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Production of reactive oxygen species after cerebral blood flow disruption may enhance tissue damage through multiple molecular pathways. Changes in nitric oxide (NO) metabolism and oxidative stress status were investigated in 47 patients with ischemic stroke by measuring plasma nitric oxide (NO) and peroxynitrite (ONOO–) levels.A correlation was sought between these two parameters and i) baseline stroke severity based on the National Institute of Health stroke scale (NIHSS) and ii) neurological outcome in terms of NIHSS changes from entry (T0) to 30 days after symptom onset (T1). The control group consisted of 30 age- and sex-matched healthy subjects. Mean plasma levels of ONOO– (arbitrary fluorescence number ± SD) were significantly higher in patients (7.70 ± 1.71 vs 5.35 ± 0.69, p < 0.001), whereas mean NO levels (nmol/mg protein) were significantly higher in controls (115.40 ± 12.40 vs. 51.10 ± 12.50, p < 0.001). Plasma ONOO– was significantly higher among patients with non-lacunar stroke (8.48 ± 1.50 vs. 6.95 ± 1.58 in those with lacunar stroke; p = 0.001), whereas NO levels were significantly higher among lacunar stroke patients (60.00 ± 7.86, vs. 41.77 ± 9.29 in patients with nonlacunar stroke; p < 0.001). Nitric oxide plasma levels were also associated with an unfavorable evolution in non-lacunar stroke, since a 10 unit increase in NO predicted a 1 point reduction in the NIHSS score at T1. Findings show that changes in NO metabolism may be considered as markers of brain injury in patients with ischemic stroke. Further work is needed to establish whether the amount of biochemical changes related to oxidative stress may influence outcome in these patients. [ABSTRACT FROM AUTHOR]

Objective: Nearly 60% of migraine patients treated with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway experience a ≥ 50% reduction in monthly migraine days (MMD) at 12 weeks compared to baseline (responders). However, approximately half of the patients not responding to anti-CGRP mAbs ≤ 12 weeks do respond ≤ 24 weeks (late responders). We assessed frequency and characteristics of patients responding to anti-CGRP mAbs only > 24 weeks (ultra-late responders)., Methods: In this multicenter (n = 16), prospective, observational, real-life study, we enrolled all consecutive adults affected by high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM), with ≥ 3 prior therapeutic failures, treated with any anti-CGRP mAbs for ≥ 48 weeks. We defined responders patients with a ≥ 50% response rate ≤ 12 weeks, late responders those with a ≥ 50% response rate ≤ 24 weeks, and ultra-late responders those achieving a ≥ 50% response only > 24 weeks., Results: A total of 572 migraine patients completed ≥ 48 weeks of anti-CGRP mAbs treatment. Responders accounted for 60.5% (346/572), late responders for 15% (86/572), and ultra-late responders for 15.7% (90/572). Among ultra-late responders, 7.3% (42/572) maintained the ≥ 50% response rate across all subsequent time intervals (weeks 28, 32, 36, 40, 44, and 48) and were considered persistent ultra-late responders, while 8.4% (48/572) missed the ≥ 50% response rate at ≥ 1 subsequent time interval and were classified as fluctuating ultra-late responders. Fifty patients (8.7%) did not respond at any time interval ≤ 48 weeks. Ultra-late responders differed from responders for higher BMI (p = 0.033), longer duration of medication overuse (p < 0.001), lower NRS (p = 0.017) and HIT-6 scores (p = 0.002), higher frequency of dopaminergic symptoms (p = 0.002), less common unilateral pain-either alone (p = 0.010) or in combination with UAS (p = 0.023), allodynia (p = 0.043), or UAS and allodynia (p = 0.012)-a higher number of comorbidities (p = 0.012), psychiatric comorbidities (p = 0.010) and a higher proportion of patients with ≥ 1 comorbidity (p = 0.020)., Conclusion: Two-thirds of patients not responding to anti-CGRP mAbs ≤ 24 weeks do respond later, while non-responders ≤ 48 weeks are quite rare (8.7%). These findings suggest to rethink the duration of migraine prophylaxis and the definition of resistant and refractory migraine, currently based on the response after 2-3 months of treatment., (© 2024. The Author(s).)

Background: The outcome of migraine patients retreated with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (anti-CGRP) or its receptor (anti-CGRPr) is not completely known., Methods: This multicentric prospective observational cohort study assessed monthly migraine days (MMDs), migraine acute medication intake (MAMI), and HIT-6 at baseline, after 90-112 days (Rev-1), after 84-90 days since Rev-1 (Rev-2) and 30 days after the last injection of anti-CGRP/CGRPr mAbs (Year-end), in the first and the second year after a discontinuation period., Results: We enrolled 226 patients (79.6% with chronic migraine; 55.3% on erenumab and 44.7% on galcanezumab or fremanezumab). MMDs, MAMI, and HIT-6-did not differ at the respective first and second-year evaluations in the entire cohort, and comparing anti-CGRP with anti-CGRPr Abs. MMDs (18.1 ± 7.8 vs. 3.4 ± 7.8), MAMI (26.7 ± 28.3 vs.17.7 ± 17.2), and HIT-6 scores (63.1 ± 5.9 vs. 67.1 ± 10.3) were lower in the second year than in the pre-treatment baseline (consistently, p < 0.0001). Second-year baseline MMDs were lower in patients on anti-CGRP mAbs (p = 0.001) and with lower pre-treatment baseline MMDs (p ≤ 0.001)., Conclusion: Anti-CGRP/CGRPr mAbs are effective in the second as in the first year. The use of anti-CGRP or CGRPr mAbs influenced the second-year baseline MMDs, but their effectiveness did not differ during the two treatment years., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: To investigate in real-life the conversion from chronic migraine (CM) to episodic migraine (EM), specifically to EM with High-Frequency (HFEM: 8-14 monthly migraine days, MMDs), Medium-Frequency (MFEM, 4-7 MMDs), and Low-Frequency EM (LFEM, 0-3 MMDs), and its persistence during 1 year of treatment with galcanezumab., Methods: Consecutive CM patients treated with galcanezumab completing 1 year of observation were enrolled. We collected data on MMDs, pain intensity (Numeric Rating Scale, NRS score), and monthly acute medication intake (MAMI) from baseline (V1) to the 12-month visit (V12)., Results: Of the 155 enrolled patients, 116 (around 75%) reverted to EM at every visit and 81 (52.3%) for the entire 1-year treatment. Patients with older onset age (p = 0.010) and fewer baseline MMDs (p = 0.005) reverted more frequently to EM. At V12, 83 participants (53.5%) presented MFEM or LFEM. Patients reverted to MFEM or LFEM for 7 months (25th 1, 75th 11). The medication overuse discontinuation rate at V12 was 82.8% and occurred for 11 months (25th 8, 75th 12). From baseline to V12, the MAMI decreased by 17 symptomatic drugs (p < 0.000001) while the NRS score reduced by almost 2 points (p < 0.000001). A consistent transition to EM for the entire treatment year was observed in 81 (52.3%) patients., Discussion: The 1-year GARLIT experience suggests that more than half of CM patients treated with galcanezumab persistently reverted to EM in real life., Trial Registration: ClinicalTrials.gov NCT04803513., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: To identify the clinical profile and aura characteristics of patients with Migraine with Aura (MwA) having acute cerebral ischemia, we compared stroke phenotype and risk factors in stroke patients with (S+MwA+) or without (S+MwA-) MwA and aura features in MwA patients with (S+MwA+) or without (S-MwA+) stroke., Methods: In this retrospective multicenter case-control study, we reviewed stroke phenotypes and vascular risk factors in S+MwA+ and S+MwA- patients younger than 60 years and risk factors and aura type, duration, onset age, and the frequency in the previous year in S+MwA+ patients and S-MwA+ subjects matched for age and disease history, investigated for patent foramen ovale (PFO)., Results: 539 stroke (7.7% S+MwA+) and 94 S-MwA + patients were enrolled. S+MwA+ patients were younger (p =.0.004) and more frequently presented PFO [OR 4.89 (95% CI 2.12-11.27)], septal interatrial aneurism [OR 2.69 (95% CI 1.15-6.27)] and cryptogenic ischemic stroke (CIS) [OR 6.80 (95% CI 3.26-14.18)] than S+MwA- subjects. Significant atherosclerosis was not detected in S+MwA+ patients. Compared to S-MwA+, S+MwA+ patients were characterized by visual [OR 3.82 (95% CI 1.36-10.66)] and shorter-lasting (20.0 min IQr 13.1 vs 30.0 min IQr 25.0; p < 0.001) aura, and PFO [OR 1.26 (95% CI 1.03-1.54)]. Regression analysis evidenced that only shorter aura duration associated with stroke (p = 0.001). High-risk PFO was equally represented in S+MwA-, S+MwA+, S-MwA+ groups., Conclusions: Shorter visual aura and CIS characterize MwA patients with stroke. Although more prevalent, PFO can not be considered the main responsible for the increased stroke risk in MwA patients but as a part of a complex multifactorial condition., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Following an ischemic stroke a highly variable clinical outcome is commonly evident despite similar onset symptoms as well as lesion characteristics. The aim of this study was to identify indexes providing early prediction of functional recovery, in addition to clinical severity and lesion dimension at onset of stroke., Methods: In 32 patients, magnetoencephalographic (MEG) parameters collected in the acute phase (<10 days from symptoms onset, T0) from affected (AH) and unaffected (UH) hemispheres at rest and evoked by sensory stimuli were evaluated in association with the clinical outcome in a stabilized phase (T1, median 7.8 months) classified with three levels: worsening, partial and full recovery., Results: Multiple multinomial logistic regression indicated AH gamma and UH delta band powers able to prognosticate clinical outcome at T1. After inclusion in this analysis, lesion volume had the strongest predictive ability, and UH delta band power remained as a predictive factor with a measurable cut-off, maximizing both sensitivity and specificity of the prediction: a patient with UH delta below cut-off would recover to some extent; a patient with UH delta above cut-off would have a probability of about 70% to worsen., Conclusions: MEG UH delta and AH gamma band powers were found to provide useful information about long-term outcome prognosis. Only the increase of delta band activity in the unaffected hemisphere contains information about the outcome in addition to the lesion volume.

Cerebral hemodynamics play a pivotal role in stroke pathogenesis. Transcranial Doppler (TCD) studies demonstrated the importance of cerebral vasomotor reactivity (VMR) on the outcome of carotid artery occlusion (CAO). So far, positron emission tomography represents the best technique for detecting both hemodynamic and metabolic aspects of cerebral perfusion adaptive processes in cerebrovascular patients. Near-infrared spectroscopy (NIRS) is a new method allowing for a non-invasive assessment of cerebral blood flow and hemoglobin (Hb) oxygenation parameters.A recent TCD and NIRS study demonstrated that patients with symptomatic CAO had lower VMR values measured by TCD and lower oxygen saturation (oxygen%) increases detected by NIRS than asymptomatic ones. The parameters were obtained simultaneously after CO(2) inhalation. The present study aims to investigate if Hb oxygen % could represent also at rest a marker of hemodynamic status in carotid disease.Thirty-five symptomatic and 17 asymptomatic patients with CAO underwent a simultaneous examination by means of TCD and NIRS at rest condition and during CO(2) reactivity test. Symptomatic patients presented with oxygen% values at rest higher (p = 0.001) and VMR values lower (p < 0.001) than asymptomatic subjects. According to a logistic model, for each unitary VMR increase, the odds of being symptomatic decreases of about 10% (OR = 0.9, p = 0.001); for each unitary increase of oxygen% at baseline, this odd increases of about 23% (OR = 1.23, p = 0.031). In addition to TCD VMR values, oxygen hemoglobin saturation at rest detected by NIRS can discriminate symptomatic from asymptomatic patients with CAO. NIRS can add an important contribution to explain pathophysiological mechanisms of stroke occurrence.

Recovery from hemiplegia is a complex phenomenon that depends on various adaptive processes involving both the affected and the unaffected hemisphere. Our aim in this study was to investigate changes in cerebral perfusion in hemiplegic stroke patients during passive movements and their correlation with the subsequent motor recovery. The study included 30 patients with single, subcortical ischemic cerebral lesions. Within 14 days (range 8 to 14 days) from stroke onset, all patients were examined for the effects of passive elbow movements on cerebral blood flow in the middle cerebral arteries (MCAs) by means of bilateral transcranial Doppler (TCD) ultrasonography. On the same day as TCD assessment, they were also evaluated clinically with the Canadian Neurological Scale (CNS) and with Medical Research Council (MRC) scale for motor deficit of the affected arm. A clinical evaluation using the same scales was repeated after two months of motor rehabilitation therapy. We investigated the relationship between changes of Mean Flow Velocity (MFV) during passive movements and degree of recovery after stroke. The logistic regression procedure indicated that out of all factors considered as possibly related to a good clinical motor deficit recovery of the affected arm, evaluated by means of MRC, only the MFV percentage increase played a predictive role. In particular, for each additional point of contralateral MFV percentage increase during passive movement of the affected arm, the relative probability of good clinical recovery increased 5.68 times (95% CI=1.76-18.40; p=0.004). Similar results were found when the clinical recovery was measured by means of the CNS (slope=0.40, p<0.001). Passive movements in hemiplegic stroke patients before clinical recovery elicit activation patterns that may be critical for the restoration of motor function.I n particular, early and consistent activation of the affected hemisphere, as detected with TCD, seems to predict the positive evolution of a motor deficit.

Transcranial Doppler ultrasonography (TCD) has been widely used to obtain information about changes in cerebral perfusion during motor activity after stroke. This type of application is greatly limited when severe motor deficits are present that impede the performance of an active motor task. In this study, we explored the effect of performing passive arm movements on cerebral perfusion. Twenty healthy subjects were investigated. A bilateral TCD monitoring of the middle cerebral artery (MCA) flow velocity was performed during the following experimental conditions: 1-min of active and passive flexion-extension elbow movement and 1-min of active and passive dorsal extension hand movement. Each task was performed with both left and right arms. The percentage increase in flow velocity from rest to task performance was calculated. Each task produced a significantly greater increase in mean flow velocity in the contralateral MCA with respect to the ipsilateral. When comparing the effect of passive and active tasks, no significant difference in mean flow velocity changes recorded in the ipsilateral and the contralateral MCA was detected regarding either elbow or hand movements. These findings demonstrate the possibility of obtaining information about changes in hemispheric cerebral perfusion during passive movements involving elbow and hand. This type of application deserves further attention in the study of cerebral functional changes following cerebral lesions.

This study assessed the use of transcranial Doppler ultrasound in detecting selective changes in cerebral blood flow velocity during emotional processes. The role of the respective hemispheres in emotional processing is controversial. Cerebral control of emotional processing has previously been investigated by analysis of patients with unilateral brain damage, experiments with selective stimulation of only one hemisphere, and more recently by imaging techniques measuring local cerebral blood flow. We investigated mean flow velocity continuously and simultaneously in both the right and left middle cerebral arteries (MCAs) in 16 healthy right-handed young subjects at rest and during the performance of three tasks: task 1: 15 slides with nonemotional content; task 2: 15 slides with negative emotional content; task 3: 15 slides with nonemotional content with different content from that in task 1. The three tasks produced significantly different effects on the right and left hemispheres. During the two nonemotional tasks the increase in mean flow velocity over basal values was similar in the two MCAs (task 1: left MCA = 3.27 +/- 1.9%; right MCA = 3.63 +/- 2.1%; task 3: left MCA = 2.42 +/- 0.7%; right MCA = 2.56 +/- 1.3%); the negative emotional task was accompanied by a significantly higher increase in the right (11.31 +/- 1.6%) than in the left MCA (4.72 +/- 3.7%; analysis of variance two-way interaction: side of recording x task, F = 43.6, P < 0.001). These results show the possibility of obtaining specific functional information from bilateral transcranial Doppler ultrasound and suggest the involvement of the right hemisphere in emotional processing.