Marcello Silvestro

Onabotulinumtoxin-A (onabotA) is a neurotoxin widely used for several indications, including chronic migraine (CM) preventive treatment, due to its well-demonstrated efficacy, tolerability, and safety. However, onabotA safety during pregnancy and breastfeeding remains unclear, as these populations are typically excluded from clinical trials. The action of onabotA starts locally at the injection sites, modulating the pain pathway with minimal systemic absorption, which theoretically minimizes risks to the fetus or breastfeeding infant. Preclinical studies demonstrate that onabotA does not distribute systemically in significant amounts after administration, although adverse fetal outcomes in rats and rabbits were reported when injected at high doses. Limited human data suggest that onabotA exposure during pregnancy may not be associated with major malformations or significant adverse outcomes for the fetus, especially when used at therapeutic doses for migraine prevention during the first trimester or earlier. Data on breastfeeding are even scarcer but indicate a low likelihood of drug transfer into breast milk. This narrative review highlights the available evidence on the use of onabotA in pregnancy and breastfeeding women, including real-word evidence, with a focus on the use for CM.

(Background) Cognitive deficits related to frontotemporal dysfunction are common in Amyotrophic Lateral Sclerosis (ALS). Visuospatial deficits, related to posterior cerebral regions, are often underestimated in ALS, though they play a crucial role in attending daily living activities. Our pilot study aims at assessing visuospatial abilities using a domain-specific tool in ALS patients compared to healthy controls (HC). (Methods) Twenty-three patients with early ALS and 23 age- and education-matched HC underwent the Battery for Visuospatial Abilities (BVA), including visuo-perceptual and visuo-representational subtests. (Results) When compared to HC, ALS scored worse in 2 out of 4 visuo-perceptual subtests (i.e., Line Length Judgment and Line Orientation Judgment) and 1 out of 4 visuo-representational tasks (i.e., Hidden Figure Identification, HFI) (p <0.01). No correlations arose between ALS clinical features and BVA performance. More than 80% of the ALS cohort obtained abnormal scores in HFI subtest. (Conclusions) Our findings revealed that ALS scored worse (compared to HC) on selective tests tapping “perceptual” and “representational” visuospatial abilities, since early stages of disease. In clinical practice, our findings highlight the need of multi-domain neuropsychological assessment, for monitoring disease course and properly organizing care management of patients with ALS.

Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response, suggesting that other pathways may play a critical role, with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family, such as adrenomedullin and amylin; molecules of the secretin family, such as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP); receptors, such as transient receptor potential (TRP) channels; intracellular downstream determinants, such as potassium channels, but also the opioid system and the purinergic pathway, have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways, highlighting, based on preclinical and clinical evidence, as well as provocative studies, their potential role as future targets for migraine preventive treatment.

Migraine is a debilitating neurological condition affecting millions of people worldwide. Until few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications and discovered by serendipity to be effective in migraine prevention although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed to identify novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response suggesting that other pathways may play a critical role with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family as adrenomedullin and amylin, molecules of the secretin family as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP), receptors as transient receptor potential (TRP) channels, intracellular downstream determinants as potassium channels but also the opioid system and the purinergic pathway have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways highlighting, based on preclinical and clinical evidences as well as provocative studies, their potential role as future targets for migraine preventive treatment.

Guidelines regarding long-term use with onabotulinumtoxinA (onaBT-A) in chronic migraine (CM) prophylaxis are lacking. This multicentric prospective real-life study aimed to assess the efficacy and safety of a long-term treatment. A total of 195 chronic migraine patients were treated with onaBT-A, every 3 months for 5 cycles (Phase 1). In the Phase 2 of the study, depending on response rate, patients were divided into “responders” (R), “partially responders” (PR) and “non-responders” (NR). Then, we proposed to R and PR patients to continue with an additional 12 months of treatment (additional 4 sessions). Response to treatment and adverse events were collected for the entire duration of the study. Of the 195 patients included (females 82.1%, mean age 47.4 ± 12.4), at the end of Phase 1 there were 52.3% of R patients, 17.9% of PR patients, 15.4% of NR patients and 14.4% drop-outs. During Phase 2 of treatment, R patients presented a maintenance of the improvement achieved during the first year of treatment, as well as PR patients. Except for three serious adverse events not related to treatment, all other adverse events were mild or moderate in severity and resolved without sequelae. In the literature, adherence to oral migraine-preventive medications among patients with CM was found to be less than 25%. The results of this prospective real-life multicenter study show efficacy, safety and adherence to a long-term treatment with onaBT-A.

Vaccines have represented the breakthrough in the fight against COVID-19. Based on reported headache attacks after vaccination in randomized controlled trials, we focused on the effects of COVID-19 vaccine administration on the migraine population, using an online questionnaire published on Italian Facebook groups oriented to headache patients. We collected data about the demographics and clinical parameters of migraine severity, COVID-19 infection, vaccination, and characteristics of headaches following vaccination. Out of 841 migraine patients filling in the questionnaire, 66.47% and 60.15% patients experienced a headache attack (from 1 hour to 7 days) after the first and the second vaccine dose, respectively. The main finding concerns headaches perceived by 57.60% of patients: attacks following vaccination were referred to as more severe (50.62% of patients), long-lasting (52.80% of patients) and hardwearing (49.69% of patients) compared to the usually experienced migraine attacks. This could be related to the production of inflammatory mediators such as type Iβ interferon. Considering the high prevalence of migraine in the general population, awareness of the possibility of headaches worsening following COVID-19 vaccination in these patients may allow both patients and clinicians to face this clinical entity with conscious serenity, and to reduce the waste of resources towards inappropriate health-care.

A neuronal dysfunction based on the imbalance between excitatory and inhibitory cortical-subcortical neurotransmission seems at the basis of migraine. Intercritical neuronal abnormal excitability can culminate in the bioelectrical phenomenon of Cortical Spreading Depression (CSD) with secondary involvement of the vascular system and release of inflammatory mediators, modulating in turn neuronal activity. Neuronal dysfunction encompasses the altered connectivity between the brain areas implicated in the genesis, maintenance and chronic evolution of migraine. Advanced neuroimaging techniques allow to identify changes in functional connectivity (FC) between brain areas involved in pain processes. Through a narrative review, we re-searched case-control studies on FC in migraine, between 2015 and 2020, by inserting the words migraine, fMRI, EEG, MEG, connectivity, pain in Pubmed. Studies on FC have shown that cortical processes, in the neurolimbic pain network, are likely to be prevalent for triggering attacks, in response to predisposing factors, and that these lead to a demodulation of the subcortical areas, at the basis of migraine maintenance. The link between brain dysfunction and peripheral interactions through the inhibition of CGRP, the main mediator of sterile migraine inflammation needs to be further investigated. Preliminary evidence could suggest that peripheral nerves inference at somatic and trigeminal levels, appears to change brain FC.

Despite the growing body of advanced studies investigating the neuronal correlates of pain processing in patients with migraine without aura (MwoA), only few similar studies have been conducted in patients with migraine with aura (MwA). Therefore, we aimed to explore the functional brain response to trigeminal noxious heat stimulation in patients with MwA. Seventeen patients with MwA and 15 age- and sex-matched healthy controls (HC) underwent whole-brain blood oxygen level–dependent (BOLD) fMRI during trigeminal noxious heat stimulation. To examine the specificity of any observed differences between patients with MwA and HC, the functional response of neural pathways to trigeminal noxious heat stimulation in patients with MwA was compared with 18 patients with MwoA. Secondary analyses investigated the correlations between BOLD signal changes and clinical parameters of migraine severity. We observed a robust cortical and subcortical pattern of BOLD response to trigeminal noxious heat stimulation across all participants. Patients with MwA showed a significantly increased activity in higher cortical areas known to be part of a distributed network involved in advanced visual processing, including lingual gyrus, inferior parietal lobule, inferior frontal gyrus and medial frontal gyrus. Moreover, a significantly greater cerebellar activation was observed in patients with MwA when compared with both patients with MwA and HC. Interestingly, no correlations were found between migraine severity parameters and magnitude of BOLD response in patients with MwA. Our findings, characterized by abnormal visual pathway response to trigeminal noxious heat stimulation, support the role of a functional integration between visual and trigeminal pain networks in the pathophysiological mechanisms underlying migraine with aura. Moreover, they expand the concept of “neurolimbic-pain network” as a model of MwoA including both limbic dysfunction and cortical dys-excitability. Indeed, we suggest a model of “neurolimbic-visual-pain network” in MwA patients, characterized by dysfunctional correlations between pain-modulating circuits not only with the cortical limbic areas but with advanced visual areas as well. Furthermore, the abnormal cerebellar response to trigeminal noxious heat stimulation may suggest a dysfunctional cerebellar inhibitory control on thalamic sensory gating, impinging on the advanced visual processing cortical areas in patients with MwA.