Methodological considerations on real-world evidence studies of monoclonal antibodies against the CGRP-pathway for migraine: a systematic review.

BACKGROUND: Real-world data are accumulating on the effectiveness, tolerability and safety of anti-calcitonin gene-related peptide pathway monoclonal antibodies for the preventive treatment of migraine. We performed a systematic review of the methodology of prospective, observational, clinic-based real-world evidence studies with these drugs in both episodic and chronic migraine. METHODS: The objectives were to evaluate the definitions and reported outcomes used, and to perform a risk of bias assessment for each of the different studies. PubMed and EMBASE were systematically queried for relevant scientific articles. Study quality assessment of the included studies was conducted using the "National Heart, Lung and Blood Institute (NHLBI) Study Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group". RESULTS: Forty-six studies fitted the criteria for the systematic review and were included in the analysis. Ten studies (21.7%) defined a migraine day for the study, while only 5 studies defined a headache day for the study (10.9%). The most common primary endpoint/objective of the studies was change in monthly migraine days (n = 16, 34.8%), followed by responder rate (n = 15, 32.6%) and change in monthly headache days (n = 5, 10.9%). Eight studies (17.4%) did not define the primary endpoint/objective. Thirty-three studies were graded as "good" quality and 13 studies were graded as "fair". CONCLUSION: Our analysis shows rather significant heterogeneity and/or lack of predefined primary outcomes/objectives, definitions of outcomes measures and the use of longitudinal monitoring (e.g. headache diaries). Standardization of terminology, definitions and protocol procedures for real-world evidence studies of preventive treatments for migraine are recommended. TRIAL REGISTRATION: This study was registered with PROSPERO with ID CRD42022369366.

Ten open questions in migraine prophylaxis with monoclonal antibodies blocking the calcitonin-gene related peptide pathway: a narrative review.

The monoclonal antibodies (mAbs) blocking the calcitonin-gene related peptide (CGRP) pathway, collectively called here "anti-CGRP/rec mAbs", have dramatically improved preventive migraine treatment. Although their efficacy and tolerability were proven in a number of randomized controlled trials (RCTs) and, maybe even more convincingly, in real world settings, a number of open questions remain. In this narrative review, we will analyze published data allowing insight in some of the uncertainties related to the use of anti-CGRP/rec mAbs in clinical practice: their differential efficacy in migraine subtypes, outcome predictors, switching between molecules, use in children and adolescents, long-term treatment adherence and persistence, effect persistence after discontinuation, combined treatment with botulinum toxin or gepants, added-value and cost effectiveness, effectiveness in other headache types, and potential contraindications based on known physiological effects of CGRP. While recent studies have already provided hints for some of these questions, many of them will not find reliable and definitive answers before larger studies, registries or dedicated RCTs are available.

Genome-Wide Association Study Identifies Risk Loci for Cluster Headache.

OBJECTIVE: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. METHODS: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. RESULTS: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. INTERPRETATION: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.

mBrain: towards the continuous follow-up and headache classification of primary headache disorder patients.

BACKGROUND: The diagnosis of headache disorders relies on the correct classification of individual headache attacks. Currently, this is mainly done by clinicians in a clinical setting, which is dependent on subjective self-reported input from patients. Existing classification apps also rely on self-reported information and lack validation. Therefore, the exploratory mBrain study investigates moving to continuous, semi-autonomous and objective follow-up and classification based on both self-reported and objective physiological and contextual data. METHODS: The data collection set-up of the observational, longitudinal mBrain study involved physiological data from the Empatica E4 wearable, data-driven machine learning (ML) algorithms detecting activity, stress and sleep events from the wearables' data modalities, and a custom-made application to interact with these events and keep a diary of contextual and headache-specific data. A knowledge-based classification system for individual headache attacks was designed, focusing on migraine, cluster headache (CH) and tension-type headache (TTH) attacks, by using the classification criteria of ICHD-3. To show how headache and physiological data can be linked, a basic knowledge-based system for headache trigger detection is presented. RESULTS: In two waves, 14 migraine and 4 CH patients participated (mean duration 22.3 days). 133 headache attacks were registered (98 by migraine, 35 by CH patients). Strictly applying ICHD-3 criteria leads to 8/98 migraine without aura and 0/35 CH classifications. Adapted versions yield 28/98 migraine without aura and 17/35 CH classifications, with 12/18 participants having mostly diagnosis classifications when episodic TTH classifications (57/98 and 32/35) are ignored. CONCLUSIONS: Strictly applying the ICHD-3 criteria on individual attacks does not yield good classification results. Adapted versions yield better results, with the mostly classified phenotype (migraine without aura vs. CH) matching the diagnosis for 12/18 patients. The absolute number of migraine without aura and CH classifications is, however, rather low. Example cases can be identified where activity and stress events explain patient-reported headache triggers. Continuous improvement of the data collection protocol, ML algorithms, and headache classification criteria (including the investigation of integrating physiological data), will further improve future headache follow-up, classification and trigger detection. Trial registration This trial was retrospectively registered with number NCT04949204 on 24 June 2021 at www. CLINICALTRIALS: gov .

Using natural language processing to automatically classify written self-reported narratives by patients with migraine or cluster headache.

BACKGROUND: Headache medicine is largely based on detailed history taking by physicians analysing patients' descriptions of headache. Natural language processing (NLP) structures and processes linguistic data into quantifiable units. In this study, we apply these digital techniques on self-reported narratives by patients with headache disorders to research the potential of analysing and automatically classifying human-generated text and information extraction in clinical contexts. METHODS: A prospective cross-sectional clinical trial collected self-reported narratives on headache disorders from participants with either migraine or cluster headache. NLP was applied for the analysis of lexical, semantic and thematic properties of the texts. Machine learning (ML) algorithms were applied to classify the descriptions of headache attacks from individual participants into their correct group (migraine versus cluster headache). RESULTS: One-hundred and twenty-one patients (81 participants with migraine and 40 participants with cluster headache) provided a self-reported narrative on their headache disorder. Lexical analysis of this text corpus resulted in several specific key words per diagnostic group (cluster headache: Dutch (nl): "oog" | English (en): "eye", nl: "pijn" | en: "pain" and nl: "terug" | en: "back/to come back"; migraine: nl: "hoofdpijn" | en: "headache", nl: "stress" | en: "stress" and nl: "misselijkheid" | en: "nausea"). Thematic and sentiment analysis of text revealed largely negative sentiment in texts by both patients with migraine and cluster headache. Logistic regression and support vector machine algorithms with different feature groups performed best for the classification of attack descriptions (with F1-scores for detecting cluster headache varying between 0.82 and 0.86) compared to naïve Bayes classifiers. CONCLUSIONS: Differences in lexical choices between patients with migraine and cluster headache are detected with NLP and are congruent with domain expert knowledge of the disorders. Our research shows that ML algorithms have potential to classify patients' self-reported narratives of migraine or cluster headache with good performance. NLP shows its capability to discern relevant linguistic aspects in narratives from patients with different headache disorders and demonstrates relevance in clinical information extraction. The potential benefits on the classification performance of larger datasets and neural NLP methods can be investigated in the future. TRIAL REGISTRATION: This study was registered with clinicaltrials.gov with ID NCT05377437.

CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs.

BACKGROUND: Several drugs are available for the preventive treatment of both episodic and chronic migraine. The choice of which therapy to initiate first, second, or third is not straightforward and is based on multiple factors, including general efficacy, tolerability, potential for serious adverse events, comorbid conditions, and costs. Recently, a new class of migraine preventive drugs was introduced, i.e. monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor. METHODS: The present article summarizes the evidence gathered with this new migraine preventive drug class from randomized placebo-controlled clinical trials. It further puts this into perspective next to the evidence gained by the most widely used agents for the prevention of episodic and chronic migraine with an emphasis on efficacy and the robustness with which this efficacy signal was obtained. RESULTS: Although being a relatively new class of migraine preventive drugs, monoclonal antibodies blocking the CGRP pathway have an efficacy which is at least comparable if not higher than those of the currently used preventive drugs. Moreover, the robustness of this efficacy signal is substantiated by several randomized clinical trials each including large numbers of patients. In addition, because of their excellent tolerability and with long-term safety data emerging, they seem to have an unprecedented efficacy over adverse effect profile, clearly resulting in an added value for migraine prevention. CONCLUSIONS: Balancing the data presented in the current manuscript with additional data concerning long term safety on the one hand and cost issues on the other hand, can be of particular use to health policy makers to implement this new drug class in the prevention of migraine.

Structured headache services as the solution to the ill-health burden of headache. 2. Modelling effectiveness and cost-effectiveness of implementation in Europe: methodology.

BACKGROUND: Health economic evaluations support health-care decision-making by providing information on the costs and consequences of health interventions. No universally accepted methodology exists for modelling effectiveness and cost-effectiveness of interventions designed to close treatment gaps for headache disorders in countries of Europe (or elsewhere). Our aim here, within the European Brain Council's Value-of-Treatment project, was to develop headache-type-specific analytical models to be applied to implementation of structured headache services in Europe as the health-care solution to headache. METHODS: We developed three headache-type-specific decision-analytical models using the WHO-CHOICE framework and adapted these for three European Region country settings (Luxembourg, Russia and Spain), diverse in geographical location, population size, income level and health-care systems and for which we had population-based data. Each model compared current (suboptimal) care vs target care (delivered in accordance with the structured headache services model). Epidemiological and economic data were drawn from studies conducted by the Global Campaign against Headache; data on efficacy of treatments were taken from published randomized controlled trials; assumptions on uptake of treatments, and those made for Healthy Life Year (HLY) calculations and target-care benefits, were agreed with experts. We made annual and 5-year cost estimates from health-care provider (main analyses) and societal (secondary analyses) perspectives (2020 figures, euros). RESULTS: The analytical models were successfully developed and applied to each country setting. Headache-related costs (including use of health-care resources and lost productivity) and health outcomes (HLYs) were mapped across populations. The same calculations were repeated for each alternative (current vs target care). Analyses of the differences in costs and health outcomes between alternatives and the incremental cost-effectiveness ratios are presented elsewhere. CONCLUSIONS: This study presents the first headache-type-specific analytical models to evaluate effectiveness and cost-effectiveness of implementing structured headache services in countries in the European Region. The models are robust, and can assist policy makers in allocating health budgets between interventions to maximize the health of populations.

Structured headache services as the solution to the ill-health burden of headache. 3. Modelling effectiveness and cost-effectiveness of implementation in Europe: findings and conclusions.

BACKGROUND: There have been several calls for estimations of costs and consequences of headache interventions to inform European public-health policies. In a previous paper, in the absence of universally accepted methodology, we developed headache-type-specific analytical models to be applied to implementation of structured headache services in Europe as the health-care solution to headache. Here we apply this methodology and present the findings. METHODS: Data sources were published evidence and expert opinions, including those from an earlier economic evaluation framework using the WHO-CHOICE model. We used three headache-type-specific analytical models, for migraine, tension-type-headache (TTH) and medication-overuse-headache (MOH). We considered three European Region case studies, from Luxembourg, Russia and Spain to include a range of health-care systems, comparing current (suboptimal) care versus target care (structured services implemented, with provider-training and consumer-education). We made annual and 5-year cost estimates from health-care provider and societal perspectives (2020 figures, euros). We expressed effectiveness as healthy life years (HLYs) gained, and cost-effectiveness as incremental cost-effectiveness-ratios (ICERs; cost to be invested/HLY gained). We applied WHO thresholds for cost-effectiveness. RESULTS: The models demonstrated increased effectiveness, and cost-effectiveness (migraine) or cost saving (TTH, MOH) from the provider perspective over one and 5 years and consistently across the health-care systems and settings. From the societal perspective, we found structured headache services would be economically successful, not only delivering increased effectiveness but also cost saving across headache types and over time. The predicted magnitude of cost saving correlated positively with country wage levels. Lost productivity had a major impact on these estimates, but sensitivity analyses showed the intervention remained cost-effective across all models when we assumed that remedying disability would recover only 20% of lost productivity. CONCLUSIONS: This is the first study to propose a health-care solution for headache, in the form of structured headache services, and evaluate it economically in multiple settings. Despite numerous challenges, we demonstrated that economic evaluation of headache services, in terms of outcomes and costs, is feasible as well as necessary. Furthermore, it is strongly supportive of the proposed intervention, while its framework is general enough to be easily adapted and implemented across Europe.

Structured headache services as the solution to the ill-health burden of headache: 1. Rationale and description

In countries where headache services exist at all, their focus is usually on specialist (tertiary) care. This is clinically and economically inappropriate: most headache disorders can effectively and more efficiently (and at lower cost) be treated in educationally supported primary care. At the same time, compartmentalizing divisions between primary, secondary and tertiary care in many health-care systems create multiple inefficiencies, confronting patients attempting to navigate these levels (the "patient journey") with perplexing obstacles.High demand for headache care, estimated here in a needs-assessment exercise, is the biggest of the challenges to reform. It is also the principal reason why reform is necessary.The structured headache services model presented here by experts from all world regions on behalf of the Global Campaign against Headache is the suggested health-care solution to headache. It develops and refines previous proposals, responding to the challenge of high demand by basing headache services in primary care, with two supporting arguments. First, only primary care can deliver headache services equitably to the large numbers of people needing it. Second, with educational supports, they can do so effectively to most of these people. The model calls for vertical integration between care levels (primary, secondary and tertiary), and protection of the more advanced levels for the minority of patients who need them. At the same time, it is amenable to horizontal integration with other care services. It is adaptable according to the broader national or regional health services in which headache services should be embedded.It is, according to evidence and argument presented, an efficient and cost-effective model, but these are claims to be tested in formal economic analyses.

The Many Faces of Medication-Overuse Headache in Clinical Practice.

The management of medication-overuse headache (MOH) is multifaceted and headache experts have different views on the optimal strategy to tackle this type of secondary headache. The purpose of this review is to provide an overview of the literature on the management of MOH, and to highlight important considerations in the clinical evaluation of the MOH patient. Managing MOH in clinical practice starts by evaluating the headache patient with medication overuse, determining the overused drug(s), assessing the impact of headaches on the patient and assessing comorbid conditions and disorders. Withdrawal of the overused medication is the cornerstone of treatment. An inpatient or outpatient setting is chosen based on the clinical profile of the patient. There is evidence for abrupt withdrawal combined with headache preventive treatment. Bridging therapy to bring relief to withdrawal headaches and/or symptoms should be offered. Education and motivational work through multidisciplinary assessment show benefits in sustaining withdrawal and preventing relapse. Although the reversal of chronic headache after cessation of overused acute medication has been noticed worldwide, different aspects of the management of MOH, such as complete or gradual withdrawal, or preventive treatment with or without withdrawal are still debated.

Efficacy and safety of erenumab in women with a history of menstrual migraine.

BACKGROUND: We performed a post hoc, subgroup analysis of a phase 3, randomized, double-blind, placebo-controlled study of erenumab for prevention of episodic migraine (STRIVE) to determine the efficacy and safety of erenumab in women with self-reported menstrual migraine. METHODS: Patients received placebo, erenumab 70 mg, or erenumab 140 mg subcutaneously once monthly during the 6-month double-blind treatment phase of STRIVE. Women who reported history of menstrual migraine and who were ≤ 50 years old were included in the analysis. Endpoints were change from baseline in monthly migraine days (MMD) and monthly acute migraine-specific medication days (MSMD; among patients who took acute migraine-specific medications at baseline), proportion of patients achieving ≥ 50% reduction from baseline in MMD, and incidence of adverse events. RESULTS: Among 814 women enrolled in STRIVE, 232 (28.5%) reported a history of menstrual migraine and were ≤ 50 years old. Of the 232 patients, 214 (92%) had a baseline MMD > 5, suggesting a high proportion of women with attacks outside of the 5-day perimenstrual window (2 days before and 3 days after the start of menstruation). Information on "migraine days" includes (and does not discriminate between) perimenstrual and intermenstrual migraine attacks. Between-group differences from placebo over months 4-6 for erenumab 70 mg and 140 mg were - 1.8 (P = 0.001) and - 2.1 (P < 0.001) days for MMD and - 1.6 (P = 0.002) and - 2.4 (P < 0.001) days for acute MSMD, respectively. The odds of having a ≥ 50% reduction from baseline in MMD over months 4-6 were 2.2 (P = 0.024) and 2.8 (P = 0.002) times greater for erenumab 70 mg and 140 mg, respectively, than for placebo. Erenumab had an overall safety profile comparable to placebo. CONCLUSION: Data from this subgroup analysis of women with menstrual migraine are consistent with data from the overall STRIVE episodic migraine population, supporting the efficacy and safety of erenumab in women who experience menstrual migraine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02456740. Registered 28 May 2015.

Efficacy and safety of erenumab (AMG334) in episodic migraine patients with prior preventive treatment failure: A subgroup analysis of a randomized, double-blind, placebo-controlled study.

BACKGROUND: Erenumab was effective and well tolerated in a pivotal clinical trial of episodic migraine that included subjects both naïve to, and those who had failed, previous preventives. Here we evaluated the efficacy and safety of erenumab (70 mg or 140 mg) versus placebo in the subgroup of patients who had previously failed preventive treatment(s): ≥1 or ≥2 prior failed migraine preventive categories, and in patients who had never failed. METHODS: Prespecified subgroup analyses evaluated change from baseline to months 4-6 (the primary endpoint of the blinded study phase) in monthly migraine days, achievement of ≥50% and ≥75% reduction in monthly migraine days, and change from baseline in acute migraine-specific medication days. Adverse events were also evaluated. RESULTS: Treatment with both doses of erenumab resulted in greater reductions in monthly migraine days at months 4-6 (treatment difference versus placebo [95% CI], never failed subgroup: -0.9 [-1.5, -0.3] for 70 mg and -1.3 [-1.9, -0.7] for 140 mg; ≥1 prior failed medication categories subgroup: -2.0 [-2.8, -1.2] for 70 mg and -2.5 [-3.4, -1.7] for 140 mg; ≥2 prior failed medication categories subgroup: -1.3 [-2.6, 0.0] for 70 mg and -2.7 [-4.0, -1.4] for 140 mg). Similar results were observed in the monthly acute migraine-specific medication days endpoint, and in the achievement of ≥50% and ≥75% reduction in monthly migraine days. For the ≥50% reduction in monthly migraine day endpoint, placebo response in the no prior treatment failed group was 32.6%, in the ≥1 failed treatment 17.5%, and in the ≥2 failed treatments 11.1%. CONCLUSION: Erenumab showed consistent efficacy in episodic migraine patients who had failed prior preventive treatments and was well tolerated across subgroups. The data suggest prior patients with prior treatment failures have lower placebo response rates.

Calcitonin-gene-related peptide pathway mAbs and migraine prevention.

PURPOSE OF REVIEW: Monoclonal antibodies (mAbs) targeting the calcitonin-gene-related peptide (CGRP) pathway have been developed for episodic and chronic migraine prevention, either through binding the CGRP ligand (eptinezumab, fremanezumab, galcanezumab) or the CGRP receptor (erenumab). We provide an update on published Phase 2 and Phase 3 trials, safety/tolerability data, pharmacokinetics and mechanism of action of these biologicals. RECENT FINDINGS: The efficacy data from Phase 2 trials are corroborated by those from published Phase 3 trials, with a multitude of publications expected in 2018. Review of safety data concluded there was no difference in total adverse events or main adverse events (including upper respiratory tract infection, nasopharyngitis, nausea, injection-site pain and back pain) between the mAbs and placebo injections except apparently for dizziness. The site of action of these mAbs is not fully elucidated but current insight is that their effect resides in the periphery; a contribution of central effect(s) can however not be excluded at present. SUMMARY: Although efficacy of all four drugs is modest over placebo in episodic and chronic migraine prevention and overall comparable with available oral preventive treatments, current tolerability and (short-term) safety data of this new treatment approach certainly promise a major step forward for migraine patients.

A decision support system to follow up and diagnose primary headache patients using semantically enriched data.

BACKGROUND: Headache disorders are an important health burden, having a large health-economic impact worldwide. Current treatment & follow-up processes are often archaic, creating opportunities for computer-aided and decision support systems to increase their efficiency. Existing systems are mostly completely data-driven, and the underlying models are a black-box, deteriorating interpretability and transparency, which are key factors in order to be deployed in a clinical setting. METHODS: In this paper, a decision support system is proposed, composed of three components: (i) a cross-platform mobile application to capture the required data from patients to formulate a diagnosis, (ii) an automated diagnosis support module that generates an interpretable decision tree, based on data semantically annotated with expert knowledge, in order to support physicians in formulating the correct diagnosis and (iii) a web application such that the physician can efficiently interpret captured data and learned insights by means of visualizations. RESULTS: We show that decision tree induction techniques achieve competitive accuracy rates, compared to other black- and white-box techniques, on a publicly available dataset, referred to as migbase. Migbase contains aggregated information of headache attacks from 849 patients. Each sample is labeled with one of three possible primary headache disorders. We demonstrate that we are able to reduce the classification error, statistically significant (ρ≤0.05), with more than 10% by balancing the dataset using prior expert knowledge. Furthermore, we achieve high accuracy rates by using features extracted using the Weisfeiler-Lehman kernel, which is completely unsupervised. This makes it an ideal approach to solve a potential cold start problem. CONCLUSION: Decision trees are the perfect candidate for the automated diagnosis support module. They achieve predictive performances competitive to other techniques on the migbase dataset and are, foremost, completely interpretable. Moreover, the incorporation of prior knowledge increases both predictive performance as well as transparency of the resulting predictive model on the studied dataset.

European headache federation guideline on idiopathic intracranial hypertension.

BACKGROUND: Idiopathic Intracranial Hypertension (IIH) is characterized by an elevation of intracranial pressure (ICP no identifiable cause. The aetiology remains largely unknown, however observations made in a number of recent clinical studies are increasing the understanding of the disease and now provide the basis for evidence-based treatment strategies. METHODS: The Embase, CDSR, CENTRAL, DARE and MEDLINE databases were searched up to 1st June 2018. We analyzed randomized controlled trials and systematic reviews that investigate IIH. RESULTS: Diagnostic uncertainty, headache morbidity and visual loss are among the highest concerns of clinicians and patients in this disease area. Research in this field is infrequent due to the rarity of the disease and the lack of understanding of the underlying pathology. CONCLUSIONS: This European Headache Federation consensus paper provides evidence-based recommendations and practical advice on the investigation and management of IIH.

Medication-overuse headache: a widely recognized entity amidst ongoing debate.

Medication overuse in primary headache disorders is a worldwide phenomenon and has a role in the chronification of headache disorders. The burden of disease on individuals and societies is significant due to high costs and comorbidities. In the Third Edition of the International Classification of Headache Disorders, medication-overuse headache is recognized as a separate secondary entity next to mostly primary headache disorders, although many clinicians see the disease as a sole complication of primary headache disorders. In this review, we explore the historical background of medication-overuse headache, its epidemiology, phenomenology, pathophysiology and treatment options. The review explores relevant unanswered questions and summarizes the current debates in medication-overuse headache.

Effect of exogenous estrogens and progestogens on the course of migraine during reproductive age: a consensus statement by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH).

We systematically reviewed data about the effect of exogenous estrogens and progestogens on the course of migraine during reproductive age. Thereafter a consensus procedure among international experts was undertaken to develop statements to support clinical decision making, in terms of possible effects on migraine course of exogenous estrogens and progestogens and on possible treatment of headache associated with the use or with the withdrawal of hormones. Overall, quality of current evidence is low. Recommendations are provided for all the compounds with available evidence including the conventional 21/7 combined hormonal contraception, the desogestrel only oral pill, combined oral contraceptives with shortened pill-free interval, combined oral contraceptives with estradiol supplementation during the pill-free interval, extended regimen of combined hormonal contraceptive with pill or patch, combined hormonal contraceptive vaginal ring, transdermal estradiol supplementation with gel, transdermal estradiol supplementation with patch, subcutaneous estrogen implant with cyclical oral progestogen. As the quality of available data is poor, further research is needed on this topic to improve the knowledge about the use of estrogens and progestogens in women with migraine. There is a need for better management of headaches related to the use of hormones or their withdrawal.

Association of Cerebral Venous Thrombosis and Intracranial Hypotension: Review of 3 Cases.

Cerebral venous thrombosis is a rare complication of intracranial hypotension. We describe 3 cases in which this phenomenon occurred, as a result of a lumbar puncture or due to a spontaneous cerebrospinal fluid leak. We emphasize the importance of early detection of the intracranial hypotension syndrome, the most common clinical manifestation being orthostatic headache. It is not an innocent condition as it is associated with other potential complications such as subdural hygroma/hematoma, cranial nerve palsies, cerebellar tonsillar descent, and even brainstem manifestations. Any change in the typical features of the syndrome should lead to further investigation. Repeat cerebral imaging is important in that situation, including ruling out cerebral venous thrombosis.

The use of the trendelenburg position in the surgical treatment of extreme cerebellar slump.

BACKGROUND: State-of-the-art treatment for Chiari Malformation I (CM-I) consists of decompression by posterior fossa craniectomy. A rare but severe complication that develops over months to years after this procedure is cerebellar slump. Treatment options for this condition are limited. We present a new and promising approach to treat this rare condition. METHODS: The patients were placed in the Trendelenburg position to facilitate ascent of the cerebellum. After almost complete dissolution of neurologic symptoms, surgical reconstruction was performed by tonsillar resection and the creation of a new structural support using a bone graft. RESULTS: Both patients experienced good clinical and morphological outcomes immediately after surgery, and for two years thereafter. CONCLUSIONS: Neurological symptoms related to cerebellar or brainstem slump can be adequately reversed by placing the patient in the Trendelenburg position. After uneventful gravitational reversal of the slump, safe surgical reconstruction of the cerebellar support can be performed to securely preserve the anatomical reversal.

Chronic cluster headache and the pituitary gland.

BACKGROUND: Cluster headache is classified as a primary headache by definition not caused by an underlying pathology. However, symptomatic cases of otherwise typical cluster headache have been reported. CASE PRESENTATION: A 47-year-old male suffered from primary chronic cluster headache (CCH, ICHD-3 beta criteria fulfilled) since the age of 35 years. A magnetic resonance imaging (MRI) study of the brain in 2006 came back normal. He tried several prophylactic treatments but was never longer than 1 month without attacks. He was under chronic treatment with verapamil with only a limited effect on the attack frequency. Subcutaneous sumatriptan 6 mg injections were very effective in aborting attacks. By February 2014 the patient developed a continuous interictal pain ipsilateral to the right-sided cluster headache attacks. An indomethacin test (up to 225 mg/day orally) was negative. Because of the change in headache pattern we performed a new brain MRI, which showed a cystic structure in the pituitary gland. The differential diagnosis was between a Rathke cleft cyst and a cystic adenoma. Pituitary function tests showed an elevated serum prolactin level. A dopamine agonist (cabergoline) was started and the headache subsided completely. Potential pathophysiological mechanisms of pituitary tumor-associated headache are discussed. CONCLUSION: Neuroimaging should be considered in all patients with CCH, especially those with an atypical presentation or evolution. Response to acute treatment does not exclude a secondary form of cluster headache. There may be shared pathophysiological mechanisms of primary and secondary cluster headache.