns formed by the different inflammatory CSF parameters and their relationship with disease severity, age, and disease duration are subtype-characteristic. Moreover, signs for multiple sclerosis-like chronic inflammation are present in a subgroup of patients with NMDAR-E. These CSF patterns might be markers for the different immunopathogeneses of LGI1-E and NMDAR-E.

Changes in ischemic stroke presentations and associated workflow during the first wave of the COVID-19 pandemic: A population study in Alberta, Canada

Background: Pandemics may promote hospital avoidance among patients with emergencies, and added precautions may exacerbate treatment delays. There is a paucity of population-based data on these phenomena for stroke. We examined the effect of the COVID-19 pandemic on the presentation and treatment of ischemic stroke in an entire population. Methods: We used linked provincial administrative data and data from the Quality Improvement and Clinical Research Alberta Stroke Program, a registry capturing stroke-related data on the entire population of Alberta(4.3 million), to identify all patients presenting with stroke in the pre-pandemic(1-January-2016 to 27-February-2020, n=19,531) and pandemic(28-February-2020 to 30-August-2020, n=2,255) periods. We examined changes in thrombolysis and endovascular therapy(EVT) rates, workflow, and in-hospital outcomes. Results: Hospitalizations/presentations for ischemic stroke dropped (weekly adjusted-incidence-rate-ratio[aIRR]:0.48, 95%CI:0.46-0.50, adjusted for age, sex, comorbidities, pre-admission care needs), as did population-level incidence of thrombolysis(aIRR:0.49,0.44-0.56) or EVT(aIRR:0.59,0.49-0.69). However, the proportions of presenting patients receiving acute therapies did not decline (e.g. thrombolysis:11.7% pre-pandemic vs 13.1% during-pandemic, aOR:1.02,0.75-1.38). Onset-to-door times were prolonged; EVT recipients experienced longer door-to-reperfusion times (median door-to-reperfusion:110-minutes, IQR:77-156 pre-pandemic vs 132.5-minutes, 99-179 during-pandemic; adjusted-coefficient:18.7-minutes, 95%CI:1.45-36.0). Hospitalizations were shorter but stroke severity and in-hospital mortality did not differ. Interpretation: The first COVID-19 wave was associated with a halving of presentations and acute therapy utilization for ischemic stroke at a population level, and greater pre-hospital and in-hospital treatment delays. Our data can inform public health messaging and stroke care in current and future waves. Messaging should encourage attendance for emergencies and stroke systems should re-examine code stroke protocols to mitigate inefficiencies.

ADP-receptor antagonists in patients with acute myocardial infarction complicated by cardiogenic shock: a pooled IABP-SHOCK II and CULPRIT-SHOCK trial sub-analysis

Purpose The purpose of this pooled analysis is to compare the clinical outcome of patients with acute myocardial infarction complicated by cardiogenic shock treated with either clopidogrel or the newer, more potent ADP-receptor antagonists prasugrel or ticagrelor. Patients from the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) and Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial were included. Methods and results For the current analysis, the primary endpoint was 1-year mortality and the secondary safety endpoint was moderate or severe bleedings until hospital discharge with respect to three different ADP-receptor antagonists. Eight hundred fifty-six patients were eligible for analysis. Of these, five hundred seven patients (59.2%) received clopidogrel, one hundred seventy-eight patients (20.8%) prasugrel and one hundred seventy-one patients (20.0%) ticagrelor as acute antiplatelet therapy. The adjusted rate of mortality after 1-year did not differ between prasugrel and clopidogrel (hazard ratio [HR]: 0.81, 95% confidence interval [CI] 0.60–1.09, padj=0.17) or between ticagrelor and clopidogrel treated patients (HR: 0.86, 95% CI 0.65–1.15, padj=0.31). In-hospital bleeding events were significantly less frequent in patients treated with ticagrelor vs. clopidogrel (HR: 0.37, 95% CI 0.20–0.69, padj=0.002) and not different in patients treated with prasugrel vs. clopidogrel (HR: 0.73, 95% CI 0.43–1.24, padj=0.24), see Table 1. Conclusion This pooled sub-analysis is the largest analysis on safety and efficacy of three oral ADP-receptor antagonists and shows that an acute therapy with either clopidogrel, prasugrel or ticagrelor is no predictor of 1-year mortality. Treatment with ticagrelor seems to be associated with less in-hospital moderate and severe bleeding events in comparison to clopidogrel. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): German Heart FoundationEuropean Union 7th Framework Program

Comparing Perimenstrual and Nonperimenstrual Migraine Attacks Using an e-Diary

BackgroundEndogenous and exogenous female sex hormones are considered important contributors to migraine pathophysiology. Previous studies have cautiously suggested that perimenstrual migraine attacks have a longer duration and are associated with higher disability compared to non-perimenstrual attacks, but they showed conflicting results on acute therapy efficacy, pain intensity, and associated symptoms.ObjectivesTo compare perimenstrual and non-perimenstrual migraine attack characteristics and assess premenstrual syndrome (PMS) in women with migraine.MethodsWomen with migraine were invited to complete a headache E-diary. Characteristics of perimenstrual attacks and non-perimenstrual attacks were compared. The primary outcome was attack duration. Secondary outcomes were headache intensity, accompanying symptoms, acute medication intake and pain coping. Mixed effects models were used to account for multiple attacks within patients. PMS was assessed in those without hormonal contraceptives. Subgroup analyses were performed for women with menstrually related migraine (MRM) and non-menstrually related migraine (non-MRM), and women with a natural menstrual cycle and women using hormonal contraceptives.ResultsA representative group of n=500 participants completed the E-diary for at least one month. Perimenstrual migraine attacks (n=998) compared with non-perimenstrual attacks (n=4097) were associated with longer duration (20.0 vs 16.1 hours, 95%CI [0.2-0.4]), higher recurrence risk (OR 2.4 [2.0-2.9]), increased triptan intake (OR 1.2 [1.1-1.4]), higher headache intensity (OR 1.4 [1.2-1.7]), less pain coping (mean difference -0.2 [-0.3- -0.1]), more pronounced photophobia (OR 1.3 [1.2-1.4]) and phonophobia (OR 1.2 [1.1-1.4]) and less aura (OR 0.8 [0.6-1.0]). In total 396/500 women completed the diary for ≥3 consecutive menstrual cycles, of whom 56% (221/396) fulfilled MRM criteria. Differences in attack characteristics became more pronounced when focusing on women with MRM and women using hormonal contraceptives. Prevalence of PMS was not different for women with MRM compared to non-MRM (11% vs. 15%).DiscussionThe longer duration of perimenstrual migraine attacks in women (with MRM) is associated with higher recurrence risk and increased triptan use. This may increase the risk of medication overuse and emphasizes the need to develop female-specific prophylactic treatment.