Objective To collect pairs of nonfactual information and their interpretations and rate their usefulness in distinguishing between primary and secondary headache disorders. Background Physicians use clinical indicators such as Red Flags and ask about exposure to potential causes to differentiate primary from secondary headaches; however, these approaches have limitations and may result in unnecessary diagnostic procedures. Methods Using the Delphi process, the participants proposed information-interpretation pairs in the first round and rated them anonymously in two subsequent rounds. The ratings relied on quality estimators to evaluate the reliability, validity, relevance, and frequency on 5-point Likert scales, ranging from 0 to 5. We considered pairs with an average rating of 4.0 or higher to have reached consensus. Results Four proposals reached consensus, of which two referred to nonfactual information: (i) “A headache that feels familiar indicates a primary headache.” (ii) “A headache that feels completely different from any previous headache raises the suspicion of a secondary headache.” Conclusions The participants generally found little use for nonfactual information for distinguishing between primary and secondary headache disorders. Solely the presence and absence of patients’ notion of a familiar headache were deemed helpful. While the participants viewed the former as being associated with a primary headache, they felt that the latter pointed towards a secondary headache. Further research is necessary to evaluate their usefulness in clinical practice.

Cluster headache (CH) is a rare primary headache disorder characterized by recurrent episodes of strictly unilateral excruciating pain accompanied by trigemino-autonomic signs, which significantly impacts the quality of life, social interactions, and occupational functioning of those who are affected. To promote a better understanding of this disabling condition and to foster research on the topic, this review provides a comprehensive description of the hallmarks of CH, including its clinical presentation, diagnostic challenges, pathophysiology, and current and novel therapeutic targets. It concludes by describing the disease burden and advocating for significant improvements in healthcare systems, and promoting health equity, as well as reducing stigma. Despite its distinctive clinical and chronobiological features, CH may be mistaken for other primary headache disorders or different types of orofacial pain. Key pathogenic characteristics include the activation of the trigeminal-autonomic system with the release of several neuropeptides, the involvement of the hypothalamus in regulating the circadian rhythm, genetic variants, and the mesolimbic system. Both invasive and non-invasive neuromodulation treatments have been used to target the trigemino-cervical, parasympathetic, and hypothalamic systems. Additionally, novel therapeutic targets are currently being study. Alongside canonical therapies, several complementary approaches have been explored over the years, with most evidence deriving from uncontrolled research involving individuals who do not respond to standard pharmacological treatments. Despite advancements in our understanding of this complex disease, CH continues to pose considerable social, economic, and psychological challenges. Advocacy is essential and should prioritize early diagnosis, alleviate stigma, provide specialized training for healthcare professionals, and offer support to and through patient associations. CH is characterised by a complex, multifactorial, pathophysiology that is still not fully understood. Precise diagnosis, additional research studies, and robust psychosocial and institutional support are necessary to improve the quality of life for individuals affected by this debilitating condition.

BackgroundThis systematic review and meta-analysis synthesized migraine-related disability outcomes according to headache frequency subclassifications, including low-frequency episodic migraine (LFEM), high-frequency episodic migraine (HFEM) and chronic migraine (CM).MethodsWe searched the PubMed and Cochrane Library (CENTRAL) up to 16 October 2024 for peer-reviewed non-interventional studies reporting migraine-related disability outcomes in CM and subclassifications of episodic migraine (e.g. LFEM and HFEM). Eligible studies with an HFEM subgroup were grouped by headache frequency measure (monthly migraine days [MMD] or monthly headache days [MHD]), HFEM subgroup, disability parameter and study setting. Random-effects meta-analyses were conducted on groups with three or more studies, with the results presented in forest plots. Risk of bias was assessed using Joanna Briggs Institute tools.ResultsOf the 32 included studies, 27 were grouped, yielding five meta-analysis groups containing three or more studies. All five groups had an HFEM subgroup of 8-14 MHD. Accordingly, we classified LFEM as 0-7 MHD and CM as ≥15 MHD. Ten studies contributed data to the five meta-analysis groups. Estimated pooled values are reported by headache frequency subgroup for each meta-analysis group: LFEM (95% confidence interval [CI]), HFEM (95% CI) and CM (95% CI). For meta-analysis group 1, four population-based studies reported Migraine Disability Assessment (MIDAS) Grade IV proportions, with pooled values of 11.1% (7.1-17.1), 43.9% (31.8-56.9) and 57.5% (42.7-71.1), respectively. For meta-analysis group 2, five population-based studies documented Work Productivity and Activity Impairment (WPAI) outcomes. Pooled mean overall work productivity impairment (OWPI) scores were 36.9% (30.8-43.1), 44.7% (38.4-51.0) and 52.0% (47.7-56.3), respectively. Pooled mean activity impairment (AI) scores were 36.4% (33.7-39.1), 46.4% (42.8-50.0) and 53.5% (52.1-54.8), respectively. For meta-analysis group 3, three clinic-based studies presented MIDAS Grade IV proportions. Pooled values were 15.0% (4.4-40.5), 42.4% (17.1-72.4) and 65.7% (30.3-89.4), respectively. For meta-analysis group 4, three clinic-based studies reported WPAI outcomes. Pooled mean OWPI scores were 28.8% (21.6-35.9), 40.2% (36.2-44.2) and 49.6% (46.3-52.9), respectively. Pooled mean AI scores were 29.4% (21.9-36.9), 43.5% (39.0-48.1) and 51.6% (48.8-54.4), respectively. For meta-analysis group 5, three clinic-based studies detailed MIDAS scores. Pooled mean scores were 10.7 (3.9-17.5), 23.9 (9.4-38.4) and 49.6 (15.8-83.3), respectively.ConclusionsThis study showed a pattern of increasing migraine-related disability with rising headache frequency. Regardless of study setting, our meta-analyses also suggested a severe level of disability in many individuals (42%-44%) with HFEM, highlighting an unmet need for more effective migraine management. Disability burden and headache frequency should both be considered when determining treatment needs and therapy access, particularly for patients with HFEM.Study Registration: INPLASY2024120039.

Trigeminal neuralgia (TN) is a facial pain disorder characterized by intense and paroxysmal pain that profoundly affects quality of life and presents complex challenges in diagnosis and treatment. TN can be categorized as classical, secondary and idiopathic. Epidemiological studies show variable incidence rates and an increased prevalence in women and in the elderly, with familial cases suggesting genetic factors. The pathophysiology of TN is multifactorial and involves genetic predisposition, anatomical changes, and neurophysiological factors, leading to hyperexcitable neuronal states, central sensitization and widespread neural plasticity changes. Neurovascular compression of the trigeminal root, which undergoes major morphological changes, and focal demyelination of primary trigeminal afferents are key aetiological factors in TN. Structural and functional brain imaging studies in patients with TN demonstrated abnormalities in brain regions responsible for pain modulation and emotional processing of pain. Treatment of TN involves a multifaceted approach that considers patient-specific factors, including the type of TN, with initial pharmacotherapy followed by surgical options if necessary. First-line pharmacological treatments include carbamazepine and oxcarbazepine. Surgical interventions, including microvascular decompression and percutaneous neuroablative procedures, can be considered at an early stage if pharmacotherapy is not sufficient for pain control or has intolerable adverse effects or contraindications. In this Primer, Ashina et al. discuss the epidemiology, pathophysiology, diagnosis, management and quality of life of patients with trigeminal neuralgia, a chronic neuropathic facial pain disorder involving one or more branches of the trigeminal nerve that causes intense paroxysms of electric shock-like pain.

Erenumab is a monoclonal antibody specifically targeting the CGRP-receptor. Several studies showed efficacy and safety in patients with migraine. Less is known regarding dosage increase, especially in a difficult to treat patients. The aim of the study is to evaluate the increased dosage under real world conditions with particular focus on 70 mg non-responders. In a retrospective analysis, patients treated in tertiary headache centers (Halle or Jena, Germany) receiving 70 mg erenumab for at least 3 months with a dosage increase to 140 mg were analyzed. Data were evaluated regarding headache days, intake of acute medication, previous prophylaxis, and medication overuse. Baseline and all treatment intervals were determined as three-month periods. Datasets of 52 migraine patients (90.4

Identification of substances that may cause or trigger headache is important to start effective treatment early to prevent unnecessary suffering, deterioration in quality of life , and the development of chronic pain. Treatment in case of medication overuse and other chronic headache should be decisive and effective. Drug withdrawal and introduction of effective prophylactic medication for the underlying headache disorder should be the primary treatment strategy. Typical headache-inducing substances are nitric oxide , phosphodiesterase , cocaine, alcohol, histamine, carbon oxide, and calcitonin gene-related peptide. The withdrawal of caffeine, estrogen, and opioids is most often associated with the development of headache.

BACKGROUND AND PURPOSE:Previous studies demonstrated cognitive deficits in patients with peripheral vestibulopathy (PVP) with dysfunction of spatial navigation and orientation, but also documented cognitive decline in nonspatial abilities. This study evaluates cognitive deficits in patients with unilateral vestibulopathy (UVP) as well as bilateral vestibulopathy (BVP) in multiple cognitive domains using common screening tests to reliably detect these deficits in clinical practice. METHODS:This prospective study compared patients with UVP and BVP to age- and sex-matched healthy controls (HC). Tests included the Alzheimer's Disease Assessment Scale (ADAS), Mini-Mental Status Examination (MMSE), Trail Making Test Part A and B, Clock Drawing Task, Executive Interview-25 (EXIT25), Dementia Detection (DemTect), and the Judgment of Line Orientation (JLO). The Montgomery-Åsberg Depression Rating Scale was used to control for depression. Videonystagmography objectively reconfirmed PVP. The Vertigo Symptoms Scale and the Dizziness Handicap Inventory were used to assess for symptom severity and restrictions of activities of daily living. RESULTS:Eighty-one patients (65 UVP, 16 BVP) were compared to 55 HC. Patients showed impairment in ADAS, MMSE, DemTect, EXIT25, and JLO. No differences between UVP and BVP were detected. The relative risk (RR) estimates of developing cognitive deficits following PVP were increased. The RR for the ADAS was higher in BVP (RR = 4.91, 95% confidence interval [CI] = 1.87-12.9, p = 0.001) than in UVP (RR = 3.75, 95% CI = 1.65-8.51, p = 0.002), but was similar for the MMSE and DemTect between groups. CONCLUSIONS:Patients with PVP showed deficits in multiple cognitive domains including nonspatial cognitive abilities. Vestibulopathy could be a risk factor for the development of cognitive impairment.

Objective To identify grey matter alterations in patients suffering new daily persistent headache to enrich the pathophysiological concept of this rare headache disorder characterised by a distinct, clearly remembered onset and its instant chronification. Method Magnetic resonance-based voxel-based and surface-based morphometry was used to investigate 23 patients suffering from new daily persistent headache and 23 age- and gender-matched healthy controls with 1.5 Tesla MRI. Independent statistical analysis was performed at three sites using statistical parametric mapping, as well as FSL(FMRIB Software Library)-based approaches. Results No grey matter changes were detected using this sophisticated and cross-checked method. Conclusion The absence of structural brain changes in patients with new daily persistent headache contribute to the recent discussion regarding structural alterations in primary headache disorders in general and does not provide evidence for grey matter changes being associated with the pathophysiology of new daily persistent headache. Future research will have to determine the underlying pathophysiological mechanisms of this disorder.

BACKGROUND:Secondary headaches attributed to exposure to or the overuse of a substance are classified under chapter eight in the International Classification of Headache Disorders 3rd edition. Three distinct sub-chapters consider: 1. Headache attributed to exposure to a substance, 2. Medication overuse headache, and 3. Headache attributed to substance withdrawal. Headache attributed to exposure to a substance refers to a headache with onset immediately or within hours after the exposure, while medication overuse headache is a headache occurring on 15 or more days per month that has developed as a consequence of regular usage of acute headache medication(s) for more than three consecutive months in a patient with a pre-existing primary headache disorder. The withdrawal of caffeine, oestrogen, and opioids is most often associated with the development of headache.DISCUSSION:Despite the current headache classification, there is no certainty of a causal relationship between the use of any substance and the development of headache. Some substances are likely to provoke headache in patients that suffer from a primary headache disorder like migraine, tension-type headache or cluster headache, while others were described to cause headache even in people that generally do not get headaches. Toxic agents, such as carbon monoxide (CO) are difficult to investigate systematically, while other substances such as nitric oxide (NO) were specifically used to induce headache experimentally. If a patient with an underlying primary headache disorder develops a headache, in temporal relation to exposure to a substance, which is significantly worse than the usual headache it is considered secondary. This is even more the case if the headache phenotype is different from the usually experienced headache characteristics. Medication overuse headache is a well-described, distinct disease entity with only marginally understood pathophysiology and associated psychological factors. Managing medication overuse headache patients includes education, detoxification, prophylactic treatments and treating comorbidities, which is reflected in available guidelines. Viewing medication overuse headache as a separate entity helps clinicians and researchers better recognise, treat and study the disorder.CONCLUSION:Identification of substances that may cause or trigger secondary headache is important in order to educate patients and health care professionals about potential effects of these substances and prevent unnecessary suffering, as well as deterioration in quality of life. Treatment in case of medication overuse and other chronic headache should be decisive and effective.

BACKGROUND AND PURPOSE:Vestibular migraine (VM) patients are ictally and interictally hypersensitive for self-motion and visual perception. Increased cortical excitability of the vestibular system represented by lowered motion perception thresholds might play an important role in the pathophysiology of VM. We aimed to compare motion perception thresholds and the vegetative response to rotatory motion, as well as the vestibulo-ocular reflex (VOR) during rotation in VM patients compared to healthy controls (HC).METHODS:In this cross-sectional study, 28 female VM patients in the interictal state and 33 age- and gender-matched HC were investigated sitting in a motorized rotary chair shielded regarding visual and acoustic stimuli for 20 min with slowly increasing velocity (maximum = 72°/s). The motion perception threshold was indicated by the participants by pushing a button. During and after rotation, participants rated the presence and extent of motion sickness using a sickness rating scale.RESULTS:We detected lower motion perception thresholds (7.54°/s vs. 23.49°/s; p < 0.001) in VM patients compared to HC but no difference at the basic VOR thresholds. Furthermore, the patients showed enhanced susceptibility to motion sickness during and after the rotation.CONCLUSIONS:We provide evidence for decreased motion perception thresholds and pronounced susceptibility to motion sickness in VM patients in the interictal state, which could indicate alterations in higher levels of vestibular processing. Future studies should determine whether this could be the pathophysiological hallmark of VM either as a unique disease entity or in differentiation from other forms of migraine.

Persistent postural-perceptual dizziness (PPPD) is the most common functional vestibular disorder. A multisensory mismatch altered by psychological influences is considered to be an important pathophysiological mechanism. Increased cortical and subcortical excitability may play a role in the pathophysiology of PPPD. We hypothesized that decreased motion perception thresholds reflect one mechanism of the abnormal vestibular responsiveness in this disorder. We investigated the vestibular perception thresholds and the vestibular ocular reflex with a rotatory chair experiment to gain insights in the processing and adaption to vestibular provocation. In this cross-sectional study 26 female PPPD patients and 33 healthy female age matched controls (HC) were investigated sitting in a motorized rotary chair shielded regarding visual and acoustic stimuli. The chair was rotated for 20 minutes with slowly increasing velocity to a maximum of 72°/s. We functionally tested motion perception thresholds and vegetative responses to rotation as well as vestibular-ocular reflex thresholds. We additionally investigated several psychological comorbidities (i.e. depression, anxiety, somatosensory amplification) using validated scores. Conventional dizziness scores were obtained to quantify the experienced dizziness and impact on daily life. PPPD patients showed a significant reduced vestibulo-perceptual threshold (PPPD: 10.9°/s vs. HC: 29.5°/s; p<0.001) with increased motion sensitivity and concomitant vegetative response during and after the chair rotation compared to healthy controls. The extent of increased vestibular sensitivity was in correlation with the duration of the disease (p=0.043). No significant difference was measured regarding nystagmus parameters between both groups. PPPD patients showed increased vegetative response as well as decreased vestibulo-perceptual thresholds which are related to disease duration. This is of interest as PPPD might be sustained by increased vestibular excitability leading to motion intolerance and induction of dizziness when exposed to movement.

BackgroundPrednisone is commonly used for initial short-term therapy of episodic cluster headaches before preventive medication such as verapamil becomes effective, but this strategy has not been tested in large randomised trials. We aimed to access the safety and efficacy of this treatment approach.MethodsThis study was a multicentre, randomised, double-blind, placebo-controlled trial done in ten specialised headache centres in Germany. Patients with episodic cluster headaches who were aged between 18 and 65 years and within a current pain episode for not more than 30 days, received 100 mg oral prednisone for 5 days followed by tapering of 20 mg every 3 days, or matching placebo (17 days total exposure). All patients received oral verapamil for long-term prevention, starting with 40 mg three times daily and increasing to 120 mg three times daily by day 19; patients then continued with verapamil 120 mg throughout the study. Randomisation was computer-generated at a 1:1 ratio by use of an interactive web-response system, with stratification according to age, sex, and participating site. Participants, investigators, and those assessing outcomes were unaware of treatment allocation. The primary endpoint was the mean number of attacks within the first week of treatment with prednisone compared with placebo. An attack was defined as a unilateral headache with moderate-to-severe intensity of at least five on a numerical rating scale. All efficacy and safety analyses were done in the modified intention-to-treat (mITT) population, which consisted of all patients who had been randomly assigned to a trial group and received at least one dose of prednisone or placebo. The study was stopped early due to slow recruitment and expired funding. The study was registered with EudraCT (2011–006204–13) and with the German Clinical Trials Register (DRKS00004716).FindingsBetween April 5, 2013, and Jan 11, 2018, 118 patients were enrolled in the study. Two patients dropped out immediately and 116 patients were randomly assigned (57 patients to prednisone and 59 patients to placebo); 109 patients were included in the mITT analysis (53 patients assigned to prednisone and 56 patients assigned to placebo). Participants in the prednisone group had a mean of 7·1 (SD 6·5) attacks within the first week compared with 9·5 (6·0) attacks in the placebo group (difference −2·4 attacks, 95% CI −4·8 to −0·03; p=0·002). Two serious adverse events occurred, both in the placebo group (inguinal hernia and severe deterioration of cluster headache). A total of 270 adverse events were observed: in the prednisone group, 37 (71%) of 52 patients reported 135 adverse events (most common were headache, palpitations, dizziness, and nausea) and in the placebo group, 39 (71%) of 55 patients had 135 adverse events (most common were nausea, dizziness, and headache).InterpretationOral prednisone was an effective short-term preventive therapy in our population of patients with episodic cluster headache. Our findings support the use of prednisone as a first-line treatment in parallel to the up-titration of verapamil, although the efficacy of prednisone alongside other long-term prevention requires additional investigation.FundingGerman Federal Ministry for Education and Research.

ZUSAMMENFASSUNG Sekundäre Kopfschmerzen, die auf die Exposition, den Übergebrauch oder den Entzug einer Substanz zurückzuführen sind, sind in Kapitel 8 der 3. Auflage der Internationalen Klassifikation von Kopfschmerzerkrankungen (ICHD-3) aufgeführt. Es werden 3 Unterkapitel unterschieden: 8.1. Kopfschmerz zurückzuführen auf Substanzgebrauch oder Substanzexposition, 8.2. Kopfschmerz zurückzuführen auf einen Medikamentenübergebrauch und 8.3. Kopfschmerz zurückzuführen auf den Entzug einer Substanz. Ersterer – Kopfschmerz zurückzuführen auf Substanzgebrauch oder Substanzexposition – bezieht sich auf einen Kopfschmerz mit Beginn unmittelbar oder innerhalb von Stunden nach der Exposition. Hingegen ist der „Kopfschmerz zurückzuführen auf einen Medikamentenübergebrauch“ (MOH) definiert als ein Kopfschmerz, der an 15 oder mehr Tagen pro Monat bei Patienten mit einer vorbestehenden primären Kopfschmerzerkrankung auftritt und sich als Folge der regelmäßigen Einnahme akuter Kopfschmerzmedikamenten über einen Zeitraum von mehr als 3 aufeinanderfolgende Monate entwickelt hat. Bezüglich letzterem, ist der Entzug von Koffein, Östrogen und Opioiden am häufigsten mit der Entwicklung von Kopfschmerzen assoziiert. Der vorliegende Artikel soll einen Überblick über die neuesten Erkenntnisse zur Klassifikation, Pathophysiologie und zu Behandlungsstrategien dieser sekundären Kopfschmerzentitäten geben und legt den Schwerpunkt dabei auf die Unterkapitel 8.1 und 8.2. der ICHD-3-Klassifikation.

Chronic hepatitis C virus (HCV) infection is a highly prevalent systemic disease, which can cause a variety of neurological complications. The HCV-associated symptoms can be differentiated into central and peripheral nervous systems as well as the musculature. Important pathomechanisms are HCV-associated autoimmunity (e.g. mixed cryoglobulinemia with polyneuropathy) and direct neurotoxic effects of the virus (e.g. HCV-associated cognitive deficits). Distal symmetric polyneuropathies, small fiber neuropathies and cognitive deficits are the most prevalent neurological manifestations. Furthermore, HCV infection is a risk factor for ischemic and hemorrhagic stroke as well as Parkinson's disease. As HCV infection has become a permanently curable disease in >90% of patients, early identification and antiviral treatment of HCV positive patients is of utmost importance.

Objective The aim of this study was to collect and rate Green Flags, that is, symptoms or pieces of information indicating that a patient is more likely to suffer from a primary than from a secondary headache. Background When assessing headaches, a central question to be answered is whether the pain is primary or secondary to another disorder. To maximize the likelihood of a correct diagnosis, relevant signs and symptoms must be sought, identified, and weighed against each other. Methods The project was designed as a Delphi study. In the first round, an expert panel proposed green flags that were rated anonymously in two subsequent rounds. Proposals with an average rating of 4.0 and higher on a scale from 0 to 5 reached consensus. Results Five Green Flags reached consensus: (i) "The current headache has already been present during childhood"; (ii) "The headache occurs in temporal relationship with the menstrual cycle"; (iii) "The patient has headache-free days"; (iv) "Close family members have the same headache phenotype"; and (v) "Headache occurred or stopped more than one week ago." Conclusions We propose five Green Flags for primary headache disorders. None being a pathognomonic sign, we recommend searching for both Green Flags and Red Flags. If both are present, a secondary headache should be suspected. Overall, the application of the Green Flag concept in clinical practice is likely to increase diagnostic accuracy and improve diagnostic resource allocation. Prospective studies in clinical populations should be conducted to validate these Green Flags.