What contributes to disability in progressive MS? A brain and cervical cord-matched quantitative MRI study.

BACKGROUND: We assessed the ability of a brain-and-cord-matched quantitative magnetic resonance imaging (qMRI) protocol to differentiate patients with progressive multiple sclerosis (PMS) from controls, in terms of normal-appearing (NA) tissue abnormalities, and explain disability. METHODS: A total of 27 patients and 16 controls were assessed on the Expanded Disability Status Scale (EDSS), 25-foot timed walk (TWT), 9-hole peg (9HPT) and symbol digit modalities (SDMT) tests. All underwent 3T brain and (C2-C3) cord structural imaging and qMRI (relaxometry, quantitative magnetisation transfer, multi-shell diffusion-weighted imaging), using a fast brain-and-cord-matched protocol with brain-and-cord-unified imaging readouts. Lesion and NA-tissue volumes and qMRI metrics reflecting demyelination and axonal loss were obtained. Random forest analyses identified the most relevant volumetric/qMRI measures to clinical outcomes. Confounder-adjusted linear regression estimated the actual MRI-clinical associations. RESULTS: Several qMRI/volumetric differences between patients and controls were observed (p < 0.01). Higher NA-deep grey matter quantitative-T1 (EDSS: beta = 7.96, p = 0.006; 9HPT: beta = -0.09, p = 0.004), higher NA-white matter orientation dispersion index (TWT: beta = -3.21, p = 0.005; SDMT: beta = -847.10, p < 0.001), lower whole-cord bound pool fraction (9HPT: beta = 0.79, p = 0.001) and higher NA-cortical grey matter quantitative-T1 (SDMT = -94.31, p < 0.001) emerged as particularly relevant predictors of greater disability. CONCLUSION: Fast brain-and-cord-matched qMRI protocols are feasible and identify demyelination - combined with other mechanisms - as key for disability accumulation in PMS.

Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials. METHODS: This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed. RESULTS: Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60. CONCLUSIONS: The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.

Biomarkers of Migraine: An Integrated Evaluation of Preclinical and Clinical Findings.

In recent years, numerous efforts have been made to identify reliable biomarkers useful in migraine diagnosis and progression or associated with the response to a specific treatment. The purpose of this review is to summarize the alleged diagnostic and therapeutic migraine biomarkers found in biofluids and to discuss their role in the pathogenesis of the disease. We included the most informative data from clinical or preclinical studies, with a particular emphasis on calcitonin gene-related peptide (CGRP), cytokines, endocannabinoids, and other biomolecules, the majority of which are related to the inflammatory aspects and mechanisms of migraine, as well as other actors that play a role in the disease. The potential issues affecting biomarker analysis are also discussed, such as how to deal with bias and confounding data. CGRP and other biological factors associated with the trigeminovascular system may offer intriguing and novel precision medicine opportunities, although the biological stability of the samples used, as well as the effects of the confounding role of age, gender, diet, and metabolic factors should be considered.

BoNT-A efficacy in high frequency migraine: an open label, single arm, exploratory study applying the PREEMPT paradigm.

INTRODUCTION: In this open label, single-arm trial we evaluated the efficacy of onabotulinum toxin-A in the prevention of high-frequency episodic migraine (8-14 migraine days/month). METHODS: We enrolled 32 high-frequency episodic migraine subjects (age 44.8 ± 11.9 years, 11.0 ± 2.2 migraine days, 11.5 ± 2.1 headache days, 7 females). After a 28-day baseline period, subjects underwent 4 subsequent onabotulinum toxin-A treatments according to the phase III research evaluating migraine prophylaxis therapy (PREEMPT) paradigm, 12-weeks apart. The primary outcome was the reduction of monthly migraine days from baseline in the 12-week period following the last onabotulinum toxin-A treatment. RESULTS: Onabotulinum toxin-A reduced monthly migraine days by 3.68 days (-33.1%, p < 0.01). Thirty-nine percent of the patients experienced a ≥50% reduction in monthly migraine days. Onabotulinum toxin-A also reduced the number of headache days (-33.9%, p < 0.01) and the intake of acute medications (-22.9%, p = 0.03). Disability and quality of life (QoL) scores improved markedly (migraine disability assessment (MIDAS) -41.7%; migraine specific questionnaire (MSQ) -31.7%, p < 0.01). CONCLUSIONS: The findings suggest that, when administered according to the PREEMPT paradigm, onabotulinum toxin-A is effective in the prevention of high-frequency episodic migraine.Trial Registration: NCT04578782.

Does MIDAS reduction at 3 months predict the outcome of erenumab treatment? A real-world, open-label trial.

BACKGROUND: In Italy, monoclonal antibodies targeting the CGRP pathway are subsidized for the preventive treatment of high frequency and chronic migraine (CM) in patients with a MIgraine Disability ASsessment (MIDAS) score ≥ 11. Eligibility to treatment continuation requires a ≥ 50% MIDAS score reduction at three months (T3). In this study, we evaluate whether a ≥ 50% MIDAS score reduction at T3 is a reliable predictor of response to one-year erenumab treatment. METHODS: In this prospective, open-label, real-world study, 77 CM patients were treated with erenumab 70-140 mg s.c. every 28 days for one year (T13). We collected the following variables: monthly migraine days (MMDs), monthly headache days (MHDs), days of acute medication intake, MIDAS, HIT-6, anxiety, depression, quality of life and allodynia. Response to erenumab was evaluated as: i) average reduction in MMDs during the 1-year treatment period; and ii) percentage of patients with ≥ 50% reduction in MMDs during the last 4 weeks after the 13th injection (RespondersT13). RESULTS: Erenumab induced a sustained reduction in MMDs, MHDs and intake of acute medications across the 12-month treatment period, with 64.9% of patients qualifying as RespondersT13. At T3, 55.8% of patients reported a ≥ 50% reduction in MIDAS score (MIDASRes) and 55.4% of patients reported a ≥ 50% reduction in MMDs (MMDRes). MIDASRes and MMDRes patients showed a more pronounced reduction in MMDs during the 1-year treatment as compared to NON-MIDASRes (MIDASRes: T0: 23.5 ± 4.9 vs. T13: 7.7 ± 6.2; NON- MIDASRes: T0: 21.6 ± 5.4 vs. T13: 11.3 ± 8.8, p = 0.045) and NON-MMDRes (MMDRes: T0: 23.0 ± 4.5 vs. T13: 6.6 ± 4.8; NON-MMDRes: T0: 22.3 ± 6.0 vs. T13: 12.7 ± 9.2, p < 0.001) groups. The percentage of RespondersT13 did not differ between MIDASRes (74.4%) and NON-MIDASRes (52.9%) patients (p = 0.058), while the percentage of RespondersT13 was higher in the MMDRes group (83.3%) when compared to NON-MMDRes (42.9%) (p = 0.001). MMDRes predicted the long-term outcome according to a multivariate analysis (Exp(B) = 7.128; p = 0.001), while MIDASRes did not. Treatment discontinuation based on MIDASRes would have early excluded 36.0% of RespondersT13. Discontinuation based on "either MIDASRes or MMDRes" would have excluded a lower percentage (16%) of RespondersT13. CONCLUSION: MIDASRes only partly reflects the 12-month outcome of erenumab treatment in CM, as it excludes more than one third of responders. A criterion based on the alternative consideration of ≥ 50% reduction in MIDAS score or MMDs in the first three months of treatment represents a more precise and inclusive option. TRIAL REGISTRATION: The trial was retrospectively registered at www. CLINICALTRIALS: gov (NCT05442008). CGRP: Calcitonin Gene Related Peptide. MIDAS: MIgraine Disability Assessment. MMDs: monthly migraine days. MIDASRes: Patients with a MIDAS score reduction of at least 50% at T3. MMDRes: Patients with a MMDs reduction of at least 50% at T3. ResponderT13: Patients with a MMDs reduction from baseline of at least 50% in the last 4 weeks of observation period (after 13 erenumab administrations). T0: First erenumab administration. T3, T6, T9, T12: Follow-up visits at three, six, nine, and twelve months after first erenumab administration. T13: Last visit of the protocol.

Guidelines of the International Headache Society for clinical trials with neuromodulation devices for the treatment of migraine.

BACKGROUND: Although the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical trials of neuromodulation devices. In recognition of the distinct needs and challenges associated with their assessment in controlled trials, the Committee provides these recommendations for optimizing the design and conduct of controlled trials of neuromodulation devices for the acute and/or preventive treatment of migraine. METHODS: An international group of headache scientists and clinicians with expertise in neuromodulation evaluated clinical trials involving neuromodulation devices that have been published since 2000. The Clinical Trials Committee incorporated findings from this expert analysis into a new guideline for clinical trials of neuromodulation devices for the treatment of migraine. RESULTS: Key terms were defined and recommendations provided relative to the assessment of neuromodulation devices for acute treatment in adults, preventive treatment in adults, and acute and preventive treatment in children and adolescents. Ethical and administrative responsibilities were outlined, and a bibliography of previous research involving neuromodulation devices was created. CONCLUSIONS: Adoption of these recommendations will improve the quality of evidence regarding this important area in migraine treatment.

Psychological predictors of negative treatment outcome with Erenumab in chronic migraine: data from an open label long-term prospective study.

BACKGROUND: Monoclonal antibodies (mABs) targeting the calcitonin gene-related peptide (CGRP) pathway represent the first disease-specific preventive migraine therapy. Growing evidence suggests that they are effective in the preventive treatment of difficult-to-treat patients. In this study, we evaluated the psychological predictors of the outcome of treatment with the anti-CGRP monoclonal antibody erenumab in patients with chronic migraine (CM). METHODS: Seventy-five patients with CM who had already failed at least 3 preventive therapies received erenumab every 28 days for a period of 12 months. Before the first administration, patients received a full psychological evaluation using The Structured Clinical Interview for DSM-5 Clinician Version (SCID-5-CV) to assess personality disturbances (primary outcome), mood and anxiety disorders, and as well specific questionnaires to evaluate alexithymia traits, childhood traumas, and current stressors (secondary outcomes). RESULTS: After 12 months of treatment, 53 patients reported a reduction of at least 50% in headache days/per month (Responders), whereas 22 did not (Non Responders). When compared to Responders, Non Responders were characterized by a higher prevalence of personality disorders belonging to Cluster C (avoidant, dependent, and obsessive-compulsive) (77% vs 37%, p = .001). Non Responders were also characterized by a higher prevalence of anxiety disorders (90% vs 60%, p = 0.007), showed more alexithymic traits (51.7 ± 13.7 vs 42.9 ± 14.3, p = 0.017), and reported a higher number of 'at least serious' current stressors (3.2 ± 4.0 vs 0.8 ± 1.4, p < .0001) than Responders. At the multivariate analysis, higher prevalence of Cluster C personality disorders (OR 3.697; p = 0.05) and higher number of 'at least serious' life events (OR 1.382; p = 0.017) arose as prognostic factors of erenumab failure. CONCLUSIONS: Erenumab confirmed its effectiveness in a population of difficult-to-treat migraine. The presence of "anxious-fearful" personality together with current stressors and anxiety represent negative predictors of treatment outcome. TRIAL REGISTRATION: The study protocol was registered at clinicaltrials.gov ( NCT04361721 ).

Comorbidities of primary headache disorders: a literature review with meta-analysis.

BACKGROUND: Primary headache disorders are common and burdensome conditions. They are associated to several comorbidities, such as cardiovascular or psychiatric ones, which, in turn, contribute to the global burden of headache. The aim of this study is to provide a comprehensive description of the pooled prevalence of comorbidities of primary headache disorders using a meta-analytical approach based on studies published between 2000 and 2020. METHODS: Scopus was searched for primary research (clinical and population studies) in which medical comorbidities were described in adults with primary headache disorders. Comorbidities were extracted using a taxonomy derived from the Global Burden of Disease (GBD) study. We compared prevalence of comorbidities among headache sufferers against general population using GBD-2019 estimates, and compared comorbidities' proportions in clinical vs. population studies, and by age and gender. RESULTS: A total of 139 studies reporting information on 4.19 million subjects with primary headaches were included: in total 2.75 million comorbidities were reported (median per subject 0.64, interquartile range 0.32-1.07). The most frequently addressed comorbidities were: depressive disorders, addressed in 51 studies (pooled proportion 23 %, 95 % CI 20-26 %); hypertension, addressed in 48 studies (pooled proportion 24 %, 95 % CI 22-26 %); anxiety disorders addressed in 40 studies (pooled proportion 25 %, 95 % CI 22-28 %). For conditions such as anxiety, depression and back pain, prevalence among headache sufferers was higher than in GBD-2109 estimates. Associations with average age and female prevalence within studies showed that hypertension was more frequent in studies with higher age and less females, whereas fibromyalgia, restless leg syndrome, and depressive disorders were more frequent in studies with younger age and more female. CONCLUSIONS: Some of the most relevant comorbidities of primary headache disorders - back pain, anxiety and depression, diabetes, ischemic heart disease and stroke - are among the most burdensome conditions, together with headache themselves, according to the GBD study. A joint treatment of headaches and of these comorbidities may positively impact on headache sufferers' health status and contribute to reduce the impact of a group of highly burdensome diseases.

Neurophysiological and biomolecular effects of erenumab in chronic migraine: An open label study.

INTRODUCTION: Anti-calcitonin gene-related peptide antibodies proved effective in the preventive treatment of chronic migraine. In this open label study, we aim to assess the effects of erenumab administration on neurophysiological and biomolecular profiles in a representative cohort of chronic migraine patients. METHODS: Forty patients with a history of chronic migraine for at least 12 months prior to enrollment, and previous failure of at least two different preventive therapies, were enrolled. After a 1-month observation period (T0), patients were treated with erenumab 70 mg s.c. (every 28 days) for a total of three administrations. At week 12, they returned for the end-of-protocol visit (T3). At T0 and T3, patients underwent recording of clinical features, recording of single stimulus (RTh), temporal summation (TST) thresholds of the nociceptive withdrawal reflex, venous blood sampling for miR-382-5p, and miR-34a-5p quantification. RESULTS: At T3, 31 patients (77.5%) qualified as 30% Responders (reduction in monthly migraine days by at least 30% in the last 4-week observation period). RTh (T0: 15.4 ± 8.1 mA, T3: 19.7 ± 8.2 mA) as well as TST (T0: 11.2 ± 5.8 mA, T3: 13.4 ± 5.0 mA) significantly increased at T3 in 30% Responders (p = 0.001 for both), while we did not observe significant changes in NON-responder patients. MiR-382-5p and miR-34a-5p levels were significantly lower after erenumab administration in the overall study population (p = 0.015, and p = 0.001, respectively), without significant differences between 30% Responder and NON-responder groups. CONCLUSIONS: Different migraine phenotypes, characterized by different treatment susceptibility, may exist as suggested by the divergent behavior between neurophysiological and biomolecular findings in 30% Responder vs. NON-responder patients.The study protocol was registered at clinicaltrials.gov (NCT04361721).

Guidelines of the International Headache Society for controlled trials of preventive treatment of migraine attacks in episodic migraine in adults.

Clinical trials are a key component of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. Advances in drugs, devices, and biologicals, as well as novel trial designs, have prompted several updates over the nearly 30 years since, including most recently the Guidelines for controlled trials of preventive treatment of chronic migraine (2018), the Guidelines for controlled trials of acute treatment of migraine attacks in adults (2019), and Guidelines for controlled trials of preventive treatment of migraine in children and adolescents (2019). The present update incorporates findings from new research and is intended to optimize the design of controlled trials of preventive pharmacological treatment of episodic migraine in adults. A guideline for clinical trials with devices will be published separately.

Migraine neuroscience: from experimental models to target therapy.

Migraine sciences have witnessed tremendous advances in recent years. Pre-clinical and clinical experimental models have contributed significantly to provide useful insights into the brain structures that mediate migraine attacks. These models have contributed to elucidate the role of neurotransmission pathways and to identify the role of important molecules within the complex network involved in migraine pathogenesis. The contribution and efforts of several research groups from all over the world has ultimately lead to the generation of novel therapeutic approaches, specifically targeted for the prevention of migraine attacks, the monoclonal antibodies directed against calcitonin gene-related peptide or its receptor. These drugs have been validated in randomized placebo-controlled trials and are now ready to improve the lives of a large multitude of migraine sufferers. Others are in the pipeline and will soon be available.

Adherence to the 2008 IHS guidelines for controlled trials of drugs for the preventive treatment of chronic migraine in adults.

INTRODUCTION: Since the definition of chronic migraine as a new disease entity in 2004, numerous clinical trials have examined the efficacy of preventive treatments in chronic migraine. Our aim was to assess the adherence of these trials to the Guidelines of the International Headache Society published in 2008. METHODS: We searched PubMed for controlled clinical trials investigating preventive treatment for chronic migraine in adults designed after the release of the Guidelines and published until December 2017. Trial quality was evaluated with a 13-item scoring system enlisting essential recommendations adapted from the Guidelines. RESULTS: Out of 3352 retrieved records, we included 16 papers in the analysis dealing with pharmacological treatment of chronic migraine. The median score was 6.5 (range 2-13). All trials were randomized, the large majority (81.25%) were placebo-controlled and double-blinded (87.5%). Adherence was lowest on i) a priori definition of outcomes (31.25%), ii) primary endpoint definition (37.5%%) and iii) trial registration (37.5%). DISCUSSION: Most clinical trials adhered to the recommendations of the IHS, whereas adherence to migraine-specific recommendations was lower. Greater awareness and adherence to the guidelines are essential to improve the quality of clinical trials, validity of publications and the generalizability of the results.

Limitations in daily activities and general perception of quality of life: Long term follow-up in patients with anti-myelin-glycoprotein antibody polyneuropathy.

In this study, we assessed the modifications over time of daily activities and quality of life (QoL) in 32 subjects with anti-myelin-glycoprotein (MAG) antibody neuropathy. A widespread panel including clinical scores and patient-reported questionnaires, in compliance of the terms by the International Classification of Functioning, Disability, and Health (ICF) of the World Health Organization (WHO), was employed at enrollment (T0) and at follow-up evaluation (T1) after a mean interval of 15.4 ± 5.7 months. The Sensory Modality Sum score (SMS) at four limbs showed a significant worsening over time (mean score 27.2 ± 3.9 at T0 vs 25.7 ± 3 at T1 at upper limbs, P = .03; 20.5 ± 4.8 at T0 vs 18.6 ± 5.9 at T1 at lower limbs, P = .04). The Visual Analogue Scale (VAS) for pain significantly worsened at upper limbs at T1 (mean values 0.84 ± 1.95 at T0 vs 1.78 ± 2.6 at T1, P = .03). All the other tests did not show significant differences between T0 and T1. In the subgroup who underwent rituximab (15/32 treated before T0, 3/32 patients treated between T0 and T1 with median interval of 1 year), no significant differences were observed between T0 and T1. Despite the quite long follow-up, statistical significance was not achieved either for the limited number of patients or for the lack of sensitive outcome measures. In our cohort, the significant worsening of the SMS and VAS after a median of 14 months can be considered as a reliable expression of the natural history of the disease, and suggest that these scales might represent possible outcome measures in anti-MAG antibody neuropathy.

Peripheral vagal nerve stimulation modulates the nociceptive withdrawal reflex in healthy subjects: A randomized, cross-over, sham-controlled study.

Introduction The mechanism of action of non-invasive vagal nerve stimulation in the treatment of migraine is elusive. We studied its effect in a human model of pain, the nociceptive withdrawal reflex. Methods We enrolled 10 healthy subjects who underwent active non-invasive vagal nerve stimulation and sham treatment in a randomized, cross-over, sham-controlled study. Non-invasive vagal nerve stimulation was delivered with gammaCore®. The assessment of the nociceptive withdrawal reflex was performed at baseline (T0) and at 5 (T5) and 30 (T30) minutes after stimulation. Results Non-invasive vagal nerve stimulation significantly increased the reflex threshold to single stimulus at both T5 and T30 and the temporal summation threshold at T30. Sham treatment did not modify any parameters. Discussion These findings are consistent with a modulation of central descending pathways for pain control. An altered spinal and supraspinal control of pain has been described in primary headache, so this effect may partially explain the therapeutic effect of non-invasive vagal nerve stimulation.

MRI signatures of the frontotemporal lobar degeneration continuum.

OBJECTIVE: To identify overlapping and unique grey (GM) and white matter (WM) signatures within the frontotemporal lobar degeneration (FTLD) continuum, and discriminate likely FTLD-TAU and FTLD-TDP patients using structural and diffusion tensor (DT) magnetic resonance imaging (MRI). METHODS: T1-weighted and DT MRI were collected from 121 subjects: 35 motor neuron disease (MND), 14 behavioral variant of frontotemporal dementia, 12 semantic and 11 nonfluent primary progressive aphasia, 21 progressive supranuclear palsy syndrome patients, and 28 healthy controls. Patterns of GM atrophy were established using voxel-based morphometry. Tract-based spatial statistics was used to perform a WM voxelwise analysis of mean diffusivity and fractional anisotropy. RESULTS: In all clinical FTLD phenotypes, the pattern of WM damage was more distributed than that of GM atrophy. All patient groups, with the exception of MND cases with a pure motor syndrome, shared a focal GM atrophy centered around the dorsolateral and medial frontal cortex and a largely overlapping pattern of WM damage involving the genu and body of the corpus callosum and ventral frontotemporal and dorsal frontoparietal WM pathways. Surrounding this common area, phenotype (symptom)-specific GM and WM regions of damage were found in each group. CONCLUSIONS: In the FTLD spectrum, WM disruption is more severe than GM damage. Frontal cortex and WM pathways represent the common target of neurodegeneration in these conditions. The topographic pattern of damage supports a "prion-like" protein propagation through WM connections as underlying mechanism of the stereotyped progression of FTLD.

Nonspecific analgesics, combination analgesics, and antiemetics.

The acute treatment of migraine attacks should provide rapid, effective, and long-lasting symptom relief, causing minimal adverse effects. For this purpose, there are several specific and nonspecific acute treatments. In this chapter, we focus on molecules not specifically designed for migraines, including anti-inflammatory not specific analgesics, such as acetaminophen, acetylsalicylic acid, and other non-steroidal anti-inflammatory drugs (or COX-2 inhibitors); antinausea medications like metoclopramide or prochlorperazine, which can alleviate sickness and vomiting associated with migraines, and may also have a direct painkiller effect; combinations of simple analgesics or association of a painkiller with caffeine. This stimulant can help enhance the pain-relieving effects of some headache medications and provide its own analgesic effect; physical approaches: applying cold packs or heating pads on the forehead or neck, can help relieve migraine pain; other classes with limited to no evidence to support their use, such as intravenous corticosteroids or antiepileptic drugs as sodium valproate. Finally, we will briefly mention opioids, barbiturates, or medical cannabis, bearing in mind that their use is not recommended by current guidelines.

The role of stroke-induced immunosuppression as a predictor of functional outcome in the neurorehabilitation setting.

Stroke affects the interconnection between the nervous and immune systems, leading to a down-regulation of immunity called stroke-induced immunosuppression (SII). The primary aim of this study is to investigate SII role as a predictor of functional, neurological, and motor outcomes in the neurorehabilitation setting (NRB). We conducted a prospective observational study enrolling post-acute stroke patients hospitalized for neurorehabilitation. At NRB admission (T0) and discharge (T1), we assessed presence of SII (defined by a neutrophil-to-lymphocyte ratio ≥ 5) and we evaluated functional independence (Functional Independence Measure-FIM, Barthel Index-BI), motor performances (Tinetti Score, Hauser Ambulation Index) and neurological impairment (NIHSS). We enrolled 96 patients (45.8% females, 70.6 ± 13.9 years, 88.5% ischemic stroke). At T0, 15.6% of patients (15/96) had SII. When compared to immunocompetent patients (IC), the SII group was characterized by worse baseline functional independence, motor performances and neurological disability. The same was confirmed at T1 (FIM p = 0.012, BI p = 0.007, Tinetti p = 0.034, NIHSS p = 0.001). Neurological disability demonstrated a less pronounced improvement in SII (ΔNIHSS: SII: - 2.1 ± 2.3 vs. IC: - 3.1 ± 2.5, p = 0.035). SII group presented a higher percentage of infectious complications during the neurorehabilitation period (SII 80% vs. IC 25.9%; p = 0.001). SII may represent a negative prognostic factor in the neurorehabilitation setting. SII patients were characterized by poorer functional, motor, neurological performances and higher risk of infectious complications. ClinicaTrial registration: NCT05889169.

Searching for the Predictors of Response to BoNT-A in Migraine Using Machine Learning Approaches.

OnabotulinumtoxinA (BonT-A) reduces migraine frequency in a considerable portion of patients with migraine. So far, predictive characteristics of response are lacking. Here, we applied machine learning (ML) algorithms to identify clinical characteristics able to predict treatment response. We collected demographic and clinical data of patients with chronic migraine (CM) or high-frequency episodic migraine (HFEM) treated with BoNT-A at our clinic in the last 5 years. Patients received BoNT-A according to the PREEMPT (Phase III Research Evaluating Migraine Prophylaxis Therapy) paradigm and were classified according to the monthly migraine days reduction in the 12 weeks after the fourth BoNT-A cycle, as compared to baseline. Data were used as input features to run ML algorithms. Of the 212 patients enrolled, 35 qualified as excellent responders to BoNT-A administration and 38 as nonresponders. None of the anamnestic characteristics were able to discriminate responders from nonresponders in the CM group. Nevertheless, a pattern of four features (age at onset of migraine, opioid use, anxiety subscore at the hospital anxiety and depression scale (HADS-a) and Migraine Disability Assessment (MIDAS) score correctly predicted response in HFEM. Our findings suggest that routine anamnestic features acquired in real-life settings cannot accurately predict BoNT-A response in migraine and call for a more complex modality of patient profiling.

A Retrospective Real-Life Multicenter Study on Concurrent Oral Preventive Treatments in Patients with Chronic Migraine Treated with OnabotulinumtoxinA.

BACKGROUND AND OBJECTIVE: OnabotulinumtoxinA (BoNTA) is a relatively safe and effective treatment for chronic migraine. The local mode of action of BoNTA favors the combination of oral treatments with systemic action. However, little is known about the possible interactions with other preventive treatments. The objective of the study was to describe the use of oral preventive treatments in patients with chronic migraine treated with BoNTA in routine clinical care and discuss the tolerability and efficacy according to the presence or absence of concomitant oral treatments. METHODS: In this multicenter, observational, retrospective, cohort study, we collected data from patients with chronic migraine receiving prophylactic treatment with BoNTA. Patients were eligible if aged ≥18 years, diagnosed with chronic migraine according to the International Classification of Headache Disorders, Third Edition criteria, and treated with BoNTA according to the PREEMPT paradigm. We documented the proportion of patients with at least one concomitant treatment prescribed specifically for migraine (CT+M) and their side effects during four BoNTA treatment cycles. Additionally, we collected monthly headache days and monthly acute medication days from the patients' headache diaries. Patients with CT+M were compared to those without concomitant treatment (CT-) using a nonparametric approach. RESULTS: Our cohort included 181 patients taking BoNTA, of whom 77 (42.5%) received a CT+M. The most frequently prescribed concomitant treatments were antidepressants and antihypertensive drugs. Side effects in the CT+M group occurred in 14 patients (18.2%). Only in three of them (3.9%), the side effects had a significant interference with the patient's functioning (all in topiramate 200-mg/day users). Both CT+M and CT- groups had a significant reduction in monthly headache days of respectively - 6 (95% confidence interval - 9, - 3; p < 0.001; w = 0.200) during cycle 4 compared with baseline versus - 9 (95% confidence interval - 13, -6; p < 0.001; w = 0.469). However, the reduction in monthly headache days was significantly smaller in patients with CT+M after the fourth treatment cycle compared with patients with CT- (p = 0.004). CONCLUSIONS: Prescription of oral concomitant preventive treatment is common in patients with chronic migraine receiving BoNTA. We did not identify any unexpected safety or tolerability issues in patients receiving BoNTA and a CT+M. However, patients with a CT+M experienced a smaller reduction in monthly headache days when compared with those with CT-, which might be associated with a higher resistance to treatment in that subgroup of patients.