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Background: Idiopathic intracranial hypertension (IIH) is increasingly prevalent, yet longitudinal outcome data are scarce. This study aimed to characterise demographic and longitudinal clinical changes in a cohort of patients with IIH., Methods: Retrospective cohort analysis on adult patients diagnosed with IIH (Friedman criteria) enrolled in the neuro-ophthalmology database (NODE) across two tertiary centres. Baseline demographic data was obtained at first assessment, with clinical and paraclinical outcomes collected longitudinally. Multivariable statistical analysis identified factors associated with poorer visual outcomes., Results: A total of 221 patients were included. 91.8% were female (ratio 11:1). Mean age at presentation was 29.2 ± 8.1 years with mean body mass index (kg/m 2 ) at diagnosis of 38.7 ± 9.4. Headache was the most common symptom. Papilloedema was found in 95.5% of patients at baseline. Mean CSF opening pressure was 32.67 ± 6.85cmCSF (range 25-76). Visual outcomes remained stable over time. Trajectory plots showed no deviations in visual acuity, while regression models found no associations with sex, site or age. A higher retinal nerve fibre layer thickness and greater baseline Frisen grade were associated with worse outcomes. Baseline papilloedema grade and CSF opening pressure emerged as early prognostic indicators, aiding risk stratification for those with a greater probability of persistent optic nerve abnormalities including higher retinal nerve fibre layer elevation and sustained atrophic changes over time., Conclusions: This study offers insights into visual outcomes in IIH, emphasising the importance of early recognition, risk stratification, and intervention in those with a more severe clinical phenotype at presentation., Competing Interests: Declarations. Conflicts of interest: BDC, PGS, AF, MNLN, RK, RC, SS, SR, NS, EH, and CLF report no conflicts. JF receives funding from Genzyme and Biogen and has received honorarium from Novartis. OW has received honoraria from Novartis, Merck, and Genzyme, and has served on Advisory Boards for Merck, Novartis, Roche, and Biogen. He is Chief Medical Officer for Braineye P/L. LDP has received research funding from Alcon laboratories. AVDW has served on advisory boards for Novartis, Biogen, Merck and Roche and NervGen. She received unrestricted research grants from Novartis, Biogen, Merck, and Roche. She is currently a co-Principal investigator on a co-sponsored observational study with Roche, evaluating a Roche-developed smartphone app, Floodlight-MS. She has received speaker’s honoraria and travel support from Novartis, Roche, Biogen, and Merck. She serves as the Chief operating Officer of the MSBase Foundation (not for profit). Her primary research support is from the National Health and Medical Research Council of Australia and MS Research Australia. Ethical approval: This study has been approved by the Human Research Ethics Committee of Alfred Health (Project No. 53125, local reference number 312/19)., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Cognitive symptoms are reported commonly throughout all phases of a migraine; however, there is a paucity of objective cognitive profiling. Previous studies have been limited by practice effect, and variable populations., Methods: Participants completed 1 month of daily testing with a computerised cognitive battery involving a simple reaction (SRT), choice reaction (CRT) and a working memory test (WM). Results were correlated with their diary to identify interictal scores, and scores during each phase of a migraine, and non-migraine headache days., Results: A total of 16 patients with episodic migraine participated. During the headache phase of a migraine, responses to SRT, CRT and WM tasks were significantly slower and less accurate than interictally. During the postdrome, WM task performance was slower and less accurate. Non-migraine headache days were not associated with significant change., Conclusion: The headache and postdromal phase of a migraine day was associated with objective evidence of cognitive dysfunction in patients with episodic migraine., (© 2024. The Author(s).)

Idiopathic intracranial hypertension (IIH) is a condition of significant morbidity and rising prevalence. It typically affects young people living with obesity, mostly women of reproductive age, and can present with headaches, visual abnormalities, tinnitus and cognitive dysfunction. Raised intracranial pressure without a secondary identified cause remains a key diagnostic feature of this condition, however, the underlying pathophysiological mechanisms that drive this increase are poorly understood. Previous theories have focused on cerebrospinal fluid (CSF) hypersecretion or impaired reabsorption, however, the recent characterisation of the glymphatic system in many other neurological conditions necessitates a re-evaluation of these hypotheses. Further, the impact of metabolic dysfunction and hormonal dysregulation in this population group must also be considered. Given the emerging evidence, it is likely that IIH is triggered by the interaction of multiple aetiological factors that ultimately results in the disruption of CSF dynamics. This review aims to provide a comprehensive update on the current theories regarding the pathogenesis of IIH., Competing Interests: Competing interests: PS has co-authored manuscripts with medical writing provided by Novo Nordisk and Eli Lilly. She is supported by an Investigator Grant from the National Health and Medical Research Council (1178482). JF receives funding from Genzyme and Biogen and has received honorarium from Novartis. AvdW has received travel support and served on advisory boards for Novartis, Biogen, Merck Serono, Roche and Teva. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Clinical trials show that calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are effective preventative treatments for chronic migraine. Their efficacy over longer time periods and in cohorts originally excluded from trials remains uncertain. This study aims to explore the impact of CGRP mAbs in an Australian real-life setting., Methods: A multicentre cohort study was performed in the tertiary headache clinics of the Alfred and Austin Hospitals, Melbourne, Australia. Patients were commenced on a CGRP mAb for chronic migraine and asked to keep a headache diary, recorded at 3 monthly appointments for 12 months. Primary outcome was a ≥50% reduction in monthly headache days (MHD)., Results: From a population of 105 patients, 90 patients commenced galcanezumab and 15 commenced fremanezumab. The ≥50% responder rate of the cohort was 52.4% after 3 months. Over 12 months follow-up, 25.7% of the cohort ceased due to a lack of efficacy and 16.2% ceased due to an adverse event. There was no difference in response or cessation between medications. There was poor agreement in 3-month and 12-month response rates (Cohen's κ=0.130; p=0.171). On subgroup analysis, continuous headache at baseline and number of trialled preventative treatments were the only factors associated with efficacy., Conclusion: CGRP mAbs were associated with sustained reductions in MHD over 12-month follow-up in patients with resistant migraine in Australia. Further studies are required to determine treatment options for patients with continuous headache. Poor agreement between outcomes at 3 and 12 months highlights the need to assess some patients at later timepoints., Competing Interests: Competing interests: JCR has received funding for educational presentations from Allergan, Novartis and has served on medical advisory boards for Pfizer, Viatris and Lilly. SC and LD report no potential conflict of interest. MM serves on the advisory board for Allergan, Novartis, Eli Lilly, Autonomic Technologies and Teva and has received payment for the development of educational presentations from Allergan, electroCore, Eli Lilly, Novartis and Teva. EJH has served on advisory boards for Sanofi-Genzyme, Novartis, Teva, Eli Lilly, Allergan, Lundbeck, been involved in clinical trials sponsored by Novartis, Teva, Xalud, Cerecin and has received payment for educational presentations from Allergan, Teva, Eli Lilly and Novartis., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAb) are an effective treatment of migraine however may have possible off-target effects. Pre-clinical studies implicate CGRP in several aspects of bone turnover and homeostasis. The clinical effect of CGRP mAb on bone turnover is not known, however., Methods: Between June 2021 and July 2022, a multi-centre prospective cohort study was undertaken with eligible patients undergoing paired testing of the validated bone turnover markers procollagen type I N-terminal propeptide (P1NP) and serum C-terminal telopeptide of type I collagen (CTX) prior to and at least three months following administration of a CGRP mAb., Results: A total of 45 patients with a mean age of 41.8 (SD 11.9) were included in the final analysis, all of whom received a ligand-targeting CGRP mAb. Administration of a CGRP mAb was associated with a statistically significant increase in P1NP from 44.5 microg/L to 51.5 microg/L (p = 0.004), but no significant change in CTX., Conclusion: In otherwise homeostatic conditions, short-term administration of a CGRP mAb is associated with increased P1NP, a bone formation marker but not with increased CTX, a bone resorption marker. Further study is required to validate these findings over longer time periods, in a larger cohort, and in pre-existing states of increased calcium stress and bone-turnover.

Objective: To perform a systematic review and meta-analysis of the epidemiology, precipitants, phenotype, comorbidities, pathophysiology, treatment, and prognosis of primary new daily persistent headache., Methods: We searched PubMed/Medline, EMBASE, Cochrane, and clinicaltrials.gov until 31 December 2022. We included original research studies with any design with at least five participants with new daily persistent headache. We assessed risk of bias using National Institutes of Health Quality Assessment Tools. We used random-effects meta-analysis where suitable to calculate pooled estimates of proportions. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis compliant study is registered with PROSPERO (registration number CRD42022383561)., Results: Forty-six studies met inclusion criteria, predominantly case series, including 2155 patients. In 67% (95% CI 57-77) of cases new daily persistent headache has a chronic migraine phenotype, however new daily persistent headache has been found to be less likely than chronic migraine to be associated with a family history of headache, have fewer associated migrainous symptoms, be less vulnerable to medication overuse, and respond less well to injectable and neuromodulatory treatments., Conclusions: New daily persistent headache is a well described, recognisable disorder, which requires further research into its pathophysiology and treatment. There is a lack of high-quality evidence and, until this exists, we recommend continuing to consider new daily persistent headache a distinct disorder.

Background: The role of inflammation and cytokines in the pathophysiology of primary headache disorders is uncertain. We performed a systematic review and meta-analysis to synthesise the results of studies comparing peripheral blood cytokine levels between patients with migraine, tension-type headache, cluster headache, or new daily persistent headache (NDPH), and healthy controls; and in migraine between the ictal and interictal stages., Methods: We searched PubMed/Medline and Embase from inception until July 2022. We included original research studies which measured unstimulated levels of any cytokines in peripheral blood using enzyme-linked immunosorbent assay or similar assay. We assessed risk of bias using the Newcastle-Ottawa Quality Assessment Scale. We used random effects meta-analysis with inverse variance weighted average to calculate standardised mean difference (SMD), 95% confidence intervals, and heterogeneity for each comparison. This study is registered with PROSPERO (registration number CRD42023393363). No funding was received for this study., Results: Thirty-eight studies, including 1335 patients with migraine (32 studies), 302 with tension-type headache (nine studies), 42 with cluster headache (two studies), and 1225 healthy controls met inclusion criteria. Meta-analysis showed significantly higher interleukin (IL)-6 (SMD 1.07, 95% CI 0.40-1.73, p = 0.002), tumour necrosis factor (TNF)-α (SMD 0.61, 95% CI 0.14-1.09, p = 0.01), and IL-8 (SMD 1.56, 95% CI 0.03-3.09, p = 0.04), in patients with migraine compared to healthy controls, and significantly higher interleukin-1β (IL-1β) (SMD 0.34, 95% CI 0.06-0.62, p = 0.02) during the ictal phase of migraine compared to the interictal phase. Transforming growth factor (TGF)-β (SMD 0.52, 95% CI 0.18-0.86, p = 0.003) and TNF-α (SMD 0.64, 95% CI 0.33-0.96, p = 0.0001) were both higher in patients with tension-type headache than controls., Conclusions: The higher levels of the proinflammatory cytokines IL-6, IL-8 and TNF-α in migraine compared to controls, and IL-1β during the ictal stage, suggest a role for inflammation in the pathophysiology of migraine, however prospective studies are required to confirm causality and investigate the mechanisms for the increase in cytokine levels identified. Cytokines may also have a role in tension-type headache. Due a lack of data, no conclusions can be made regarding cluster headache or NDPH., (© 2023. The Author(s).)

Objective: To assess the prevalence and burden of autonomic symptoms in migraine, and determine the relationship with migraine frequency., Background: Autonomic symptoms in migraine have been theorized to occur in the setting of inter-ictal sympathetic hypoactivity and hyper-sensitivity. There is limited data prospectively assessing cranial and extra-cranial autonomic symptoms with a validated instrument, or longitudinal data on the relationship between migraine disease activity and autonomic symptoms., Methods: Patients attending a single tertiary academic center were recruited into a prospective cohort study between September 2020 and June 2022. In addition to standard clinical care, they completed several surveys including the Composite Autonomic Symptom Scale (COMPASS-31) questionnaire, a validated survey of autonomic symptoms., Results: A total of 43 patients (66.7% female, median age 42, IQR 17) were included in the final analysis. There was a baseline 20 monthly headache days (MHD) (IQR 21.7), and 65.1% of the population had chronic migraine by ICHD-3 criteria. A significantly elevated weighted COMPASS-31 score was reported in 60.5% of respondents (mean 30.3, SD 13.3) at baseline. After 12 months treatment, significant improvements were reported in migraine frequency (median MHD 20-8.7) and disability (median Migraine Disability Assessment Score 67-48), but not in autonomic symptoms (mean score 30.3, SD 11.2)., Conclusion: Autonomic symptoms were frequently reported in patients with migraine. However, they did not correlate with headache frequency or reversion to episodic frequency. Further study is required to elucidate specific approaches and treatments for autonomic symptoms, and further evaluate the underlying pathophysiological mechanisms., Competing Interests: Author JR has received funding from the Pharmaceutical Society of Australia and the Limbic supported by unrestricted educational grants from Viatris and Novartis respectively. Author EF has been supported by grants from the NHMRC Medical Postgraduate Research Scholarship APP1150482, The Royal Australasian College of Physicians Research Entry Scholarship, AVANT Doctors In Training Scholarship, and Monash University Bridging Postdoctoral Fellowship, and her institution has also received research grants from Brain Foundation, the Australian Epilepsy Research Fund, the Viertel Foundation, and Lundbeck, outside the submitted work. Author MM serves on the advisory board for Allergan, Novartis, Eli Lilly, Autonomic Technologies Inc., and TEVA and has received payment for the development of educational presentations from Allergan, electroCore, Eli Lilly, Novartis and TEVA. Author EH has served on advisory boards for SanofiGenzyme, Novartis, Teva, Eli Lilly, Allergan, Lundbeck, been involved in clinical trials sponsored by Novartis, Teva, Xalud, Cerecin, and has received payment for educational presentations from Allergan, Teva, Eli Lilly and Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ray, Cheema, Foster, Gunasekera, Mehta, Corcoran, Matharu and Hutton.)

Background: Headache is a common presentation of postural tachycardia syndrome, yet robust prevalence data is lacking., Objectives: To undertake a systematic review and meta-analysis to estimate the prevalence of headache disorders in postural tachycardia syndrome, and to explore the potential shared pathophysiological mechanisms that underpin these conditions as well as treatment options., Methods: Three databases were searched for publications evaluating prevalence of migraine (primary outcome) and general and orthostatic headache (secondary outcomes) in patients with postural tachycardia syndrome. Two independent reviewers selected studies and extracted data. A random-effects meta-analysis calculated the pooled prevalence of migraine in postural tachycardia syndrome. A narrative literature review explored the pathophysiology and treatment options for concurrent headache disorders and postural tachycardia syndrome., Results: Twenty-three articles met inclusion criteria. Estimated pooled prevalence of migraine in postural tachycardia syndrome was 36.8% (95% CI 2.9-70.7%). Various shared pathophysiological pathways for these conditions, as well as proposed treatment strategies, were identified. Limitations : Heterogeneity of study design, populations, and methodology for identifying headache disorders and postural tachycardia syndrome limited the generalisability of results., Conclusions: Migraine is a commonly reported comorbidity in POTS, however the true prevalence cannot be determined from the current literature. Further studies are required to assess this comorbidity and investigate the underlying mechanisms, as well as identify effective treatment strategies.

Background: Arterial and venous thromboembolic events (TEEs) have been associated with intravenous Ig use, but the risk has been poorly quantified. We aimed to calculate the risk of TEEs associated with exposure to intravenous Ig., Methods: We included participants from UK Biobank recruited over 3 years, data extracted September 2020.The study endpoints were incidence of myocardial infarction, other acute ischaemic heart disease, stroke, pulmonary embolism and other venous embolism and thrombosis.Predictors included known TEE risk factors: age, sex, hypertension, smoking status, type 2 diabetes mellitus, hypercholesterolaemia, cancer and past history of TEE. Intravenous Ig and six other predictors were added in the sensitivity analysis.Information from participants was collected prospectively, while data from linked resources, including death, cancer, hospital admissions and primary care records were collected retrospectively and prospectively.  FINDINGS: 14 794 of 502 492 individuals had an incident TEE during the study period. The rate of incident events was threefold higher in those with prior history of TEE (8 .7%) than those without previous history of TEE (3.0%).In the prior TEE category, intravenous Ig exposure was independently associated with increased risk of incident TEE (OR=3.69 (95% CI 1.15 to 11.92), p=0.03) on multivariate analysis. The number needed to harm by exposure to intravenous Ig in those with a history of TEE was 5.8 (95% CI 2.3 to 88.3).Intravenous Ig exposure did not increase risk of TEE in those with no previous history of TEE., Interpretation: Intravenous Ig is associated with increased risk of further TEE in individuals with prior history of an event with one further TEE for every six people exposed. In practice, this will influence how clinicians consent for and manage overall TEE risk on intravenous Ig exposure., Competing Interests: Competing interests: MK reports Grifols sponsorship for attendance at meeting. ASC reports Grifols sponsorship for attendance at meeting and honorarium from CSL and Lupin for an advisory role. MPL was a Primary Investigator in studies for CSL Behring, UCB Pharma, Novartis, Octapharma. He has also received ad hoc consulting fees from CSL Behring, UCB and an honorarium from Terumo BCT. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with a suspected change in intracranial pressure or a trigeminal autonomic cephalgia require MRI. The need for investigation for other headache disorders is guided by the clinical evaluation of the patient. Particular care should be taken to identify any 'red flags'. Incidental findings on MRI occur in approximately 2% of patients. Patients with migraine have an increased rate of white matter lesions, but these are of uncertain clinical significance., Competing Interests: Conflicts of interest: Jason Ray has received compensation from the Pharmaceutical Society of Australia, sponsored by Viatris for educational material. Elspeth Hutton has served on advisory boards for Sanofi-Genzyme, Novartis, Teva, Eli Lilly, Allergan, Lundbeck, been involved in clinical trials sponsored by Novartis, Teva, Xalud, Daewong and Novotech, and received payment for educational presentations from Allergan, Teva, Eli Lilly and Novartis., ((c) NPS MedicineWise.)

Introduction: Status migrainosus is a disabling complication of migraine, which frequently results in hospitalisation. For patients who fail to respond to simple analgesia, triptans and intravenous prochlorperazine or chlorpromazine, there are limited treatment options, and a paucity of high-quality evidence to guide clinical practice. Eptinezumab, an intravenous monoclonal antibody specific for the calcitonin gene-related peptide ligand which achieves maximal plasma concentration immediately following administration and may improve migraines from day one. Intravenous lignocaine is an anaesthetic medication used in treatment of status migrainosus, often requiring prolonged admissions and with potential cardiac adverse events. The aim of this study is to assess the efficacy and safety of eptinezumab in the treatment of status migrainosus in comparison to intravenous lidocaine., Methods and Analysis: Status migrainosus inpatient treatment with eptinezumab is a randomised, controlled, single-centre clinical trial conducted in a parallel design with an active comparator conducted in Melbourne, Australia. This study randomises forty patients (1:1) to receive either eptinezumab or an infusion of intravenous lignocaine for up to 5 days. It will assess the effect of eptinezumab compared with intravenous lignocaine in aborting status migrainosus, with the primary outcome of time from infusion until resolution of pain. It will explore several secondary measures including change in health resource utilisation, effect on patient reported outcomes of migraine disability and the safety and tolerability of each medication., Ethics and Dissemination: This study has been reviewed and approved by the Human Research Ethics Committee of Alfred Health, local reference number 443/21, and all participants will provide informed consent for participation in the trial and dissemination of results., Trial Registration Number: The trial registration number is ACTRN12621001616864. The results of this study will be disseminated through peer-reviewed journals, conference presentations and social media., Competing Interests: Competing interests: JCR has received compensation from the Pharmaceutical Society of Australia, sponsored by Viatris for educational material. ZC is supported by an Early Career Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (GNT1156444). He/his institution has received consultancy fees and/or research grants from Arvelle Therapeutics and UCB Pharma for works outside the submitted work. EJH has served on advisory boards for Sanofi-Genzyme, Novartis, Teva, Eli Lilly, Allergan, Lundbeck, been involved in clinical trials sponsored by Novartis, Teva, Xalud, Daewong and Novotech, and has received payment for educational presentations from Allergan, Teva, Eli Lilly and Novartis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cluster headache is characterised by attacks of very severe, unilateral headache lasting 15-180 minutes, up to eight times per day. The attacks are associated with cranial autonomic symptoms on the same side and a sense of agitation or restlessness First-line acute abortive treatments include intranasal or subcutaneous sumatriptan or high-flow oxygen. Neuromodulation may benefit some patients First-line preventive therapy is high-dose verapamil. Close monitoring is required for the adverse effect of arrhythmia There are several emerging therapies that have either proven efficacy, or possible benefit for cluster headache. They include drugs aimed at the calcitonin gene-related peptide., Competing Interests: Conflicts of interest: Jason Ray has received compensation from the Pharmaceutical Society of Australia, sponsored by Viatris for educational material. Richard Stark has served on advisory boards for Novartis, Teva, Eli Lilly, Allergan, Lundbeck and has received payment for educational presentations from Allergan, Teva, Eli Lilly and Novartis. Elspeth Hutton has served on advisory boards for Sanofi-Genzyme, Novartis, Teva, Eli Lilly, Allergan, Lundbeck, been involved in clinical trials sponsored by Novartis, Teva, Xalud, Daewong and Novotech, and has received payment for educational presentations from Allergan, Teva, Eli Lilly and Novarti, ((c) NPS MedicineWise.)

Migraine is the second largest cause of years lost to disability globally among all diseases, with a worldwide prevalence over 1 billion. Despite the global burden of migraine, few classes of therapeutics have been specifically developed to combat migraine. After 30 years of translational research, calcitonin gene-related peptide (CGRP) inhibitors have emerged as a promising new tool in the prevention of migraine. Like all new therapeutics; however, we have limited real-world experience and CGRP has several known systemic actions that warrant consideration. This article provides a narrative review of the evidence for CGRP antagonists and summarises the known and potential side effects that should be considered., Competing Interests: Competing interests: MM serves on the advisory board for Allergan, Novartis, Eli Lilly, Autonomic Technologies and TEVA and has received payment for the development of educational presentations from Allergan, electroCore, Eli Lilly, Novartis and TEVA. RJS has been a member of Advisory Boards for Allergan, Novartis, Teva and Eli Lilly and has received Lecture Fees from Allergan, Novartis, Teva and Eli Lilly and Biogen. EJH has served on advisory boards for Sanofi-Genzyme, Novartis, Teva, Eli Lilly, Allergan, been involved in clinical trials sponsored by Novartis and Teva, and has received payment for educational presentations from Allergan, Teva, Eli Lilly and Novartis. S-JW has served on the advisory boards of Eli Lilly, Daiichi-Sankyo and Taiwan Norvatis. He has received honoraria as a moderator from Allergan, Pfizer, Eli Lilly, Bayer, and Eisai. He has received research grants from the Taiwan Minister of Technology and Science, Brain Research Center, National Yang-Ming University from The Featured Areas Research Center Programme within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan, Taipei Veterans General Hospital, and Taiwan Headache Society. LB serves on the advisory board for Allergan, Novartis, Eli Lilly and Teva, has been involved in clinical trials sponsored by Novartis and has received payment for educational presentations from Allergan, Teva and Novartis. JR and MK report no potential conflict of interest. Figure created with biorender.com., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Migraine is a common neurological disorder, affecting one in seven people, and is the second leading cause of disability worldwide., Objective: The aim of this article is to summarise the diagnosis, pathophysiology and treatment of migraine., Discussion: Key to limiting the disability of migraine and progression to chronic migraine is addressing modifiable risk factors, including implementing effective preventive treatment and avoiding overuse of acute treatment. In this article, the authors review strategies for effective acute and preventive treatment of migraine and introduce the new treatments of migraine targeting calcitonin gene-related peptide signalling.

The diagnosis of fat embolism syndrome typically involves neurological, respiratory and dermatological manifestations of microvascular occlusion 24-72 h after a precipitating event. However, fat embolism causing cerebral large vessel occlusion strokes and their sequelae have rarely been reported in the literature. This case series reports three patients with fat emboli post operatively causing cerebral large vessel occlusions, as well as a review of the literature to identify differences in clinical presentations and outcomes in stroke secondary to fat emboli causing large vessel occlusions compared to those with fat embolism syndrome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ooi, Raviskanthan, Campbell, Hutton, Mitchell and Cloud.)

Background: Calcitonin gene-related peptide (CGRP) is expressed throughout the body and is a known mediator of migraine, exerting this biological effect through activation of trigeminovascular, meningeal and associated neuronal pathways located in close proximity to the central nervous system. Monoclonal antibodies (mAb) targeting the CGRP pathway are an effective new preventive treatment for migraine, with a generally favourable adverse event profile. Pre-clinical evidence supports an anti-inflammatory/immunoregulatory role for CGRP in other organ systems, and therefore inhibition of the normal action of this peptide may promote a pro-inflammatory response., Cases: We present a case series of eight patients with new or significantly worsened inflammatory pathology in close temporal association with the commencement of CGRP mAb therapy., Conclusion: This case series provides novel insights on the potential molecular mechanisms and side-effects of CGRP antagonism in migraine and supports clinical vigilance in patient care going forward., (© 2021. The Author(s).)

The efficacy of onabotulinumtoxinA (OnaB-A) as a preventative treatment for chronic migraine, emerging fortuitously from clinical observation is now supported by class one evidence and over two decades of real-world clinical data. There is still limited ability to predict a clinically meaningful response to OnaB-A for individual patients, however. This review summarises briefly the proposed mechanism of OnaB-A in chronic migraine, the literature of predictors of clinical response, and recent developments in the field.

Aims: Patients with Fabry disease (FD) characteristically develop peripheral neuropathy at an early age, with pain being a crucial symptom of underlying pathology. However, the diagnosis of pain is challenging due to the heterogeneous and nonspecific symptoms. Practical guidance on the diagnosis and management of pain in FD is needed., Methods: In 2014, experts met to discuss recent advances on this topic and update clinical guidance., Results: Emerging disease-specific tools, including FabryScan, Fabry-specific Pediatric Health and Pain Questionnaire, and Würzburg Fabry Pain Questionnaire, and more general tools like the Total Symptom Score can aid diagnosis, characterization, and monitoring of pain in patients with FD. These tools can be complemented by more objective and quantifiable sensory testing. In male and female patients of any age, pain related to FD can be an early indication to start disease-specific enzyme replacement therapy before potentially irreversible organ damage to the kidneys, heart, or brain occurs., Conclusion: To improve treatment outcomes, pain should be diagnosed early in unrecognized or newly identified FD patients. Treatment should include: (a) enzyme replacement therapy controlling the progression of underlying pathology; (b) adjunctive, symptomatic pain management with analgesics for chronic neuropathic and acute nociceptive, and inflammatory or mixed pain; and (c) lifestyle modifications., (© 2016 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: Charcot-Marie-Tooth (CMT) disease type 1A is the most common form of CMT. The main clinical features are distal weakness, sensory loss, and skeletal deformities. Although pain is a frequent complaint, small fiber involvement in CMT1A has not been studied extensively., Methods: We assessed pain and small fiber involvement in 49 CMT1A patients using a variety of pain scales, pain questionnaires, and thermal thresholds., Results: Forty-three of 49 patients (88%) complained of pain. The pain was localized to the feet in 61% of patients. Only 18% of patients had neuropathic pain. Cold and warm detection thresholds were elevated in 53% and 12% of patients, respectively., Conclusions: Our findings confirm that CMT1A patients have significant pain, which is more likely to be multifactorial in origin and suggests that a proportion of patients have small fiber dysfunction affecting mainly thinly myelinated Aδ fibers., (Copyright © 2014 Wiley Periodicals, Inc.)

Schwann cell dedifferentiation following nerve injury is important to permit neural survival and axonal regrowth. Animal studies have shown that the transcription factor c-Jun is upregulated in Schwann cells of injured and pathological nerves where it acts as an important regulator of Schwann cell plasticity, promoting dedifferentiation and demyelination. This pilot immunohistochemical study investigates whether c-Jun is also upregulated in human neuropathies. We examined c-Jun expression in normal and diseased human nerves, as well as in dermal myelinated nerve fibres. Our findings show that although as predicted c-Jun is rarely expressed in normal nerves, it is expressed in Schwann cell nuclei of pathological nerves as predicted by animal studies. Pathological dermal myelinated nerve fibres also show clear nuclear c-Jun expression. Further studies of c-Jun expression will help clarify its role in human neuropathies., (© 2011 Peripheral Nerve Society.)

This review focuses on recent developments in the treatment of inflammatory neuropathies arising from immune dysregulation, rather than from infectious causes. The dysimmune inflammatory neuropathies are diseases of the peripheral nerves that have varying etiologies and may respond to immunomodulatory therapies. They are characterized by inflammatory changes in the nerve with associated destruction of myelin and axons. The underlying immune mechanisms are better understood in some of these conditions than others. Correct diagnosis and treatment is important to prevent clinical progression. Randomized controlled trials of some treatments in the more common inflammatory neuropathies have clarified their effectiveness; however, there are still groups of patients who are resistant to currently available treatments and for whom little effective treatment is available. Newer, targeted biologics and larger controlled trials of existing and novel therapies in these conditions offer promise of improved morbidity and mortality in this group of diseases.

The development of the primary sensory innervation of the superficial dorsal horn (SDH) was studied in postnatal opossums Monodelphis domestica by using DiI labelling of primary afferents and with GSA-IB(4) lectin binding and calcitonin gene-related peptide (CGRP) immunoreactivity to label primary afferent subpopulations. We also compared the timing of SDH innervation in the cervical and lumbar regions of the spinal cord. The first primary afferent projections to SDH emerge from the most lateral part of the dorsal root entry zone at postnatal day 5 and project around the lateral edge of the SDH toward lamina V. Innervation of the SDH occurs slowly over the second and third postnatal weeks, with the most dorsal aspect becoming populated by mediolaterally oriented varicose fibers before the rest of the dorsoventral thickness of the SDH becomes innervated by fine branching varicose fibers. Labelling with GSA-IB(4) lectin also labelled fibers at the lateral edge of the dorsal horn and SDH at P5, indicating that the GSA-IB(4) is expressed on SDH/lamina V primary afferents at the time when they are making their projections into the spinal cord. In contrast, CGRP-immunoreactive afferents were not evident until postnatal day 7, when a few short projections into the lateral dorsal horn were observed. These afferents then followed a pattern similar to the development of GSA-IB(4) projects but with a latency of several days. The adult pattern of labelling by GSA-IB(4) is achieved by about postnatal day 20, whereas the adult pattern of CGRP labelling was not seen until postnatal day 30. Electron microscopy revealed a few immature synapses in the region of the developing SDH at postnatal day 10, and processes considered to be precursors of glomerular synapses (and thus of primary afferent origin) were first seen at postnatal day 16 and adopted their definitive appearance between postnatal days 28 and 55. Although structural and functional development of forelimbs of neonatal Monodelphis is more advanced than the hindlimbs, we found little evidence of a significant delay in the invasion of the spinal cord by primary afferents in cervical and lumbar regions. These observations, together with the broadly similar maturational appearance of histological sections of rostral and caudal spinal cord, suggest that, unlike the limbs they innervate, the spinal regions do not exhibit a large rostrocaudal gradient in their maturation., (J. Comp. Neurol. 495:37-52, 2006. (c) 2006 Wiley-Liss, Inc.)

Although long known to be a liver-derived fetal plasma glycoprotein, fetuin has more recently been shown to be present in sub-populations of neurons in the developing nervous system of a number of mammalian species. We have extended these observations to examine the fetuin immunoreactivity (IR) in developing rat retina and cerebellum. Fetuin-IR was first seen in the retina on embryonic day (E)19 in a sub-population of cells in the retinal ganglion cell layer and a small proportion of cells in the neuroblastic layer. The proportion of cells in the ganglion layer exhibiting fetuin-IR increased until postnatal day (P)10 when all cells in this layer were strongly immunoreactive. From P14 onwards fetuin-IR was absent or very weak and restricted to a small proportion of ganglion cells. In the developing cerebellum, the outer and inner granule cell layers, the deep nuclei and cells in the sub-cortical white matter exhibited fetuin-IR from E19 to P10. There was little fetuin-IR in the cerebellum at ages P14 and older, and Purkinje cells did not exhibit fetuin-IR at any time. The results show that fetuin appears in many neurons in the retina and cerebellum that are differentiating during the period from E19 to P10. The concentration of fetuin in cerebrospinal fluid is at its highest in this same period which suggests that some sub-populations of neurons could obtain fetuin from extracellular fluid during this period; however, the lack of fetuin-IR in other neuronal populations suggests that fetuin uptake is not a general property of developing neurons.