AimThe TACHIS study (from the ancient Greek adjective "tachýs" meaning rapid) aimed to evaluate eptinezumab effectiveness and tolerability in routine clinical practice, integrating patient-reported outcomes and use of International Headache Society (IHS)-endorsed categories of migraine control by treatment.BackgroundEptinezumab is the only intravenous anti-calcitonin gene related peptide (CGRP) monoclonal antibody (mAb) approved for migraine prevention. While its efficacy has been demonstrated in RCTs, real-world evidence in patients with prior preventive treatment failures is still limited.MethodsTACHIS is a prospective, multicenter, observational study conducted in Italy. Adults with episodic or chronic migraine initiating eptinezumab were followed for 24 weeks. Primary outcomes included change from baseline in monthly migraine days (MMDs) and ≥50% responder rate. Secondary outcomes included changes from baseline in acute medication use, Migraine Disability Assessment (MIDAS) and Headache Impact Test-6 (HIT-6) and IHS-defined residual burden categories. Logistic regression identified factors of response status.ResultsA total of 128 patients were included (82% female; 82% chronic migraine). MMDs decreased overall by 5.7 days (95% CI: -7.2 to -4.3) at week 12 and 6.9 (95% CI: -8.5 to -5.2) at week 24 (p < 0.001). A ≥ 50% response was achieved in 43.8% and 48.2% of patients at weeks 12 and 24, respectively. Over 40% of patients achieved optimal or modest migraine control. CGRP targeted therapy-naïve patients experienced significant greater benefit, though non-naïve patients also improved. Female sex and chronic migraine diagnosis were independently associated with response at 12 weeks. Adverse events were infrequent (4.7%) and mild, with no discontinuations due to safety concerns.ConclusionsEptinezumab demonstrated effectiveness and tolerability in a real-world population of patients with migraine and prior preventive treatment failures. The integration of migraine control metrics provides a comprehensive evaluation of therapeutic impact and supports eptinezumab use in routine care.Trial RegistrationThe TACHIS study was preregistered on clinicaltrial.gov, NCT06409845.

BACKGROUND:This study aimed at identifying neuropsychological sub-phenotypes in amyotrophic lateral sclerosis (ALS) within the mild cognitive impairment (MCI) and mild behavioral impairment (MBI) frameworks. METHODS:We used individual task-/item-level data from the cognitive and behavioral sections of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) from 901 non-demented ALS to derive neuropsychological sub-phenotypes pursuant to classical MCI and MBI frameworks and in accordance with an expanded version of Strong's criteria, which also addressed memory and visuo-spatial measures. RESULTS:The prevalence of MCI and MBI was 39% and 37%, respectively in this retrospective review. The following MCI sub-phenotypes were identified: dysexecutive MCI-single- and multiple-domain (dMCI-sd: 63%; dMCI-md: 24%, respectively); non-dysexecutive MCI-single- and multiple-domain (ndMCI-sd: 12%; ndMCI-md: 1%, respectively). MBI was classified as follows: apathetic MBI-single- and multiple-domain (aMBI-sd: 40%; aMBI-md: 20%, respectively); apathetic-disinihibited/perseverative MBI-multiple domain (ad/pMBI-md: 21%); disinihibited/perseverative MBI-multiple domain (d/pMBI-md: 7%); psychotic MBI-single- and multiple-domain (psyMBI-sd: 2%; psyMBI-md: 3%, respectively); unclassifiable MBI-multiple domain (uMBI-md: 1%). 143 (16%) of patients exhibited mild cognitive and behavioral impairment (MCBI). CONCLUSIONS:This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients, which, with further validation, might be useful for both research and clinical purposes.

This study aimed to compare different algorithms based on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) to classify patients with amyotrophic lateral sclerosis (ALS) according to their neuropsychological phenotype to identify possible discrepancies among these systems. ECAS-Cognitive and -Carer Interview (ECAS-C/-CI) scores of N = 901 patients with ALS without a formal diagnosis of dementia were retrospectively retrieved. Patients were classified, pursuant to Strong et al.’s criteria, as cognitively and behaviourally normal (ALScbn), cognitively and/or behaviourally impaired (ALSci/bi/cbi), or Possible ALS-FTD, according the following ECAS-based algorithms: (1) Abrahams’, solely addressing ECAS-C total and ALS-Specific subtotals; (2) Poletti et al.’s, addressing single task-level ECAS-C scores; (3) “Subscale”, addressing ECAS-C subscales (i.e., Language, Executive, Fluency, Memory and Visuospatial). All algorithms relied on single-item-level ECAS-CI scores for behavioural classifications. Whilst agreement rates among these classifications were moderate to high (84–86

IntroductionEptinezumab is an intravenous anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) approved for the prevention of episodic and chronic migraine. We aimed to explore the earliest changes in migraine pain intensity and associated symptoms during the first 30 min of eptinezumab infusion in a real-world setting, particularly when an acute migraine attack was ongoing.MethodsThe BE-FREE study is an ongoing Italian observational, multicenter, independent, real-world, and prospective study. We enrolled patients affected with episodic migraine (EM) and chronic migraine (CM) who were experiencing an ongoing migraine attack. Eptinezumab was administered within 1–12 h of the onset of the qualifying migraine attack. Data collected included monthly migraine days (MMDs), headache pain intensity, the number of monthly acute medications, and the use of concomitant or past standard preventive treatments (SPTs). The Numerical Rating Scale (NRS), associated symptoms, and pain freedom (PF) were recorded before infusion (T0) and at intervals of 10 (T10), 20 (T20), and 30 (T30) min during infusion.ResultsWe enrolled 31 patients (87% female), with a mean age of 43.1 years (SD 2.7); of these, 68% had CM. NRS scores significantly reduced at T10 (p = 0.011) and T20 (p = 0.004). Photophobia was less frequent at T10 (p = 0.045), phonophobia at T20 (p = 0.014), and osmophobia at T30 (p = 0.046) compared with T0. PF was reported by 6.5% of patients at T10, 19.4% at T20, 29.0% at T30, and 19.4% at T60, T90, and T120.DiscussionThe BE-FREE study results, representing the first real-world evidence, demonstrate the rapid effect of eptinezumab during the first 30 min of infusion in patients experiencing an ongoing migraine attack.

Background Clinically relevant anxiety can be detected in patients with amyotrophic lateral sclerosis (ALS), but its prevalence and determinants have not yet been fully assessed. Aims This study aimed at assessing the prevalence and clinical underpinnings of anxiety in ALS. Method Non-demented ALS patients (N = 433) and healthy controls (N = 313) were administered the State- and Trait-Anxiety Inventory – Form Y (STAI-Y1 for state-anxiety and STAI-Y2 for trait-anxiety) and the Beck Depression Inventory (BDI). Patients were further assessed for cognition (Edinburgh Cognitive and Behavioural ALS Screen), behaviour (Frontal Behavioural Inventory) and motor status (disease duration, ALS Functional Rating Scale-Revised and progression rate). The prevalence of clinically significant state- and trait-anxiety were estimated by applying age-stratified cut-offs to STAI-Y1/-Y2 t-scores. Linear and logistic regressions were run to test the determinants of STAI-Y1/-Y2 scores. Results STAI-Y1 and -Y2 scores above cut-off were detected in 18.2 and 13.9% of patients, respectively – with proportions being higher in cases versus controls (ps < 0.001). BDI, but neither cognitive/behavioural nor motor variables, was identified as a significant predictor of STAI-Y1/-Y2 scores (ps < 0.003). The cognitive–affective subscale of BDI was the sole predictor of scores above cut-off on both STAI-Y1 and STAI-Y2 (ps < 0.001). Conclusions Clinically significant levels of state- and trait-anxiety occur in ∼18 and ∼14% of non-demented ALS patients, respectively, mostly driven by cognitive and affective facets of depression, and are independent of motor and cognitive/behavioural features.

Long-term (> 24 weeks) real-world evidence of eptinezumab’s effectiveness is limited. We evaluated ≥ 50

Real-world evidence on atogepant remains limited. GIANT2 explores the 24-week real-life effectiveness of atogepant in patients with high-frequency episodic migraine (HFEM) or chronic migraine (CM) under routine clinical conditions. GIANT2 is a 24-week, prospective, multicenter, real-world, study including consecutive patients with HFEM or CM with ≥3 preventive treatment failures, treated with atogepant 60 mg once daily. Co-primary endpoints: proportions achieving ≥50

AimTo assess whether the timing of atogepant administration influences its tolerability and effectiveness over 12 weeks in patients with episodic and chronic migraine in a real-world setting.MethodsThis is a post-hoc analysis of the STAR study, a prospective, Italian, multicenter study evaluating atogepant 60 mg for migraine prevention. Data were collected at baseline (T0) and after the first 12 weeks (T3) of treatment. Patients were grouped by administration timing (morning vs. evening) and by administration with or without food. Changes in monthly headache days (MHDs), monthly migraine days (MMDs), and Migraine Disability Assessment (MIDAS) were measured. Tolerability was evaluated via adverse events (AEs). Linear mixed-effects models (LMMs) were used.ResultsEighty-one patients (86% females, mean age 50.8 ± 13.7 years) were included. At T3, MMDs decreased from 16.6 to 9.7 (p < 0.001) and MHDs from 19.8 to 11.9 (p < 0.001); 60% of patients achieved ≥50% reduction in MMDs. AEs occurred in 34 (42%) participants. Atogepant was taken in the morning by 57% and in the evening by 43% of patients. Fifty-seven out of 81 participants (70.4%) took atogepant with food. No significant differences in MMDs, MHDs, or AEs emerged between morning and evening users. Evening users had higher baseline MIDAS scores (estimated marginal means [EMMs]: 69.9 vs. 39.9, p = 0.034) that showed a greater reduction compared to morning users (F(1,63) = 6.29, p = 0.015), reaching similar final scores after 12 weeks (EMMs: 25.1 vs. 23.8). No difference in atogepant effectiveness and tolerability according to intake with or without food, except for a reduction in MHDs for patients who took atogepant without food (EMMs from 21.3 to 9.9 vs with food: EMMs from 18.4 to 12.7; F(1,79) = 8.553, p = 0.005).ConclusionsAtogepant significantly reduced migraine burden over 12 weeks in a real-world setting. Overall, the timing of atogepant administration did not affect its effectiveness or tolerability. However, a greater reduction in MIDAS scores was observed among evening users. Whether this reflects a pharmacological advantage or a ceiling effect remains unclear. Taking atogepant without food was associated with a significantly greater reduction in MHDs, whereas changes in MMDs and MIDAS scores did not differ between groups. Long-term and dedicated studies are needed to evaluate and confirm these findings.Trial RegistrationThe main study (STAR) was preregistered on clinicaltrial.gov, NCT06414044.

ObjectiveThe recent examination of a woman who presented a migraine attack with visual aura and unilateral mydriasis, followed, a few days later, by an episode of Takotsubo Syndrome, prompted us to review the existing literature correlating migraine and TS as well as the most recent studies regarding the association between Takotsubo Syndrome and neurological dysfunction. Our aim is to define the role of dysautonomia and the contribution of the Autonomic Nervous System in the pathogenesis of both diseases, also, to define the functional role of the hypothalamus in the both the determination of headache attacks and the onset of clinical manifestations in other organs and tissues.BackgroundMigraine with aura and Takotsubo Syndrome (TS) share emotional, psychological and physical triggering factors which are implicated in the pathogenetic process. The autonomic nervous system plays a crucial, though antipodal, role in both pathologies. Indeed, migraine clinical manifestations imply the activation of the parasympathetic system whereas a massive catecholamine release following sympathetic nervous system activation is pivotal in triggering the Takotsubo Syndrome.MethodsReview of anatomy, physiology and neural regulation in both physiological and stress responses. Examination of the functional connections of the hypothalamus.Results and discussionThe coexistence of psycho-emotional stressors, endocrine/hormonal factors and a possible genetic predisposition might explain the pathophysiological overlap between these two distinct clinical manifestations. The hypothalamus is functionally connected with all the pain-related brain regions and pathways and can be responsible for the clinical manifestations in both the nervous system and the cardiovascular apparatus. Migraine is the most frequent chronic, early onset condition associated with TS.

BackgroundThe improved prevention of migraine, driven by the introduction of calcitonin gene-related peptide (CGRP)-targeted therapies, has prompted the International Headache Society (IHS) to propose new goals in migraine management. This study aimed to evaluate the safety and effectiveness of atogepant for migraine prevention over 24 weeks, in accordance with the IHS-defined goals.MethodsThis is a multicenter, prospective, observational, real-world study on patients starting atogepant 60 mg for migraine prevention. We describe efficacy and safety outcomes at weeks 9-12 (T3) and 21-24 (T6) relative to baseline (T0) from the initiation of atogepant treatment. We also report the proportion of patients achieving migraine freedom, optimal, modest or insufficient control according to the IHS position paper categories.ResultsOne hundred twenty-eight (n = 128) patients (63 (49.2%) with chronic migraine, 115 (89.9%) female, aged 48.3 ± 13.3 years) from 17 centers were analyzed. Monthly migraine days decreased from 16.5 ± 8.5 at T0 to 8.0 ± 8.4 at T3 (p < 0.001 vs. T0) and 8.6 ± 9.2 at T6 (p < 0001 vs. T0, p = 0.265 compared to T3). Overall, 64.8% of patients were responders (at least 50% reduction in monthly migraine days from T0) at T3 and 61.7% at T6; 81.9% of responders at T3 maintained the responder status at T6, while 24.4% of patients among non-responders at T3 became responders at T6. At T3 and T6, 39.1% of the entire cohort achieved at least optimal migraine control (20.6% in chronic migraine and 56.9% in episodic migraine).ConclusionsThe STAR study demonstrates, in a real-world setting, the safety and the sustained effectiveness of atogepant 60 mg over 24 weeks and indicates that more than one-third of treated patients can achieve at least optimal disease control, with markedly better outcomes in episodic than in chronic migraine.Trial RegistrationThe study was preregistered on clinicaltrial.gov, NCT06414044.

BACKGROUND:This study aimed to determine whether educational attainment-a common proxy of cognitive reserve (CR)-influences the association between motor and cognitive/behavioural outcomes in a large cohort of ALS patients without dementia. METHODS:N = 726 ALS patients without FTD were assessed for motor (ALSFRS-R), cognitive (Edinburgh Cognitive and Behavioural ALS Screen, ECAS) and behavioural outcomes (ECAS-Carer Interview, ECAS-CI). CR was operationalized via educational attainment (in years). Moderation models were run on each subscale of the cognitive section of the ECAS and on the ECAS-CI by addressing ALSFRS-R as the predictor and education as the moderator. RESULTS:Education was associated with both the ALSFRS-R and all the cognitive subscales of the ECAS, while not with the ECAS-CI. As to moderation models, a significant Education*ALSFRS-R interaction was detected solely with regard to the ECAS-Executive-with its simple slope-based decomposition revealing that higher ALSFRS-R scores were associated with higher scores on the ECAS-Executive for patients with low (p < 0.001) and average (p = 0.007), while not high, levels of education. DISCUSSION:Education seems to moderate the association between motor involvement and executive status in ALS patients without dementia, thus possibly exerting a protective role towards both motor function and cognition in this population.

Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3–5 years of disease onset. Although roughly 10

OBJECTIVE:Plasma glial fibrillary acidic protein (pGFAP) and plasma neurofilament light chain (pNfL) levels reflect astrocyte activation and neuronal damage, respectively. Whether these phenomena play a role in migraine is unknown. This study aimed to compare pGFAP and pNfL levels in patients with chronic migraine (CM) and age-matched controls and to analyze their relation with clinical features. METHODS:The study evaluated two independent cohorts of patients, including in total 58 CM and 69 controls. pGFAP and pNfL were quantified with single molecule array (Simoa) technology. Demographic and clinical data were collected for each subject; differences in NfL/GFAP levels between CM and controls were evaluated in analyses adjusted for the effect of age and sex; clinical characteristics associated with NfL/GFAP levels were separately evaluated in the two cohorts. RESULTS:In both cohorts, we did not find a significant difference in pGFAP or pNFL levels between CM and matched controls. The study did not find any correlation between pGFAP or pNfL levels and any migraine characteristics (namely presence of migraine aura, attack frequency, migraine intensity, years of disease). CONCLUSIONS:Our negative results support the assumption that migraine represents a benign condition, characterized by transient functional brain alterations and not by the accumulation over time of neuroaxonal damage and/or associated astrocyte activation detectable by neurodegeneration marker proteins.

OBJECTIVE:Despite its clinical heterogeneity, amyotrophic lateral sclerosis is unified by early and prominent alterations in cortical excitability, increasingly recognized as contributors to disease progression. This study assessed whether the ratio between motor evoked potential (MEP) amplitude, reflecting upper motor neuron integrity, and compound muscle action potential (CMAP) amplitude, indexing lower motor neuron function, could provide an accessible marker of corticospinal excitability to stratify patients by phenotype, stage, and survival. METHODS:In this multicenter retrospective study, 743 amyotrophic lateral sclerosis patients from 16 tertiary centers in Italy were analyzed. The MEP:CMAP ratio, recorded from upper limb muscles, was categorized as hyperexcitable, normal, or hypoexcitable. Phenotypes included progressive muscular atrophy (or lower motor neuron), flail arm/leg, classic, bulbar, patient with predominant upper motor neuron signs (or pyramidal), and primary lateral sclerosis. Disease stage was assessed using King's staging. Survival was analyzed using Kaplan-Meier curves and Cox regression models. RESULTS:The MEP:CMAP ratio differed significantly across phenotypes (p < 0.0001), with hyperexcitability predominating in lower motor neuron, flail, classic, and bulbar forms, and hypoexcitability in pyramidal and primary lateral sclerosis. Hypoexcitability increased in advanced King's stages (p < 0.0001). Hyperexcitable patients had shorter survival (p = 0.004), including when tested within 1 year of onset (p = 0.006). Cox regression identified the MEP:CMAP ratio as an independent survival predictor (HR 1.84, 95% CI 1.12-3.03, p = 0.016). INTERPRETATION:This real-world study supports the clinical value of the MEP:CMAP ratio as a scalable biomarker of cortical excitability in amyotrophic lateral sclerosis, with prognostic relevance across phenotypes and disease stages. ANN NEUROL 2025;98:801-813.

BackgroundFocusing on calcitonin gene-related peptide (CGRP) as a specific target has changed and improved migraine management. After the positive results of monoclonal antibodies directed to the CGRP pathway (anti-CGRP mAbs), randomized controlled trials also demonstrated the efficacy of gepants in migraine prevention. The present study aimed to assess the effectiveness of atogepant in preventing migraine after a 12-week treatment in clinical practice.MethodsAdult patients with a clinical indication for atogepant 60 mg daily were screened for participation in this multicentric prospective observational cohort study. At baseline (T0) and after 12 weeks (T3) since the first atogepant administration, monthly migraine days (MMDs), monthly headache days (MHDs) and monthly acute medications (MAMs) were assessed. The co-primary endpoints were the changes in MMDs from T0 to T3 and the percentage of T3 Responders (those with a reduction of MMDs ≥50%, i.e. 50% response rate (RR)). At T0 and T3, we also collected the Headache Impact Test (HIT-6), the Migraine Disability Assessment (MIDAS) questionnaire, the Migraine Treatment Optimization Questionnaire-6 (mTOQ-6), the Migraine-Specific Quality-of-Life Questionnaire (MSQ), the 12-item Allodynia Symptom Checklist (ASC-12) and the Migraine Interictal Burden Scale (MIBS-4).ResultsOne hundred and six patients (56/106 (52.8%) with chronic migraine (CM), 93/106 (87.7%) female, aged 50.6 ± 13.2 years) from 10 Italian centers completed the 12-week observation since the first atogepant tablet intake. From baseline to T3, a reduction of 6.9 MMDs (SD 9.7; p < 0.001) was achieved in the whole group and, specifically, of -4.9 (SD 6.6; p < 0.001) in episodic migraine (EM) and of -8.6 (SD 11.7; p < 0.001) in CM patients. Overall, 60/106 (56.6%) of patients were Responders (60.0% in the EM and 46.4% in the CM group). Non-Responders previously experienced more ineffective treatments than Responders with anti-CGRP mAbs (65.2% vs. 43.3%, respectively, p = 0.031) and with onabotulinumtoxinA (56.5% vs. 28.3%, p = 0.005), and presented more medication overuse at baseline (55.7% vs. 44.3%, p = 0.003). However, no baseline characteristics were significantly associated with the Responder status in the multiple regression analysis. For T0 to T3, MAMs, MIDAS, ASC-12 and mTOQ-6 reduced (p ≤ 0.001 consistently), and MSQ role-function restriction increased (p = 0.026), whereas HIT-6 and MIBS-4 did not change. Only seven subjects (7/106, 6.6%) dropped out of atogepant treatment: four for lack of effectiveness and three for adverse events or poor tolerability.ConclusionsThe STAR study demonstrates the effectiveness and tolerability of atogepant 60 mg at 12 weeks in a real-world setting. Previous ineffective anti-CGRP mAbs were not a relevant prognostic factor.Trial RegistrationThe study was preregistered on clinicaltrial.gov, NCT06414044.

Objectives: This study aims to unravel the association between language deficits and executive functions in non-demented amyotrophic lateral sclerosis (ALS) patients by means of 1) assessing the executive determinants of language impairment (LI) and 2) simultaneously testing the effects of both executive and language performances on phonemic verbal fluency (PVF) deficits. Methods: N = 299 non-demented ALS patients underwent the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), being also assessed for behavioral/psychiatric and motor-functional features. Two sets of logistic models were run: the first, regressing an impaired vs. unimpaired performance on each ECAS-Language (ECAS-L) tasks based on each task of the ECAS-Executive Functioning (ECAS-EF); the second, regressing an impaired vs. unimpaired performance on each ECAS-Fluency tasks based on both ECAS-L and ECAS-EF tasks. Within these models, demographic, motor-functional, and psychiatric/behavioral measures were covaried for. Results: Defective Naming and Comprehension performances were predicted by lower scores on the Sentence Completion task (p ≤ 0.002), whilst defective Spelling performances by lower Alternation scores (p < 0.001). Defective performances on Verbal fluency - S and Verbal fluency - C tasks were predicted by lower Backward Digit Span and Sentence Completion scores, respectively (p ≤ 0.008). Discussion: In ALS patients, inhibitory and set-shifting abilities majorly contribute to LI, whilst PVF deficits are mostly linked to dysexecutive features.

This study explored the impact of KIF5A rs113247976 (p.Pro986Leu), a risk allele for amyotrophic lateral sclerosis (ALS), on phenotypic variability in two Italian ALS cohorts (discovery, n = 865; replication, n = 1174). The minor allele (T) frequency was 0.015. No patients were homozygous (TT), allowing comparison between wild type and heterozygous carriers only. Heterozygous carriers showed faster disease progression (ALSFRS-R preslope). Findings were validated across both cohorts. Multiple linear regression identified p.Leu986 and age at onset as ALSFRS-R preslope predictors. In conclusion, heterozygous p.Leu986 in KIF5A is associated with faster ALS progression, supporting its consideration for genetic screening in clinical trials.