Beyond Pain Relief: Unveiling the Multifaceted Impact of Anti-CGRP/R mAbs on Comorbid Symptoms in Resistant Migraine Patients.

The study aimed to evaluate the effects of monoclonal antibodies (mAbs) acting on the calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP/R mAbs) on migraine comorbidities of depression, anxiety, and fatigue in patients resistant to traditional therapies. The issue addressed in this study is pivotal to unveiling the role of this neurotransmitter beyond pain processing. We conducted an open-label prospective study assessing comorbidities in patients with high frequency (HFEM) and chronic migraine (CM), medication overuse headache (MOH), and resistance to traditional prophylaxis. All patients were treated with anti-CGRP/R mAbs for 3 months. Seventy-seven patients were enrolled with either HFEM (21%) or CM (79%) with or without MOH (56% and 44%, respectively). We identified 21 non-responders (27%) and 56 responders (73%), defined on the reduction ≥50% of headache frequency. The two groups were highly homogeneous for the investigated comorbidities. Disease severity in terms of headache frequency, migraine-related disability, and affective comorbid symptoms was reduced in both groups with different thresholds; allodynia and fatigue were ameliorated only in responders. We found that anti-CGRP/R antibodies improved pain together with affection, fatigue, and sensory sensitization in a cohort of migraine patients resistant to traditional prophylaxis. Our results offer novel perspectives on the early efficacy of anti-CGRP/R mAbs in difficult-to-treat patients focusing on clinical features other than pain relief.

Peer victimization and developmental psychopathology in childhood and adolescence Italian psychiatric emergency unit. A single center retrospective observational study.

Peer victimization is a public health concern that affects a significant proportion of children and adolescents. The study evaluated the prevalence of peer victimization among 440 subjects referred to Emergency Department for a psychiatric consultation and analyzed the association with psychopathological symptoms. Sample was divided into two categories (6-13 and 14-18 years old). Logistics regression analysis was performed. Peer victimized were reported in 16.3% of subjects; 27.7% were younger than13 years old and 72.3% were between 14-18 years old, representing the main targets for peer victimization.A significant association was found between being peer victimized and depressive disorder (OR=4.57) in subjects younger than 13 years old and, with post-traumatic stress disorder (PTSD)(OR=6.52) in subjects older than 13 years old. Furthermore, linkage between being peer victimized and obsessive-compulsive disorder (OCD)(OR=4.45) was noted. Increased frequency of repeated hospitalizations was also documented.This is the first Italian study about children and adolescent peer victimization in psychiatric setting, showing a significant higher risk for depressive disorder in subjects younger than 13 years old and PTSD and OCD in subjects older than 13 years old. Investigating experiences of peer victimization provides an early diagnosis and a more efficient treatment plans, guaranteeing an improved clinical outcome.

Epidemiological and Psychopharmacological Study About Off-Label Treatment in Child and Adolescent Psychiatric Emergencies: A Tertiary/Single Center Experience.

OBJECTIVE: The study used an epidemiological and pharmacological description of child and adolescent psychiatric emergencies (CAPEs), during which psychotropic medications are frequently administered as off-label therapies. METHODS: We retrospectively describe CAPE in 190 patients (mean age, 14.7 years) referring in the emergency department of a single tertiary center, from June 2016 to June 2018, focusing on off-label administration rate, most of all in emergency setting. RESULTS: An intrinsic fragility was observed in this population, where 28.4% of patients present a history of self-harm, 24.7% a concomitant neurodevelopmental disorder, and 17.3% a history of substance abuse. Psychomotor agitation was the most frequent referral reason, and it represents an unspecified clinical presentation of several conditions, while self-harm showed a stronger association with depressive disorders (55.2%).Globally, 811 medications were administered both as baseline therapy (67.8% of off-label rate) and/or in the emergency setting, where the off-label rate raised to 78.3%. Benzodiazepines had the highest rate of off-label use (98.2% as baseline therapy, 92.9% in acute context). Nevertheless, in 83.5% cases of acute administrations, a singular oral benzodiazepine (mostly lorazepam) guaranteed psychomotor agitation resolution, with a lower rate of adverse effects in contrast with atypical antipsychotics. CONCLUSIONS: Off-label drug use in CAPEs is a recurrent clinical practice. An international agreement about off-label drugs is crucial to obtain standard long-term pharmacoepidemiological, safety, and efficacy data. Pharmacological pediatric trials and international guidelines are also required to regulate pharmacological treatments of CAPEs, most of all in emergency settings.

CGRP Inhibitors and Oxidative Stress Biomarkers in Resistant Migraine: A Real-Life Study with Erenumab, Fremanezumab, and Galcanezumab.

Patients with high-frequency resistant migraine and medication-overuse headache are still the main clinical challenge in tertiary headache centers. The approval of targeted antibodies against the calcitonin gene-related peptide (CGRP) and its receptor represents a powerful instrument. In this study, we observed how biological and clinical features of resistant migraineurs responded to erenumab, fremanezumab, or galcanezumab. We found a reduction in advanced oxidation protein products (AOPP) as a biomarker of improved redox state after six months of treatment. We also found that treatment efficacy was precocious and maintained with high individual responder rates. In particular, seven out of ten patients achieved a reduction of 50% from the baseline at three months, which was maintained at six months, while about one out of our patients experienced a 75% reduction in headache frequency from the first month of treatment. The migraine disability assessment (MIDAS) and the associated fatigue, anxiety, and sleep quality also significantly improved. The allodynia symptom dropped from moderate/severe to mild/absent as a sign of central sensitization reduction. Our study confirmed the safety and efficacy of CGRP inhibition in real-life, high-challenging patients. Additional evidence is needed to understand the role of oxidative stress as a migraine biomarker.

Victimization among children and adolescents accessing the Meyer pediatric hospital: A retrospective study.

PROBLEM: The consistent prevalence and occasionally severe consequences of bullying and victimization suggest the need to include a more accurate assessment of these episodes within the Emergency Departments (ED). However, the literature on mental health related symptoms of bullying/victimization treated in the ED is still scarce. The aim of this study is to assess the prevalence of peer victimization amongst children and adolescents referred to an Italian Pediatric Emergency Department. Differences between Hospital Departments, type of victimization and ages are tested. METHODS: A retrospective observational study was conducted with 705 subjects. The age range was from 6 to 18 years old (M = 13.09; SD = 3.048). FINDINGS: 15.3% of the sample reported to be victimized (8.2% occasionally; 7.1% systematically). For the Child and Adolescent Psychiatry Unit, we found a significant association between peer victimization and being adolescent (Fisher's p = 0.003). In addition, a significant association was found between verbal victimization and Child and Adolescent Psychiatry Unit (Fisher's p = 0.02) and physical victimization and Child Abuse Department (Fisher's p < 0.001). CONCLUSION: Findings suggest the importance of an accurate assessment of victimization experiences of children and adolescents with access to ED, to prevent future re-victimization and crystallization of symptoms across time.

Supersaturation of VEP in Migraine without Aura Patients Treated with Topiramate: An Anatomo-Functional Biomarker of the Disease.

Migraine is a primary headache with high prevalence among the general population, characterized by functional hypersensitivity to both exogenous and endogenous stimuli particularly affecting the nociceptive system. The hyperresponsivity of cortical neurons could be due to a disequilibrium in the excitatory/inhibitory signaling. This study aimed to investigate the anatomo-functional pathway from the retina to the primary visual cortex using visual evoked potentials (VEP). Contrast gain protocol was used in 15 patients diagnosed with migraine without aura (at baseline and after 3 months of topiramate therapy) and 13 controls. A saturation (S) index was assessed to monitor the response of VEP's amplitude to contrast gain. Non-linear nor monotone growth of VEP (S < 0.95) was defined as supersaturation. A greater percentage of migraine patients (53%) relative to controls (7%) showed this characteristic. A strong inverse correlation was found between the S index and the number of days separating the registration of VEP from the next migraine attack. Moreover, allodynia measured through the Allodynia Symptoms Check-list (ASC-12) correlates with the S index both at baseline and after 3 months of topiramate treatment. Other clinical characteristics were not related to supersaturation. Topiramate therapy, although effective, did not influence electrophysiological parameters suggesting a non-intracortical nor retinal origin of the supersaturation (with possible involvement of relay cells from the lateral geniculate nucleus). In conclusion, the elaboration of visual stimuli and visual cortex activity is different in migraine patients compared to controls. More data are necessary to confirm the potential use of the S index as a biomarker for the migraine cycle (association with the pain-phase) and cortical sensitization (allodynia).

Excessive daytime sleepiness and fatigue in neurological disorders.

Excessive daytime sleepiness (EDS) and fatigue are some of the most frequent symptoms in neurological diseases and could impact on quality of life by increasing the risk of accidents and generally affecting daily life activities. In this review, we will examine the variety of causes responsible for EDS in neurological diseases, including nocturnal sleep alterations, CNS pathological abnormalities with alterations in arousal and/or REM regulation systems, circadian rhythms disorders, drugs, and comorbid psychiatric or primary sleep disorders. Among neurological diseases, epilepsy, dementia, Parkinson disease, multiple sclerosis, and myotonic dystrophies represented a model for these interactions between EDS and neurological diseases. A complete diagnostic workup in neurological patients with EDS should be undertaken since EDS can worsen many different aspects such as psychiatric symptoms, cognitive deficit, and in some cases, the severity of the neurological disease per se. Moreover, quality of life and risk of accidents are dependent on EDS. An individualized approach to this symptom in neurological patients should be considered with a focus on modifiable causes such as SDB, psychiatric comorbidities, and drugs. When considering EDS and fatigue in neurological diseases, close attention to lifestyle and sleep hygiene is advisable. A critical review of ongoing pharmacological therapy should not be overlooked. Possible diagnosis and treatment of SDB should be always considered.

Plasma Levels of Oxidative Stress Markers, before and after BoNT/A Treatment, in Chronic Migraine.

The pathophysiological mechanisms of migraine transformation are debated. Modifications of plasma oxidative stress biomarkers have been described in chronic migraine. OnabotulintoxinA (BoNT/A) treatment, approved for chronic migraine prophylaxis, possibly reduces pain neurotransmitters release and oxidative stress products. Aims of our study were to investigate differences in the levels of selected plasmatic oxidative stress biomarkers (Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), Thiolic Groups (SH)) comparing chronic migraineurs (CM) and healthy controls (HC). We also explored possible clinical and biochemical modifications in the CM group after six months of treatment with BoNT/A. At the baseline, we found higher values of AOPP (p < 0.001), and lower values of SH (p < 0.001) and FRAP (p = 0.005) in the CM group. At the six-month follow-up we found a reduction of AOPP (p < 0.001) and an increase of FRAP (p < 0.001) and SH (p = 0.023) within the CM group. BoNT/A treatment improved migraine symptoms in the CM group. We confirmed previous reports of imbalanced antioxidant mechanisms in chronic migraine showing lower antioxidant capacities in patients than controls. BoNT/A improved the levels of plasma oxidative stress biomarkers and confirmed its role as an effective prophylactic treatment for CM. Other studies should investigate the potential antioxidant properties of BoNT/A treatment.

Putative salivary biomarkers useful to differentiate patients with fibromyalgia.

Fibromyalgia (FM) is a chronic pain disorder characterized by widespread pain and associated with unspecific symptoms. So far, no laboratory tests have been validated. The aim of the present study was to investigate the presence in saliva of potential diagnostic and/or prognostic biomarkers which could be useful for the management of FM patients. Specifically, the salivary profile of FM patients was compared with those of healthy subjects, subjects suffering migraine (model of non-inflammatory chronic pain), and patients affected by rheumatoid arthritis (model of inflammatory chronic pain). For proteomics analysis 2-DE and SELDI-TOF-MS were applied. From 2-DE serotransferrin and alpha-enolase were found differentially expressed in FM. Hence, their expression was validated by ELISA together with phosphoglycerate-mutase-I and transaldolase, which were found in a previous work. Moreover, ROC curve was calculated by comparing FM patients versus control subjects (healthy plus migraine) to investigate the discriminative power of biomarkers. The best performance was obtained by combining alpha-enolase, phosphoglycerate-mutase-I and serotransferrin. On the other hand, none of the candidate proteins showed a statistical correlation with clinical features. Finally, preliminary SELDI analysis highlighted two peaks whose identification need to be validated. Overall, these results could be useful in supporting the clinical diagnosis of FM. SIGNIFICANCE: FM is one of the most common chronic pain condition which is associated with significant disability. The fibromyalgic pain is a peculiar characteristic of this disease and FM patients suffer from reduced quality of life, daily functioning and productivity. Considering the deep complexity of FM, the discovery of more objective markers is crucial for supporting clinical diagnosis. Therefore, the aim of the present study was the selection of biomarkers effectively associated with fibromyalgic pain which will enable clinicians to achieve an unambiguous diagnosis, and to improve approaches to patients' management. We defined a panel of 3 salivary proteins which could be one of the criteria to be taken into account. Consequently, the identification of disease salivary biomarkers could be helpful in detecting FM clusters and targeted treatment. Actually, our future perspective foresees to develop a simple, rapid and not invasive point-of-care testing which will be of use during the diagnostic process. In addition, the present results can offer a clue for shedding light upon the complex entity of such a disease like FM.

Fatigue, sleep-wake pattern, depressive and anxiety symptoms and body-mass index: analysis in a sample of episodic and chronic migraine patients.

Migraine clinical presentation and life-time course can be highly heterogeneous, with a subgroup of patients developing chronic migraine; moreover, migraine clinical spectrum is expanded by the association with different coexisting conditions and interictal dysfunctions. The aim of this study was to systematically evaluate migraine clinical features, daily functioning parameters, sleep pattern, presence of depressive-anxiety symptoms and body mass index (BMI) in a sample of 75 episodic and 75 chronic migraine without aura patients. Migraine-related disability, fatigue, daily sleepiness, subjective sleep quality, anxiety and depressive symptoms were, respectively, evaluated using the following questionnaires: Fatigue Severity Scale (FSS), Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI), Generalized Anxiety Disorder 7-item Scale (GAD-7), Patient Health Questionnaire 9-item Scale (PHQ-9). Mean FSS score (p < 0.001), PSQI score (p = 0.015), GAD-7 score (p = 0.019), PHQ-9 score (p < 0.001) and BMI score (p = 0.012) were significantly higher in chronic compared to episodic migraineurs. Additionally, a correlation analysis carried out in the total sample of 150 migraine patients documented a statistically significant, positive correlation between monthly frequency of migraine attacks and FSS score (p < 0.001), PSQI score (p = 0.006), GAD-7 score (p = 0.019), PHQ-9 score (p < 0.001) and BMI score (p = 0.049). Data from the present report seem to expand the concept of migraine as a continuum or spectrum, with greater occurrence of fatigue, poor sleep quality, anxiety-depressive symptoms and higher BMI score in chronic compared to episodic migraine patients; further investigation is certainly necessary to better define the biological basis and mechanisms associated with migraine transformation from episodic to chronic pattern.

Preferential occurrence of attacks during night sleep and/or upon awakening negatively affects migraine clinical presentation.

It is well known that migraine attacks can preferentially occur during night sleep and/or upon awakening, however the possible implications of this timing on migraine clinical presentation remain unclear. The aim of this study was to assess the possible consequences of sleep-related migraine (defined as ≥ 75% of migraine attacks occurring during night sleep and/or upon awakening) on the migraine clinical picture (i.e. migraine-related disability, attack severity, use of symptomatic drugs), subjective sleep quality, excessive daytime sleepiness and fatigue. Two hundred consecutive migraine without aura patients were enrolled; patients with comorbid disorders or chronic medication use were excluded. 39% of the migraineurs included in the study received a diagnosis of sleep-related migraine. The mean frequency of migraine attacks (days per month) did not significantly differ between the patients with and those without sleep-related migraine, whereas migraine-related disability (p<0.0001), mean attack severity (p<0.0001), and monthly intake of symptomatic drugs (p<0.0001) were significantly higher in patients with migraine preferentially occurring at night-time and/or upon awakening. Subjective sleep quality and excessive daytime sleepiness did not differ significantly between the two groups, whereas fatigue was significantly more present in the patients with sleep-related migraine (p=0.0001). These data seem to support the hypothesis that patients with sleep-related migraine represent a subset of individuals with a more severe and disabling clinical presentation of migraine and greater impairment of daily functioning, as suggested by the higher degree of fatigue. Migraineurs with night-time attacks Preferential occurrence of attacks during night sleep and/or upon awakening negatively affects migraine clinical presentation also showed a greater use of symptomatic drugs, possibly related to delayed use of symptomatic treatment. The identification of subtypes of patients with a higher disability risk profile could have crucial implications for individually tailored management of migraine patients.

Evidences of Reduced Antioxidant Activity in Patients With Chronic Migraine and Medication-Overuse Headache.

BACKGROUND: Migraine is a complex multifactorial, neurobiological disorder, whose pathogenesis is not fully understood, nor are the mechanisms associated with migraine transformation from episodic to chronic pattern. A possible role of impaired oxidative mitochondrial metabolism in migraine pathogenesis has been hypothesized, and increased levels of peripheral markers of oxidative stress have been reported in migraine patients, although the literature data are limited and heterogeneous. OBJECTIVES: The aim of this cross-sectional study was to determine plasmatic levels of advanced oxidation protein products, ferric-reducing antioxidant power and total plasmatic thiol groups, all plasmatic markers related to oxidative stress, in a sample of chronic migraine patients and medication-overuse headache, compared to a control group of healthy subjects. METHODS: Thirty-three patients with a diagnosis of both chronic migraine and medication-overuse headache (International Classification of Headache Disorders,3rd edition, beta version) and 33 healthy, headache-free subjects were enrolled. Patients with comorbid/coexisting conditions were excluded, as well as patients in treatment with migraine preventive drugs. Plasmatic levels of advanced oxidation protein products, ferric-reducing antioxidant power, and total thiol groups were determined in migraine patients and controls; moreover, oxidative stress biomarkers were compared in migraine patients with triptan compared to non-steroidal anti-inflammatory drug overuse. RESULTS: The statistical analysis showed significantly lower levels of ferric-reducing antioxidant power and total plasmatic thiol groups, both expression of antioxidant power, in patients with chronic migraine and medication-overuse headache compared to controls (respectively, ferric antioxidant power median [interquartile range] 0.53 [0.22] vs 0.82 [0.11] mmol/L, P < .001; total thiol groups 0.25 [0.08] vs 0.51 [0.11] µmol/L, P < .001). Moreover, no statistically significant differences in oxidative stress biomarkers were detected between patients with triptan and nonsteroidal anti-inflammatory drug overuse. CONCLUSIONS: The data from the present study suggest that antioxidant capacity is lower in chronic migraine patients and medication-overuse headache compared to healthy headache-free subjects, with no differences between patients with triptan or nonsteroidal anti-inflammatory drug overuse. Further investigation is certainly necessary in order to define the causal or consequential role of an imbalance between pro-oxidants and antioxidant defenses in migraine pathogenesis and "chronification" and the possible therapeutic implications in clinical practice.

Migraine features in migraineurs with and without anxiety-depression symptoms: a hospital-based study.

BACKGROUND: Migraine, anxiety and depression often coexist. A "neurolimbic" model of migraine has been recently proposed accounting for a dynamic influence of pain, mood and anxiety on the migraine disease. However, very few data exist concerning clinical migraine features in patients reporting anxiety-depression symptoms. OBJECTIVE: Aim of our study was to test differences in clinical migraine features between migraineurs with anxiety-depression symptoms and migraineurs without ones. MATERIALS AND METHODS: We recruited 200 consecutive migraineurs. Other primary headaches comorbidity and migraine prophylaxis were exclusion criteria. Each patient was interviewed following a structured questionnaire including general features about migraine, triggers, allodynia. Anxiety and depression symptoms were evaluated in each patient by two brief self-reported scales: the generalized anxiety disorder 7-item scale (GAD-7) and the Patient Health Questionnaire 9-item scale (PHQ-9). A cut-off of 5 in both the GAD-7 and the PHQ-9 was considered positive for the presence of anxiety-depressive symptoms. RESULTS: One hundred and one patients (51.5%) had anxiety-depression symptoms (GAD-7 and PHQ-9 ≥ 5). They reported a more headaches/month (p = 0.004), higher number of triggers (p < 0.001), and were more allodynic (p = 0.005). In a binary logistic regression model triggers and allodynia made a unique statistical contribution on reporting anxiety-depression symptoms. CONCLUSION: Our results showed that the presence of anxiety-depression symptoms affects migraine clinical presentation. They are associated with enhanced migraine triggers susceptibility, more ictal allodynic symptoms as well as more headaches/month. An altered sensation in migraineurs with anxiety-depression symptoms could be a result of a lower pain threshold and an increased cortical excitability in a broader context of a neurolimbic dysfunction.

Clinical features associated with ictal osmophobia in migraine.

Olfactory hypersensitivity may occur during migraine attacks and has been found to be very specific for this form of headache. Aim of this study was to investigate if migraineurs with ictal osmophobia have particular clinical features comparing to patients without ictal osmophobia. We recruited 200 consecutive migraineurs. Other primary headaches comorbidity and migraine prophylaxis were exclusion criteria. Each patient was interviewed following a structured questionnaire including general features about migraine, depression and anxiety symptoms. Migraine triggers both spontaneously and selecting from a specific list. Allodynia during the migraine attack was measured using the Allodynia symptoms check-list 12 (ASC-12). Eighty four (42 %) patients are non-osmophobic vs. 116 patients (58 %) who are osmophobic. After a logistic regression analysis, pain intensity (OR 1.391; p = 0.008) and anxiety (OR 1.099; p = 0.047) were significantly higher while aura (OR 0.421; p = 0.028) is less frequent in osmophobic migraineurs. We found significant differences in clinical features of osmophobic patients in respect to non-osmophobic ones. Ictal osmophobia seems being related to a broader sensorial hypersensitivity that could lead to a more florid clinical presentation.