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Andreas A Argyriou,1,3 Athanasios P Kyritsis,2 Thomas Makatsoris,3 Haralabos P Kalofonos3 1Department of Neurology, "Saint Andrew's" General Hospital of Patras, Greece; 2Department of Neurology, University Hospital of Ioannina, Greece; 3Department of Medicine-Division of Oncology, University of Patras Medical School, Rion-Patras, Greece Abstract: Commonly used chemotherapeutic agents in oncology/hematology practice, causing toxic peripheral neuropathy, include taxanes, platinum compounds, vinca alkaloids, proteasome inhibitors, and antiangiogenic/immunomodulatory agents. This review paper intends to put together and discuss the spectrum of chemotherapy-induced peripheral neuropathy (CIPN) characteristics so as to highlight areas of future research to pursue on the topic. Current knowledge shows that the pathogenesis of CIPN still remains elusive, mostly because there are several sites of involvement in the peripheral nervous system. In any case, it is acknowledged that the dorsal root ganglia of the primary sensory neurons are the most common neural targets of CIPN. Both the incidence and severity of CIPN are clinically under- and misreported, and it has been demonstrated that scoring CIPN with common toxicity scales is associated with significant inter-observer variability. Only a proportion of chemotherapy-treated patients develop treatment-emergent and persistent CIPN, and to date it has been impossible to predict high- and low-risk subjects even within groups who receive the same drug regimen. This issue has recently been investigated in the context of pharmacogenetic analyses, but these studies have not implemented a proper methodological approach and their results are inconsistent and not really clinically relevant. As such, a stringent approach has to be implemented to validate that information. Another open issue is that, at present, there is insufficient evidence to support the use of any of the already tested chemoprotective agents to prevent or limit CIPN. The results of comprehensive interventions, including clinical, neurophysiological, and pharmacogenetic approaches, are expected to produce a consistent advantage for both doctors and patients and thus allow the registration and analysis of reliable data on the true characteristics of CIPN, eventually leading to potential preventive and therapeutic interventions. Keywords: neurotoxicity, incidence, diagnosis, treatment

Amalia A Ifanti1, Andreas A Argyriou2, Haralabos P Kalofonos2 1Department of Educational Sciences and Early Childhood Education, University of Patras, 2Department of Medicine, Division of Oncology, University Hospital of Patras, Rio, Patras, Greece Aim: In this paper we sought to explore undergraduate medical students’ views about their professional development during their studies that are considered to be related to medical professionalism. Method: A descriptive cross-sectional study using interpretative analysis of anonymous 10-item questionnaires was conducted at the University of Patras Medical School (UPMS), Greece. The study sample consisted of 134 undergraduate students in their fifth and sixth year of study at UPMS. Results: Undergraduate students emphasized the great significance of daily clinically-oriented practice in the wards in the group of behaviors consistent with medical professionalism. The integrated curriculum and informal discussions with members of the academic staff in the form of role models were also regarded as valuable approaches strongly enhancing professionalism. Students’ personal statements contained attributes regarding premium professional skills, including constancy and perfectionism throughout a lifelong learning process, so as to be able to provide high quality medical care to patients. Conclusion: According to our undergraduate medical students themselves, the last 2 years of their studies are important to understand the essence of professionalism and develop their professional medical attitudes. Clinically-oriented teaching activities together with the informal curriculum of enhanced role modeling promote medical professional behaviors and increase standards of health care provided to patients. Keywords: undergraduate students, medicine, professionalism, medical education, Greece

CONTEXT: Epothilones, belonging to the family of microtubule stabilizing agents, have shown prolonged remissions and improved survival in various types of refractory, treatment-resistant cancer. Ixabepilone (BMS-247550) is the main representative of these compounds. Peripheral neuropathy is a significant toxicity of epothilones, eventually resulting in dose modification and changes in the treatment plan. OBJECTIVES: This review critically looks at the pathogenesis, incidence, risk factors, characteristics, and management of epothilone-induced peripheral neuropathy (EIPN). We also highlight areas of future research to pursue. METHODS: References were identified by searches of PubMed from 2000 until December 2010 with related terms. RESULTS: The mechanism underlying EIPN remains rather unclear. Damage to the ganglion soma cells and peripheral axons through disruption of microtubules of the mitotic spindle and by interference with the axonal transport in the affected neurons may significantly contribute to the pathogenesis of EIPN. As a result, epothilones primarily produce an axonal, dose-dependent, sensory distal peripheral neuropathy, which is reversible in most cases on discontinuation of treatment. The incidence of EIPN is mainly related to risk factors, including cumulative dose and probably pre-existing neuropathy. To date, apart from the use of dose reduction and schedule change algorithm, there is no effective treatment with neuroprotective agents for EIPN. CONCLUSION: EIPN remains a very challenging area in the field of toxic neuropathies. As such, there is a need for further preclinical and prospective clinical studies to elucidate the pathogenesis of EIPN and provide further robust evidence on its incidence, course, and reversibility. [ABSTRACT FROM AUTHOR]

CONTEXT: Several studies have investigated the prevalence of sleep disorders in patients suffering from multiple sclerosis (MS) and have shown that up to 54% of patients may have significantly more sleep problems than the general population. To our knowledge, however, no data are available about the quality of sleep of the primary caregivers of patients with MS. OBJECTIVES: The objectives of the current cross-sectional study were to assess the quality of sleep in Greek primary caregivers of patients with MS and to investigate its relationship with the degree of caregivers' emotional distress. METHODS: Twenty-two male and 13 female primary caregivers (mean age 47.3±12.4 years) of an equal number of patients with MS, who consented to participate, completed the validated Greek version of the Pittsburgh Sleep Quality Index (PSQI) and the validated Greek version of the Hospital Anxiety and Depression Scale (HADS). Thirty-five age-, gender-, and education-matched healthy controls were used for comparisons. RESULTS: Caregivers experienced a higher degree of anxiety than depression. The mean score in the seven-item HADS-A subscale was 9.5±4 (range 3-15) and the mean score in the seven-item HADS-D subscale was 7.1±3.1 (range 2-14). The mean scores of caregivers on both HADS-A and HADS-D were significantly higher than those of controls (P<0.001). The PSQI scoring demonstrated that 19 (54.3%) caregivers had poor sleep quality (cut-off value of >5). The mean values of caregivers for the PSQI were 6.0±2.8 (range 2-12) compared with controls, who scored at a significantly lower level (1.5±0.8; P<0.001). Poor quality of sleep was significantly correlated with increased levels of anxiety (r=0.392; P=0.02) and depression (r=0.424; P=0.01). Among the PSQI components, the sleep duration and sleep latency were mostly influenced by the degree of emotional distress. CONCLUSION: A significant proportion of primary caregivers of MS patients experience poor sleep quality. The degree of their emotional distress appears to significantly influence their quality of sleep. Appropriate psychopharmacological interventions may be required for those individuals. [ABSTRACT FROM AUTHOR]

The primary aim of this study was to assess whether epoetin alfa (Ea) would improve cognitive performance in a group of anaemic cancer patients receiving chemotherapy. The secondary aim was to confirm the positive impact of Ea on haematological parameters, and quality of life (QOL). Fifty patients with solid tumours and haemoglobin (Hb) <11.0 g/dL received Ea 40 000 units once weekly for 12 weeks and were administered the Mini-Mental State Examination and the European Organization for Research and Treatment of Cancer (QLQ-C30) questionnaire prior to Ea therapy and at study completion. No clinically significant alterations were observed on cognitive function during Ea treatment. Changes in cognitive function were unrelated to Hb change and there were no significant differences in cognitive performance between Ea responders and non-responders. The analyses revealed clinically significant improvements in Hb levels, physical and role function, and clinically meaningful reductions in fatigue. Hb changes were significantly associated with the magnitude of improvement in QOL parameters. The lack of a clinical benefit in cognition observed in this study during Ea treatment may redirect the focus of research from enhancing to maintaining cognitive function, since stability in cognitive performance through time may be as well clinically important. [ABSTRACT FROM AUTHOR]

The co-occurrence of a brain tumour and demyelinating disease of the central nervous system (CNS) constitutes a rare clinical entity. We herein report the incidence of meningioma and CNS non-specific demyelination in a patient with a 6-year history of operated brain tumour (meningioma). Our case bolsters the argument that in at least some cases, the occurrence of a brain tumour could predispose to CNS non-specific demyelination. [ABSTRACT FROM AUTHOR]

Background: Osteoblastomas are rare benign bone tumors that are mostly found in the posterior spinal elements; about 20% are located in the cervical spine. Objective: The case of a destructive cervical osteoblastoma at C5 is reported in a 19-year-old man who initially presented with spastic quadriparesis. Case Report: A 19-year-old man was self-referred, reporting symptoms in keeping with a progressive spastic quadriparesis, which had suddenly developed 6 days earlier. Preceding symptoms included mild non-specific neck pain for 3 weeks. The patient was afebrile, and no ambulatory X-ray study had been performed until the time of referral. A cervical spine computed tomography (CT) scan revealed a lytic lesion involving the spinal process and the pedicles of the C5 vertebra. Cervical spine magnetic resonance imaging performed on an inpatient basis revealed a well-circumscribed, destructive lesion of the C5 vertebra, measuring approximately 3 cm. The spinal cord was significantly compressed. The patient underwent open surgical resection of the tumor through a midline posterior approach. Histopathology of the tumor specimen was in keeping with a diagnosis of osteoblastoma. Conclusion: Neuroimaging should be performed with either conventional plain X-ray study, which seems to be sufficient in patients presenting with non-specific symptomatology related to cervical spine damage, or with advanced techniques in the case of patients with persistent neck pain or neurological deficit. [ABSTRACT FROM AUTHOR]

Objective: This post-hoc analysis of data extracted from a prospective study aimed to explore for the first time if the efficacy of fremanezumab in preventing difficult-to-treat migraine, according to ICHD-III, would differ between pre-menopausal and post-menopausal women., Methods: A total of 171 (aged 18-70 years) fremanezumab-treated female migraine patients for six consecutive months were classified to those at pre-menopausal ( n  = 82) or post-menopausal ( n  = 89). Monthly headache days (MHD), disability, and quality of life (QOL) outcomes were assessed at baseline and at week 24 post-fremanezumab within subgroups and were then compared between them. Safety and tolerability were also assessed., Results: In both groups, fremanezumab demonstrated significant reductions in MHDs, reduced disability, and higher QOL scores at week 24 post-treatment, compared to baseline. However, the between-subgroup comparison documented that pre-menopausal women and those at post-menopausal comparably benefited with significant reductions in overall MHDs ( p  = 0.883). Less disability, according to MIDAS ( p  = 0.696) and HIT-6 scores ( p  = 0.912), as well as higher QOL scores at week 24 post-fremanezumab, were also comparably evident in both groups. Safety was excellent across both subgroups., Conclusion: Fremanezumab can be considered a very effective treatment option for preventing migraines in difficult-to-treat women, aged 18-70 years, regardless of their menopausal status.

Background and Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is perceived differently by patients and physicians, complicating its assessment. Current recommendations advocate combining clinical and patient-reported outcomes measures, but this approach can be challenging in patient care. This multicenter European study aims to bridge the gap between patients' perceptions and neurological impairments by aligning both perspectives to improve treatment decision-making., Methods: Data were pooled from two prospective studies of subjects (n = 372) with established CIPN. Patient and physician views regarding CIPN were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Total Neuropathy Scale-clinical version (TNSc) items, and the disease-specific quality of life - Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20) from the European Organization for Research and Treatment of Cancer (EORTC). To identify inherent neurotoxic severity patterns, we employed hierarchical cluster analysis optimized with k-means clustering and internally validated by discriminant functional analysis., Results: Both NCI-CTCAE and TNSc demonstrated a significant difference in the distribution of severity grades in relation to QLQ-CIPN20 scores. However, a proportion of subjects with different neurotoxic severity grades exhibited overlapping QLQ-CIPN20 scores. We identified three distinct clusters classifying subjects as having severely impaired, intermediately impaired, and mildly impaired CIPN based on TNSc and QLQ-CIPN20 scores. No differences in demographics, cancer type distribution, or class of drug received were observed., Conclusions: Our results confirm the heterogeneity in CIPN perception between patients and physicians and identify three well-differentiated subgroups of patients delineated by degree of CIPN impairment based on scores derived from TNSc and QLQ-CIPN20. A more refined assessment of CIPN could potentially be achieved using the calculator tool derived from the cluster equations in this study. This tool, which facilitates individual patient classification, requires prospective validation., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: A real-time biomarker in chemotherapy-induced peripheral neurotoxicity (CIPN) would be useful for clinical decision-making during treatment. Neurofilament light chain (NfL) can be detected in blood in the case of neuroaxonal damage. The aim of the study was to compare the levels of plasma NfL (pNfL) according to the type of chemotherapeutic agent and the severity of CIPN., Methods: This single-center prospective observational longitudinal study included patients treated with paclitaxel (TX; n = 34), brentuximab vedotin (BV; n = 29), or oxaliplatin (PT; n = 19). All patients were assessed using the Total Neuropathy Score-clinical version and Common Terminology Criteria for Adverse Events before, during, and up to 6-12 months after the end of treatment. Nerve conduction studies (NCS) were performed before and after chemotherapy discontinuation. Consecutive plasma samples were analyzed for NfL levels using a Simoa ® analyzer. Changes in pNfL were compared between groups and were eventually correlated with clinical and NCS data. Clinically relevant (CR) CIPN was considered to be grade ≥ 2., Results: Eighty-two patients, mostly women (59.8%), were included. One third of the patients who received TX (29.4%), BV (31%), or PT (36.8%) developed CR-CIPN, respectively, without differences among them (p = 0.854). Although pNfL significantly increased during treatment and decreased throughout the recovery period in all three groups, patients receiving TX showed significantly greater and earlier changes in pNfL levels compared to the other agents (p < 0.001)., Conclusions: A variable change in pNfL is observed depending on the type of agent and mechanism of neurotoxicity with comparable CIPN severity, strongly implying the need to identify different cutoff values for each agent., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: To identify the preferences and perceptions of migraine patients for acute and preventive treatment options and to investigate which treatment outcomes are the most important., Design and Methods: The authors performed a choice-format survey in a cohort of migraine patients from Greece and Cyprus. A self-administered questionnaire developed in collaboration with the Greek Society of Migraine Patients was used., Results: Questionnaires were collected from 617 migraine patients. Efficacy was preferred over safety as the single most important parameter, both in acute and preventive treatment. When analyzing single outcomes, patients prioritized a complete pain remission at 1-hour post-dose for acute therapies. Regarding migraine prevention, a 75% reduction in frequency, intensity of pain, accompanying symptoms and acute medication intake were considered as most important. Conversely, outcomes routinely used in clinical trials, namely complete or partial pain remission at 2-hours post-dose for acute treatment and 50% or 30% reduction in migraine frequency for prevention, were not deemed particularly relevant. Tablet formulation was mostly preferred, both in acute and preventive treatment. Conclusion: Listening to patients' needs may add a piece of the puzzle that is generally missing in clinical practice and often explains the lack of adherence in both acute and preventative anti-migraine therapies.

Objective: The Greek Society of Migraine and Headache Patients conducted its third in-line population web-based survey in 2023 to ascertain if the burden of the disease and the patients' satisfaction with conventional and novel migraine therapies are changing compared to our previous findings from 2018 and 2020. Methods: The sampling process was based on a random call to participants to reply to a specific migraine-focused self-administered questionnaire, including 83 questions in Greek, which was distributed nationwide through the online research software SurveyMonkey. Results: We eventually enrolled 2565 patients, the majority of which were females. Our findings clearly demonstrate that migraine is still a burdensome condition. The degree of its impact on all aspects of productivity depends on the monthly frequency of migraine and the response rates to acute and prophylactic treatments. A total of 1029 (42.4%) of the patients had visited the emergency room mainly for unresponsiveness to acute treatments or aura-related symptoms. Triptans seem to be partly effective as acute therapies. OnabotulinumtoxinA seems to be effective for almost half of chronic migraine patients (43.9%) to report adequate satisfaction with this treatment (27.8% were "fairly happy", 10.6% were "very happy", and 5.5% were "extremely happy"). Due to their high rates of preventative effectiveness, most respondents treated with anti-CGRP Mabs expressed their optimism concerning their future while living with their migraine (88.25%), as well as towards further improvements in their quality of life (82.8%) status, mostly with fremanezumab. Conclusions: The patients recognize the usefulness of anti-CGRP Mabs in migraine prevention and consequently seem to be more optimistic than before about living with migraine. Considering the market change that is anticipated with the use of gepants and ditans, larger longitudinal population-based studies are warranted to further explore if the new era of migraine therapeutics might further lessen the burden of the disease.

Objective: Phase II/III randomized clinical trials (RCTs) are vulnerable to many types of bias beyond randomization. Insights into the reporting quality of RCTs involving migraine patients treated with monoclonal antibodies targeting the calcitonin gene-related peptide system (anti-CGRP MAbs) are currently lacking. Our aim was to analyze the reporting quality of phase II/III RCTs involving migraine patients treated with anti-CGRP MAbs. Methods: A systematic search was performed on the PubMed and EMBASE databases, according to PRISMA guidelines, for relevant RCTs in either episodic or chronic migraine prevention. Additionally, an adapted version of the 2010 CONSORT statement checklist was utilized. The ROBvis online tool was used to document the risk of bias. Results: From the initially identified 179 articles, we finally found 31 RCTs that were eligible for evaluation. The average CONSORT compliance was 88.7% (69.7-100%), while 93.5% (N = 29) of the articles had a compliance greater than 75%. Twenty-eight CONSORT items were reported in more than 75% of the articles. The average compliance of the analyzed RCTs was 93.9% for Galcanezumab, 91.3% for Fremanezumab, followed by 85.4% for Erenumab and Eptinezumab studies. Implementation of the ROB2 tool showed some concerning "missing information" arising from the inadequate reporting. Specifically, 50% of the studies (N = 16) were categorized as having inadequate information regarding the randomization process. Conclusions: Adequate reporting quality was disclosed in the evaluated RCTs with anti-CGRP MAbs in migraine prevention. However, some methodological issues need to be highlighted to be addressed in future studies assessing the efficacy of new molecules targeting CGRP or other candidate pathways implicated in migraine pathophysiology.

Objective: To define the incidence and risk factors for developing chemotherapy-induced neuropathic pain (CINP)., Methods: Retrospective, file-based analysis on cancer patients who received any type of conventional chemotherapy and for whom neurological evaluation was asked to reveal the extent of chemotherapy-induced peripheral neurotoxicity (CIPN) with or without CINP. CINP was assessed by means of the PI-NRS and Douleur Neuropathique-4 questionnaire. The total neuropathy score-clinical version graded the severity of CIPN., Results: The medical files of 500 chemotherapy-treated cancer patients were reviewed. Any grade chronic CIPN was disclosed in 343 (68.6%) patients and CINP in 127 (37%) of them, corresponding to an overall percentage of 25.4% among all 500 included patients. The logistic regression analysis identified as independent predictors for CINP development the presence of uncomplicated diabetes (OR: 2.17; p = .039) and grade 2-3 chronic CIPN (OR: 1.61; p < .001) as also the administration of combined paclitaxel plus cisplatin (reference variable), compared to oxaliplatin (OR: 0.18; p = .001) and taxanes (OR: 0.16; p < .001). The increased severity of acute OXAIPN was associated with CINP (OR: 4.51; p < .001). OXA-treated patients with persistent CINP presented a worst likelihood to improve after chemotherapy discontinuation, than patients receiving combined paclitaxel plus cisplatin (OR: 50; p < .001)., Conclusion: The incidence of CINP in our cohort was comparable to previous reports, with severities fluctuating upwards during chemotherapy and declined post-chemotherapy. Uncomplicated diabetes, the combined paclitaxel plus cisplatin treatment and the increased severity of acute oxaliplatin neurotoxicity mostly increase the risk for developing CINP. OXA-treated patients present less possibilities to recover from CINP after chemotherapy discontinuation, than other chemotherapies., (© 2024 Peripheral Nerve Society.)

Background: We primarily aimed to ascertain whether treatment with OnabotulinumtoxinA (BoNTA) might influence the extent of the interictal burden and cutaneous allodynia in patients with chronic migraine (CM)., Methods: Seventy CM patients, who received three consecutive cycles of BoNTA, were studied. The interictal burden was assessed with the Migraine Interictal Burden Scale (MIBS-4), while cutaneous allodynia was examined with the Allodynia Symptom Checklist (ASC-12) together with PI-NRS VAS to obtain hair brushing scores, and then these were compared from baseline (T0) to the last efficacy evaluation follow-up (T1). Efficacy outcomes, mostly mean headache days (MHD) and "Headache Impact Test" scores, were also assessed between T0 and T1., Results: BONTA improved the interictal burden, with a decrease in MIBS-4 scoring by an average of -7 at T1, compared to baseline ( p < 0.001). The percentage of patients with a moderate/severe interictal burden was substantially decreased. Likewise, BoNTA reduced the extent of cutaneous allodynia, with a significant reduction in both the ASC-12 (1 vs. 6; p < 0.001) and PI-NRS VAS (1 vs. 5; p < 0.001) to hair brushing median scores at T1, compared to baseline. Reduced MHD rates were significantly associated with a smaller interictal burden at T1. The efficacy of BoNTA, with a significant reduction in MHD and HIT-6 scores at T1 compared to T0, was re-confirmed., Conclusions: BoNTA resulted in a statistically significant reduction in the interictal burden and also improved cutaneous allodynia. The reduction in ictal burden was associated with the down-scaling of the interictal burden. Hence, BoNTA improved the full spectrum of migraine impairment by diminishing the clinical expression of central sensitization.

Purpose: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research., Methods: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science., Results: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship., Conclusion: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide., Relevance to Inform Research Policy: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship., (© 2024. The Author(s).)

Objective: To investigate whether the incidence of triggers, prodromal symptoms, hypersensitivity symptoms accompanying headache and responses to triptans were modified during a continuous 9-month fremanezumab therapy for migraine prophylaxis. Patients and methods: We studied 63 patients with high-frequency episodic migraine (HFEM). Enrolled patients received fremanezumab for nine consecutive months before defining the response rates and being stratified into treatment responders (≥50-74% reduction in monthly headache days (MHDs)), super responders (≥75%), partial non-responders (<50%) and super non-responders (<30%). Through headache diaries, patients provided data in order to document the impact of fremanezumab on the incidence of triggers, associated symptoms followed by headache and response to triptans (the use of the migraine treatment optimization questionnaire-4 (mTOQ-4)) during the 9-month treatment period. Results: Fremanezumab had early (after 3 monthly cycles) beneficial effects on the response to triptans in the majority of responders with relevant increases in mTOQ-4 scoring, but also in half of partial non-responders. A significant reduction in median days with migraine-associated symptoms was seen in responders after 6 months of therapy with fremanezumab, mostly for osmophobia, photophobia, phonophobia and nausea/vomiting, but partial non-responders also benefited. Likewise, the incidence of self-reported prodromal symptoms was significantly reduced in responders and was modestly diminished in partial non-responders. Triggers remained unaffected in both responders and non-responders. Conclusions: Fremanezumab given for at least 6-9 months may exert neuromodulatory effects in the migraine brain. These effects could result both in the inhibition of migraine chronification, but also in the diminishing of the magnitude of migraine-associated symptoms, mostly in responders and in partial non-responders.

Multiple pathological mechanisms are involved in the development of chemotherapy-induced peripheral neurotoxicity (CIPN). Recent work has provided insights into the molecular mechanisms underlying chemotherapy-induced axonal degeneration. This review integrates evidence from preclinical and clinical work on the onset, progression and outcome of axonal degeneration in CIPN. We review likely triggers of axonal degeneration in CIPN and highlight evidence of molecular pathways involved in axonal degeneration and their relevance to CIPN, including SARM1-mediated axon degeneration pathway. We identify potential clinical markers of axonal dysfunction to provide early identification of toxicity as well as present potential treatment strategies to intervene in axonal degeneration pathways. A greater understanding of axonal degeneration processes in CIPN will provide important information regarding the development and progression of axonal dysfunction more broadly and will hopefully assist in the development of successful interventions for CIPN and other neurodegenerative disorders., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We sought to assess the efficacy of combining onabotulinumtoxinA (BoNTA) as add-on therapy to carbamazepine or oxcarbazepine in treatment-refractory patients with trigeminal neuralgia (TGN) who failed to respond (less than 30% response rate) to adequate monotherapy. We conducted a retrospective study on 15 patients with a definite diagnosis of TGN, according to the established criteria, and underwent BoNTA as part of their treatment plan. A single BoNTA session was administered subcutaneously, according to patients' perceived zone of pain, at different dosages ranging from 30 to 200 units (mean ± standard deviation: 87.3 ± 39.2). All patients (15/15; 100%) reported large reductions in the severity of their TGN-related neuropathic pain. The mean pain score on the VAS scale significantly decreased from 9.3 ± 1.1 to 3.7 ± 1.2 at 2 weeks after injecting BoNTA ( p < 0.001) and remained stable at 4 and 24 weeks post-injection. Regarding the impact of BoNTA on patients' health-related quality of life, there were significant improvements in both the physical and mental health domains ( p < 0.05) of SF-36 tool. BoNTA may be a safe and effective treatment option for patients with refractory TGN when added on to carbamazepine or oxcarbazepine. The use of a single BoNTA session for TGN treatment may be an alternative to surgical interventions and as add-on treatment to oral medications, providing patients with a minimally invasive, effective, safe and well-tolerated option.

Objective: this post hoc analysis aimed to evaluate the efficacy of fremanezumab in difficult-to-treat chronic migraine (CM) patients with and without psychiatric comorbidities (PCs), mainly anxiety and/or depression., Methods: We assessed data from CM patients with and without PCs who failed at least 3 preventives and eventually received at least 3 consecutive monthly doses of fremanezumab 225 mg. Outcomes included the crude response (≥50% reduction in monthly headache days (MHDs)) rates to fremanezumab from the baseline to the last clinical follow-up. The changes in MHDs; MHDs of moderate/greater severity; monthly days with intake of abortive medication; and the proportion of patients' changing status from with PCs to decreased/without PCs were also compared. Disability and quality of life (QOL) outcomes were also assessed., Results: Of 107 patients enrolled, 65 (60.7%) had baseline PCs. The percentage of patients with ( n = 38/65; 58.5%) and without ( n = 28/42; 66.6%) PCs that achieved a ≥50% reduction in MHDs with fremanezumab was comparable ( p = 0.41), whereas MHDs were significantly reduced (difference vs. baseline) in both patients with PCs (mean -8.9 (standard error: 6.8); p < 0.001) and without PCs (-9.8 (7.5); p < 0.001). Both groups experienced significant improvements in all other efficacy, disability, and QOL outcomes at comparable rates, including in MHD reduction. A significant proportion of fremanezumab-treated patients with baseline PCs de-escalated in corresponding severities or even reverted to no PCs (28/65; 43.1%) post-fremanezumab., Conclusions: fremanezumab appears to be effective as a preventive treatment in difficult-to-treat CM patients with and without PCs while also being beneficial in reducing the severity of comorbid anxiety and/or depression.

Objective: To prospectively assess the efficacy and safety of fremanezumab for migraine prophylaxis in patients with failure of at least three previous preventive treatments. Changes in disability as quality-of-life outcomes after fremanezumab treatment were also examined., Methods: Two hundred and four patients with either high-frequency EM (HFEM) or chronic migraine (CM), who attained at least three consecutive monthly sessions with fremanezumab 225 mg and otherwise met the inclusion criteria, were included in the study. The crude response (at least 50% reduction in monthly headache days [MHD]) rates to fremanezumab were assessed. Scores in the following efficacy outcomes were then compared from baseline to the last efficacy evaluation follow-up: (i) MHD, (ii) monthly days with moderate/severe peak headache intensity, and (iii) monthly days with intake of abortive medication. The disability was evaluated with the Migraine Disability Assessment; the quality of life (QOL) status was assessed with the Headache Impact-6 Test, and the EQ-5D questionnaire., Results: In the majority of HFEM cases (n = 81/97; 83.5%) and CM patients (n = 67/107; 62.6%), fremanezumab proved effective in reducing the MHDs by at least 50% and was associated with clinically meaningful improvement in all other efficacy variables. The migraine-related disability experienced by our patients decreased and their QOL increased. We recorded just 36 cases reporting mild adverse events, including pain, rash or pruritus (n = 26), flu-like symptoms (n = 8), and hair loss (n = 2)., Conclusion: With our prospective results, we provide further real-world data to support the favorable benefit/risk profile of fremanezumab in the prophylaxis of both HFEM and CM., (© 2023 European Academy of Neurology.)

Objective: To define, in a real-world population of patients with high-frequency episodic (HFEM) or chronic migraine (CM), the predictive role of socio-demographic or phenotypic profiling of responders to fremanezumab., Patients and Methods: Two-hundred and four adult fremanezumab-treated patients with either HFEM or CM, who failed to at least three preventive treatments, provided data at baseline on several individual socio-demographic and phenotypic variables. These variables were analyzed for their ability to independently predict the response (50-74% response rates) or super-response (≥ 75% response rates) to fremanezumab. Patients were followed from 3-18 months of fremanezumab exposure., Results: The main finding to emerge from univariate analyses was that three baseline socio-demographic/clinical variables, i.e., age group 41-70 years ( p = 0.02); female gender ( p = 0.03); patients with HFEM ( p = 0.001), and three clinical phenotypic variables, i.e., strict unilateral pain ( p = 0.05); pain in the ophthalmic trigeminal branch ( p = 0.04); and the "imploding" quality of pain ( p = 0.05), were significantly related to fremanezumab response. However, in multivariate analysis, only HFEM ( p = 0.02), the presence of strict unilateral ( p = 0.03), and pain location in the ophthalmic trigeminal branch ( p = 0.036) were independently associated with good fremanezumab response. Allodynia ( p = 0.04) was the only clinical predictive variable of super-responsiveness to fremanezumab., Conclusions: A precise phenotypic profiling with identification of pain characteristics consistent with peripheral and/or central sensitization might reliably predict the responsiveness to fremanezumab in migraine prophylaxis.