Near-death experiences are associated with rapid eye movement (REM) sleep intrusions in migraine patients, independent of migraine aura.

BACKGROUND AND PURPOSE: Migraine aura, near-death experiences (NDEs), and rapid eye movement (REM) sleep intrusions might share common mechanisms. Here, we investigated the prevalence of NDEs and REM sleep intrusions in people with migraine. We hypothesized that NDEs and REM sleep intrusions are more prevalent in migraine patients with aura than in those without. METHODS: We conducted a prospective cross-sectional cohort study at a tertiary headache center, based on a prespecified sample size (n = 808). Migraine patients completed a series of questionnaires, including questions about demographic and headache characteristics, the 16-item Greyson NDE scale, four questions about REM sleep intrusions, and the Depression, Anxiety, and Stress Scale 21 (DASS-21). RESULTS: Of 808 migraine patients (mean age 44.4 ± 13.3 years, 87.0% women), 353 (43.7%) had a current or previous history of migraine aura. Prevalence of NDE was 2.7% and not different in patients with and without aura (2.8% vs. 2.6%; p > 0.999). REM sleep intrusions were reported by 5.4% of participants and in a similar proportion of patients with and without aura (6.3% vs. 4.9%; p = 0.43). However, participants with REM sleep intrusions had had an NDE more often than participants without REM sleep intrusions (n = 5/44, 11.4% vs. n = 17/754, 2.2%; p = 0.005). Higher DASS-21 scores were associated with REM sleep intrusions (p < 0.001). CONCLUSIONS: In this tertiary center cohort study, the prevalence of NDE and REM sleep intrusions was not influenced by migraine aura status. However, we identified an association between NDE and REM sleep intrusions, which corroborates the notion that they might share pathophysiological mechanisms.

Effect of switching to erenumab in non-responders to a CGRP ligand antibody treatment in migraine: A real-world cohort study.

Background: Therapeutic options for migraine prevention in non-responders to monoclonal antibodies (mAbs) targeting Calcitonin Gene-Related Peptide (CGRP) and its receptor are often limited. Real-world data have shown that non-responders to the CGRP-receptor mAb erenumab may benefit from switching to a CGRP ligand mAb. However, it remains unclear whether, vice versa, erenumab is effective in non-responders to CGRP ligand mAbs. In this study, we aim to assess the efficacy of erenumab in patients who have previously failed a CGRP ligand mAb. Methods: This monocentric retrospective cohort study included patients with episodic or chronic migraine in whom a non-response (< 30% reduction of monthly headache days during month 3 of treatment compared to baseline) to the CGRP ligand mAbs galcanezumab or fremanezumab led to a switch to erenumab, and who had received at least 3 administrations of erenumab. Monthly headache days were retrieved from headache diaries to assess the ≥30% responder rates and the absolute reduction of monthly headache days at 3 and 6 months of treatment with erenumab in this cohort. Results: From May 2019 to July 2022, we identified 20 patients who completed 3 months of treatment with erenumab after non-response to a CGRP ligand mAb. Fourteen patients continued treatment for ≥6 months. The ≥30% responder rate was 35% at 3 months, and 45% at 6 months of treatment with erenumab, respectively. Monthly headache days were reduced from 18.6 ± 5.9 during baseline by 4.1 ± 3.1 days during month 3, and by 7.0 ± 4.8 days during month 6 compared to the month before treatment with erenumab (p < 0.001, respectively). Responders and non-responders to erenumab did not differ with respect to demographic or headache characteristics. Conclusion: Switching to erenumab in non-responders to a CGRP ligand mAb might be beneficial in a subgroup of resistant patients, with increasing responder rates after 6 months of treatment. Larger prospective studies should aim to predict which subgroup of patients benefit from a switch.

Retinal microvascular signs and recurrent vascular events in patients with TIA or minor stroke.

BACKGROUND AND PURPOSE: Retinal pathologies are an independent risk factor for ischaemic stroke, but research on the predictive value of retinal abnormalities for recurrent vascular events in patients with prior stroke is inconclusive. We investigated the association of retinal pathologies with subsequent vascular events. METHODS: In a substudy of the Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients (INSPiRE-TMS) trial, we enrolled patients with recent transient ischaemic attack (TIA) or minor stroke with at least one modifiable risk factor. Primary outcome was the composite of subsequent vascular events. Retinal photographs were taken at baseline and categorised into three different fundus groups by a telemedically linked ophthalmologist. RESULTS: 722 patients participated in the current study and 109 major vascular events occurred. After multivariable adjustments, we did not find a significant association between fundus categories and risk for subsequent vascular events (HRs for moderate vascular retinopathy and vascular retinopathy with vessel rarefaction in comparison to no vascular retinopathy 1.03 (95% CI 0.64 to 1.67), p=0.905 and 1.17 (95% CI 0.62 to 2.20), p=0.626). In a selective post hoc analysis in patients with diabetes mellitus and hypertension, patients with vascular retinopathy with vessel rarefaction had a higher risk for recurrent stroke (HR 24.14 (95% CI 2.74 to 212.50), p=0.004). CONCLUSIONS: Retinal changes did not predict major subsequent vascular events in patients with recent TIA or minor stroke. Further studies are needed to examine the utility of fundus photography in assessing the risk of stroke recurrence in patients with diabetes mellitus and hypertension.

Patient-Centered Outcomes in a Randomized Trial Investigating a Multimodal Prevention Program After Transient Ischemic Attack or Minor Stroke: The INSPiRE-TMS Trial.

BACKGROUND: The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes. METHODS: In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up. RESULTS: Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5-43.5); 36.1 after 2 years (95% CI, 13.1-59.7) and 29.6 (95% CI, 2.0-57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03-1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96-1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95-1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up. CONCLUSIONS: Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01586702.

Resumption of migraine preventive treatment with CGRP(-receptor) antibodies after a 3-month drug holiday: a real-world experience.

BACKGROUND: Migraine frequency increases after the cessation of successful preventive treatment with CGRP(-receptor) monoclonal antibodies (mAbs). In this study, we aimed to evaluate the course of migraine after treatment resumption. METHODS: Patients with migraine, who started treatment with the same CGRP(-R) mAb after a three-month drug holiday were included in this analysis. We collected headache data at four prospective visits: 1) during the four weeks before the initial mAb treatment (baseline); 2) during the four weeks before the last mAb injection; 3) in weeks 13-16 of the drug holiday; 4) in weeks 9-12 after treatment restart. Outcomes were the changes in monthly migraine days (MMD), monthly headache days (MHD), monthly days with acute medication use (AMD) and Headache Impact Test-6 (HIT-6) scores across the observation period. RESULTS: This study included 39 patients (erenumab n = 16; galcanezumab/ fremanezumab n = 23). MMD decreased from 12.3 ± 6.3 at the end of the drug holiday to 7.8 ± 5.5 three months after treatment restart (p = 0.001). The improvement after treatment resumption was similar to the response in the initial treatment period (baseline: 12.3 ± 6.3 MMD vs. 7.5 ± 5.2 MMD before treatment interruption). MHD and AMD showed a significant improvement after treatment restart. HIT-6 scores decreased, indicating a diminished impact of headache on everyday life. CONCLUSIONS: Reinitiation of treatment with CGRP(-R) mAbs after a drug holiday leads to a significant reduction of migraine frequency and medication use as well as improvement in quality of life.

Migraine evolution after the cessation of CGRP(-receptor) antibody prophylaxis: a prospective, longitudinal cohort study.

BACKGROUND: National and international guidelines recommend stopping migraine prophylaxis with CGRP(-receptor) monoclonal antibodies after 6-12 months of successful therapy. In this study, we aimed to analyze the course of migraine for four months after the cessation of CGRP(-receptor) antibodies use. METHODS: This longitudinal cohort study included patients with migraine who received a CGRP-(receptor) antibody for ≥8 months before treatment cessation. We analyzed headache data in the four-week period prior to mAb treatment initiation (baseline), in the month before the last mAb injection, in weeks 5-8 and 13-16 after last treatment. Primary endpoint of the study was the change of monthly migraine days from the month before last treatment to weeks 13-16. Secondary endpoints were changes in monthly headache days and monthly days with acute medication use. RESULTS: A total of 62 patients equally distributed between prophylaxis with the CGRP-receptor antibody erenumab and the CGRP antibodies galcanezumab or fremanezumab participated in the study. Patients reported 8.2 ± 6.6 monthly migraine days in the month before last treatment. Monthly migraine days gradually increased to 10.3 ± 6.8 in weeks 5-8 (p = 0.001) and to 12.5 ± 6.6 in weeks 13-16 (p < 0.001) after drug cessation. Monthly migraine days in weeks 13-16 were not different from baseline values (-0.8 ± 5.4; p > 0.999). Monthly headache days and monthly days with acute medication use showed a similar pattern. CONCLUSIONS: The cessation of CGRP(-receptor) antibodies migraine prophylaxis was associated with a significant increase of migraine frequency and acute medication intake over time.

Cardiac Troponin and Recurrent Major Vascular Events after Minor Stroke or Transient Ischemic Attack.

OBJECTIVE: This study was undertaken to investigate whether high-sensitivity cardiac troponin T (hs-cTnT) is associated with major adverse cardiovascular events (MACE) in patients with minor stroke or transient ischemic attack (TIA), and whether this association differs after risk stratification based on the Age, Blood Pressure, Clinical Features, Duration of Symptoms, Diabetes (ABCD2 ) score. METHODS: INSPiRE-TMS was a randomized controlled trial allocating patients with minor stroke or TIA to an intensified support program or conventional care. In this post hoc analysis, participants were categorized using hs-cTnT levels (5th generation; Roche Diagnostics, Manheim, Germany; 99th percentile upper reference limit [URL] = 14ng/l). Vascular risk was stratified using the ABCD2 score (lower risk = 0-5 vs higher risk = 6-7). Cox proportional hazard regression was performed using covariate adjustment and propensity score matching (PSM) for the association between hs-cTnT and MACE (stroke/nonfatal coronary event/vascular death). RESULTS: Among 889 patients (mean age = 70 years, 37% female), MACE occurred in 153 patients (17.2%) during a mean follow-up of 3.2 years. hs-cTnT was associated with MACE (9.3%/yr, >URL vs 4.4%/yr, ≤URL, adjusted hazard ratio [HR] = 1.63 [95% confidence interval (CI) = 1.13-2.35], adjusted HR [Q4 vs Q1 ] = 2.57 [95% CI = 1.35-4.97], adjusted HR [log-transformed] = 2.31 [95% CI = 1.37-3.89]). This association remained after PSM (adjusted HR = 1.76 [95% CI = 1.14-2.72]). There was a significant interaction between hs-cTnT and ABCD2 category for MACE occurrence (pinteraction  = 0.04). In the lower risk category, MACE rate was 9.5%/yr in patients with hs-cTnT > URL, which was higher than in those ≤URL (3.8%/yr) and similar to the overall rate in the higher risk category. INTERPRETATION: hs-cTnT levels are associated with incident MACE within 3 years after minor stroke or TIA and may help to identify high-risk individuals otherwise deemed at lower risk based on the ABCD2 score. If confirmed in independent validation studies, this might warrant intensified secondary prevention measures and cardiac diagnostics in stroke patients with elevated hs-cTnT. ANN NEUROL 2021;90:901-912.

Deterioration of headache impact and health-related quality of life in migraine patients after cessation of preventive treatment with CGRP(-receptor) antibodies.

BACKGROUND: Migraine preventive treatment with CGRP(-receptor) monoclonal antibodies (mAbs) has a positive effect on patients' health-related quality of life (HRQoL). The German treatment guidelines recommend discontinuing successful treatment with CGRP(-receptor) mAbs after 6-12 months. We aimed to evaluate headache-specific and generic HRQoL for three months after discontinuation of CGRP(-receptor) mAb treatment. METHODS: We conducted a prospective, longitudinal cohort study, including patients with migraine after 8-12 months of therapy with a CGRP(-R) mAb and before a planned discontinuation attempt. HRQoL was assessed at the time of the last mAbs injection (V1), eight weeks later (V2), and sixteen weeks later (V3). For headache-specific HRQoL, we used the Headache Impact Test-6 (HIT-6). Generic HRQoL was determined with the EuroQol-5-Dimension-5-Level (ED-5D-5L) form, and the Short-Form 12 (SF-12), which comprises a Physical Component Summary (PCS-12) and a Mental Component Summary (MCS-12). Questionnaires' total scores were compared across the three observation points using nonparametric procedures. RESULTS: The study cohort consisted of n = 61 patients (n = 29 treated with the CGRP-receptor mAb erenumab and n = 32 with the CGRP mAbs galcanezumab or fremanezumab). The HIT-6 sum score was 59.69 ± 6.90 at V1 and increased by 3.69 ± 6.21 at V3 (p < 0.001), indicating a greater headache impact on patients' lives. The mean total EQ-D5-L5 score declined from 0.85 ± 0.17 at V1 by - 0.07 ± 0.18 at V3 (p = 0.013). Both Mental and Physical Component Scores of the SF-12 worsened significantly during treatment discontinuation: The PCS-12 total score decreased by - 4.04 ± 7.90 from V1 to V3 (p = 0.013) and the MCS-12 score by - 2.73 ± 9.04 (p = 0.003). Changes in all questionnaires' scores but the MCS-12 were already significant in the first month of the drug holiday (V2). CONCLUSIONS: Our results show a significant decline in headache impact and generic HRQoL of migraine patients after treatment discontinuation of a CGRP(-R) mAb. The observed deterioration is above the established minimally clinically important differences for each of the questionnaires and can therefore be considered clinically meaningful. Monitoring HRQoL during a discontinuation attempt could facilitate the decision whether or not to resume preventive treatment with CGRP(-R) mAbs.

A support programme for secondary prevention in patients with transient ischaemic attack and minor stroke (INSPiRE-TMS): an open-label, randomised controlled trial.

BACKGROUND: Patients with recent stroke or transient ischaemic attack are at high risk for a further vascular event, possibly leading to permanent disability or death. Although evidence-based treatments for secondary prevention are available, many patients do not achieve recommended behavioural modifications and pharmaceutical prevention targets in the long-term. We aimed to investigate whether a support programme for enhanced secondary prevention can reduce the frequency of recurrent vascular events. METHODS: INSPiRE-TMS was an open-label, multicentre, international randomised controlled trial done at seven German hospitals with acute stroke units and a Danish stroke centre. Patients with non-disabling stroke or transient ischaemic attack within 2 weeks from study enrolment and at least one modifiable risk factor (ie, arterial hypertension, diabetes, atrial fibrillation, or smoking) were included. Computerised randomisation was used to allocate patients (1:1) either to the support programme in addition to conventional care or to conventional care alone. The support programme used feedback and motivational interviewing strategies with eight outpatient visits over 2 years aiming to improve adherence to secondary prevention targets. The primary outcome was the composite of major vascular events consisting of stroke, acute coronary syndrome, and vascular death, assessed in the intention-to-treat population (all patients who underwent randomisation, did not withdraw study participation, and had at least one follow-up). Outcomes were assessed at annual follow-ups using time-to-first-event analysis. All-cause death was monitored as a safety outcome. This trial is registered with ClinicalTrials.gov, NCT01586702. FINDINGS: From Aug 22, 2011, to Oct 30, 2017, we enrolled 2098 patients. Of those, 1048 (50·0%) were randomly assigned to the support programme group and 1050 (50·0%) patients were assigned to the conventional care group. 1030 (98·3%) patients in the support group and 1042 (99·2%) patients in the conventional care group were included in the intention-to-treat analysis. The mean age of analysed participants was 67·4 years and 700 (34%) were women. After a mean follow-up of 3·6 years, the primary outcome of major vascular events had occurred in 163 (15·8%) of 1030 patients of the support programme group and in 175 (16·8%) of 1042 patients of the conventional care group (hazard ratio [HR] 0·92, 95% CI 0·75-1·14). Total major vascular event numbers were 209 for the support programme group and 225 for the conventional care group (incidence rate ratio 0·93, 95% CI 0·77-1·12; p=0·46) and all-cause death occurred in 73 (7·1%) patients in the support programme group and 85 (8·2%) patients in the conventional care group (HR 0·85, 0·62-1·17). More patients in the support programme group achieved secondary prevention targets (eg, in 1-year-follow-up 52% vs 42% [p<0·0001] for blood pressure, 62% vs 54% [p=0·0010] for LDL, 33% vs 19% [p<0·0001] for physical activity, and 51% vs 34% [p=0·0010] for smoking cessation). INTERPRETATION: Provision of an intensified secondary prevention programme in patients with non-disabling stroke or transient ischaemic attack was associated with improved achievement of secondary prevention targets but did not lead to a significantly lower rate of major vascular events. Further research is needed to investigate the effects of support programmes in selected patients who do not achieve secondary prevention targets soon after discharge. FUNDING: German Federal Ministry of Education and Research, Pfizer, and German Stroke Foundation.

Telemedical assessment of optic nerve head and retina in patients after recent minor stroke or TIA.

The aim of the study is to telemedically assess the prevalence of simple optic nerve atrophy and retinal arteriolar anomalies in subjects who have had a minor stroke or TIA within 14 days, and to compare these results with an age-matched control group. By using a mobile examination unit, retinal photographs were taken with a 45° non-mydriatic colour fundus camera (KOWA NM-45, non-mydriatic-alpha) in patients who had suffered from a minor stroke or TIA within 14 days of the time of the examination. Retinal photographs were focused on the optic nerve head region. Pupils were not dilated. The documented medical history and the retinal images were stored on a server using browser independent web-based software running on PCs, tablets and smartphones. After completing the upload of the medical interview and the retinal images into the electronic patient chart, all retinal images were evaluated via telemedicine by an experienced senior consultant ophthalmologist. Age-matched normotensive, non-diabetic subjects (aged 40-89 years) who reported no systemic or ocular diseases were used as the control group. Both study groups were divided into five decades of life (40-49; 50-59; 60-69; 70-79; 80-89 years). We calculated the prevalences and the ratios of prevalences of optic nerve atrophy and retinal arteriolar anomalies between the stroke and the control group per decades of life. 139 minor stroke or TIA subjects (aged 40-89 years) and 1611 age-matched control subjects were examined. In the stroke group, we found significantly increased prevalences of optic nerve atrophy and retinal arteriolar anomalies throughout the 5th-8th decade of life when compared to age-matched controls. The prevalence of optic nerve atrophy in stroke subjects outranged the prevalence in the controls depending on age-class by a factor of 3-21. Simple optic nerve atrophy is frequent in patients who have suffered from an ischemic stroke or TIA, and it seems to indicate vascular damage, indicating the necessity for telemedically assisted assessment of the optic nerve.