International Headache Society global practice recommendations for the acute pharmacological treatment of migraine.

BACKGROUND: In an effort to improve migraine management around the world, the International Headache Society (IHS) has here developed a list of practical recommendations for the acute pharmacological treatment of migraine. The recommendations are categorized into optimal and essential, in order to provide treatment options for all possible settings, including those with limited access to migraine medications. METHODS: An IHS steering committee developed a list of clinical questions based on practical issues in the management of migraine. A selected group of international senior and junior headache experts developed the recommendations, following expert consensus and the review of available national and international headache guidelines and guidance documents. Following the initial search, a bibliography of twenty-one national and international guidelines was created and reviewed by the working group. RESULTS: A total of seventeen questions addressing different aspects of acute migraine treatment have been outlined. For each of them we provide an optimal recommendation, to be used whenever possible, and an essential recommendation to be used when the optimal level cannot be attained. CONCLUSION: Adoption of these international recommendations will improve the quality of acute migraine treatment around the world, even where pharmacological options remain limited.

[CGRP: from neuropeptide to the therapeutic target (background and pathophysiology)]. / CGRP: vom Neuropeptid zum therapeutischen Target (Hintergründe und Pathophysiologie).

Calcitonin gene-related peptide (CGRP) plays a pivotal role in migraine pathophysiology. The importance of CGRP in migraine became evident from numerous clinical studies investigating CGRP levels both interictally and ictally and reports on the efficacy of CGRP-based migraine therapies. In this paper, the above mentioned studies will be presented and the reader will be introduced to the development of CGRP-based medication. Finally, current study results on CGRP receptor antagonists, the so-called gepants, will be presented.

Disability in cluster headache is more than attack frequency - results from and validation of the English version of the Cluster Headache Impact Questionnaire (CHIQ).

BACKGROUND: Cluster headache (CH) is associated with high disability. The Cluster Headache Impact Questionnaire (CHIQ) is a short, disease-specific disability questionnaire first developed and validated in German. Here, we validated the English version of this questionnaire. METHODS: The CHIQ was assessed together with nonspecific headache-related disability questionnaires in CH patients from a tertiary headache center and an American self-help group. RESULTS: 155 active episodic and chronic CH patients were included. The CHIQ showed good internal consistency (Cronbach's α = 0.91) and test-retest reliability (ICC = 0.93, n = 44). Factor analysis identified a single factor. Convergent validity was shown by significant correlations with the Headache Impact Test™ (HIT-6™, ρ = 0.72, p < 0.001), the Hospital Anxiety and Depression Scale (HADS depression: ρ = 0.53, HADS anxiety: ρ = 0.61, both p < 0.001), the Perceived Stress Scale (PSS-10, ρ = 0.61, p < 0.001) and with CH attack frequency (ρ = 0.29, p < 0.001). Chronic CH patients showed the highest CHIQ scores (25.4 ± 7.9, n = 76), followed by active episodic CH and episodic CH patients in remission (active eCH: 22.2 ± 8.7, n = 79; eCH in remission: 14.1 ± 13.1, n = 127; p < 0.001). Furthermore, the CHIQ was graded into 5 levels from "no to low impact" to "extreme impact" based on the patients' perception. Higher CHIQ grading was associated with higher attack and acute medication frequency, HIT-6™, HADS and PSS scores. CONCLUSION: The English version of the CHIQ is a reliable, valid, and disease-specific patient-reported outcome measure to assess the impact of headaches on CH patients.

[Consensus statement of the migraine and headache societies (DMKG, ÖKSG, and SKG) on the duration of pharmacological migraine prophylaxis]. / Konsensusstatement der Migräne- und Kopfschmerzgesellschaften (DMKG, ÖKSG & SKG) zur Therapiedauer der medikamentösen Migräneprophylaxe.

Migraine is the most common neurological disorder and can be associated with a high degree of disability. In addition to non-pharmacological approaches to reduce migraine frequency, pharmacological migraine preventatives are available. Evidence-based guidelines from the German Migraine and Headache Society (DMKG), and German Society for Neurology (DGN), Austrian Headache Society (ÖKSG), and Swiss Headache Society (SKG) are available for indication and application. For therapy-relevant questions such as the duration of a pharmacological migraine prevention, no conclusions can be drawn from currently available study data. The aim of this review is to present a therapy consensus statement that integrates the current data situation and, where data are lacking, expert opinions. The resulting current recommendations on the duration of therapy for pharmacological migraine prophylaxis are shown here.

[Consensus statement of the migraine and headache societies (DMKG, ÖKSG, and SKG) on the duration of pharmacological migraine prophylaxis]. / Konsensusstatement der Migräne- und Kopfschmerzgesellschaften (DMKG, ÖKSG & SKG) zur Therapiedauer der medikamentösen Migräneprophylaxe.

Migraine is the most common neurological disorder and can be associated with a high degree of disability. In addition to non-pharmacological approaches to reduce migraine frequency, pharmacological migraine preventatives are available. Evidence-based guidelines from the German Migraine and Headache Society (DMKG), and German Society for Neurology (DGN), Austrian Headache Society (ÖKSG), and Swiss Headache Society (SKG) are available for indication and application. For therapy-relevant questions such as the duration of a pharmacological migraine prevention, no conclusions can be drawn from currently available study data. The aim of this review is to present a therapy consensus statement that integrates the current data situation and, where data are lacking, expert opinions. The resulting current recommendations on the duration of therapy for pharmacological migraine prophylaxis are shown here.

Effect of antibody switch in non-responders to a CGRP receptor antibody treatment in migraine: A multi-center retrospective cohort study.

BACKGROUND: Switching between antibody classes might be a treatment option in migraine patients who have not responded to one class of a CGRP-(receptor) monoclonal antibody (mAb), but there are no efficacy data so far. In this real-world analysis, we assessed the treatment response to a CGRP-mAb in patients that have previously failed the CGRP-receptor-mAb erenumab. METHODS: We analyzed retrospective headache diary data of 78 patients with migraine who switched between CGRP-mAbs classes at four German headache centers either due to lack of efficacy or intolerable side effects. Among these, we identified 25 patients who did not respond to erenumab after three treatment cycles (defined as <30% reduction of monthly headache days) and had complete headache documentation at least one month before and during both treatments. We assessed the ≥30% responder rate at month three after switching from erenumab to a CGRP-mAb (galcanezumab or fremanezumab) (primary endpoint). Secondary endpoints included ≥50% responder rate, monthly headache days, and monthly days with acute medication use. In an exploratory subgroup analysis patients were stratified for daily and non-daily headache. RESULTS: The switch from erenumab to a CGRP-mAb led to a ≥30% response in one-third (32%) of the patients after three treatment cycles. A ≥50% response was achieved in 12% of the patients. Monthly headache days were reduced in month three compared to baseline (20.8 ± 7.1 to 17.8 ± 9.1; p = 0.009). Stratified analysis revealed that no patient with daily headache (n = 9) responded to the treatment switch, while a 30% response was achieved by 50% of patients with non-daily headache (n = 16). CONCLUSION: Our findings demonstrate that a relevant proportion of erenumab non-responders might benefit from a treatment switch to a CGRP-mAb. Switching seems to be a promising treatment option especially in migraine patients with non-daily headache.

Cluster Headache Impact Questionnaire (CHIQ) - a short measure of cluster headache related disability.

BACKGROUND: Cluster headache (CH) is a severe, highly disabling primary headache disorder. However, there is little research on CH-related disability, and most of it is based on non CH-specific questionnaires. The aim of this study was to develop a short, CH-specific disability questionnaire. METHODS: The 8-item Cluster Headache Impact Questionnaire (CHIQ) was developed based on a literature review and patient and expert interviews. The questionnaire was tested in 254 CH patients (171 males; 47.5 ± 11.4 years; 111 chronic CH, 85 active episodic CH, 52 episodic CH in remission) from our tertiary headache center or from a German support group. RESULTS: Reliability and validity of the CHIQ was evaluated in active episodic and chronic CH patients (n = 196). Internal consistency (Cronbach's α = 0.88) and test-retest reliability (ICC 0.91, n = 41) were good. Factor analysis identified a single factor. Convergent validity was shown by significant correlations with the Headache Impact Test (HIT-6, r = 0.58, p < 0.001), subscales of the depression, anxiety and stress scales (DASS, r = 0.46-0.62; p < 0.001) and with CH attack frequency (r = 0.41; p < 0.001). CHIQ scores significantly differentiated between chronic CH (25.8 ± 6.5), active episodic CH (23.3 ± 6.9) and episodic CH patients in remission (13.6 ± 11.9, p < 0.05 for all 3 comparisons). CONCLUSIONS: The CHIQ is a short, reliable, valid, and easy to administer measure of CH-related disability, which makes it a useful tool for clinical use and research.

Baseline tear fluid CGRP is elevated in active cluster headache patients as long as they have not taken attack abortive medication.

BACKGROUND: Calcitonin gene-related peptide plays a key role in cluster headache pathophysiology. It is released from the trigeminal nerve, which also innervates the eye. In this study, we tested if tear fluid calcitonin gene-related peptide measurement detects elevated calcitonin gene-related peptide levels in cluster headache patients compared to controls. METHODS: Calcitonin gene-related peptide concentration in tear fluid and plasma of 16 active episodic and 11 chronic cluster headache patients (all outside acute attacks) and 60 controls were assessed using ELISA. RESULTS: Cluster headache patients without use of attack abortive medication in the last 48 h showed significantly elevated tear fluid calcitonin gene-related peptide levels (1.78 ± 1.57 ng/ml, n = 17) compared to healthy controls (0.79 ± 0.74 ng/ml, p = 0.003) and compared to cluster headache patients who had used attack abortive medication in the last 48 h (0.84 ± 1.40 ng/ml, n = 10, p = 0.022). High calcitonin gene-related peptide levels in cluster headache patients were independent of the occurrence of a cluster headache attack in the last 48 hours (no attack: 1.95 ± 1.65 ng/ml, n = 8; attack: 1.63 ± 1.59 ng/ml, n = 9, p = 0.82) as long as no acute medication was used. No significant difference in tear fluid calcitonin gene-related peptide levels between episodic (1.48 ± 1.34 ng/ml) and chronic cluster headache patients (2.21 ± 1.88 ng/ml, p = 0.364) was detected. In contrast to these results in tear fluid, there were no significant group differences in plasma calcitonin gene-related peptide levels. CONCLUSION: This study shows that active cluster headache patients have increased calcitonin gene-related peptide levels in tear fluid compared to healthy subjects, which are reduced to control levels after intake of attack abortive medication. Calcitonin gene-related peptide measurement in tear fluid is non-invasive, and has the advantage of allowing direct access to calcitonin gene-related peptide released from the trigeminal nerve.

[Post-dural puncture headache]. / Postpunktioneller Kopfschmerz.

Post-dural puncture headache belongs to the group of secondary headache disorders and is a typical complication of intended or unintended dural puncture. The main symptom is orthostatic headache, which can be accompanied by neurological symptoms such as diplopia depending on the extent of the cerebrospinal fluid leak. The course of this headache is predominantly benign, showing spontaneous improvement over a couple of days, although severe cases are described in the literature. The following article provides an overview of the current knowledge about the headache's pathophysiology, diagnostic work-up and therapy.

[Post-dural puncture headache]. / Postpunktioneller Kopfschmerz.

Post-dural puncture headache belongs to the group of secondary headache disorders and is a typical complication of intended or unintended dural puncture. The main symptom is orthostatic headache, which can be accompanied by neurological symptoms such as diplopia depending on the extent of the cerebrospinal fluid leak. The course of this headache is predominantly benign, showing spontaneous improvement over a couple of days, although severe cases are described in the literature. The following article provides an overview of the current knowledge about the headache's pathophysiology, diagnostic work-up and therapy.

Effect of calcitonin gene-related peptide (-receptor) antibodies in chronic cluster headache: Results from a retrospective case series support individual treatment attempts.

OBJECTIVE: To assess the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor in chronic cluster headache (CCH) treatment under real world conditions. BACKGROUND: Calcitonin gene-related peptide has an important pathophysiological role in cluster headache. Although the randomised controlled trial with the calcitonin gene-related peptide antibody galcanezumab was negative, chronic cluster headache patients with insufficient response to other preventive treatments have been receiving individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies. METHODS: Data from 22 chronic cluster headache patients who received at least one dose of a calcitonin gene-related peptide(-receptor) antibody and recorded attack frequency in a headache diary were retrospectively collected at eight headache centres. RESULTS: The number of previous preventive therapies was 6.5 ± 2.4 (mean ± standard deviation, range: 2-11). The average number of attacks per week was 23.3 ± 16.4 at baseline and significantly decreased by -9.2 ± 9.7 in the first month of treatment with a calcitonin gene-related peptide(-receptor) antibody (p < 0.001). Fifty-five percent of the patients were 50% responders and 36% were 75% responders with respect to attack frequency. Significant reduction of attack frequency started at week 1 (-6.8 ± 2.8 attacks, p < 0.01). Results were corroborated by significant decreases in weekly uses of acute headache medication (-9.8 ± 7.6, p < 0.001) and pain intensity during attacks (-1.2 ± 2.0, numerical rating scale (NRS) [0-10], p < 0.01) in the first month. In months 2 (n = 14) and 3 (n = 10), reduction of attack frequency from baseline was -8.0 ± 8.4 (p = 0.004) and -9.1 ± 10.0 (p = 0.024), respectively. CONCLUSION: Under real-world conditions, individual treatment with calcitonin gene-related peptide(-receptor) antibodies was effective in 55% of our chronic cluster headache patients. This finding supports individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies in chronic cluster headache patients insufficiently responding to other therapies.

[Migraine prophylaxis-all just antibodies? : Medical and nonmedical migraine preventive treatment in times of CGRP antibodies]. / Migräneprophylaxe ­ alles nur noch Antikörper? : Medikamentöse und nicht-medikamentöse Migräneprophylaxe in Zeiten der CGRP-Antikörper.

BACKGROUND: Migraine is a frequently underdiagnosed disease that is associated with a high burden on affected patients. There are a variety of prophylactic treatment options available, that have been expanded with the introduction of the CGRP-(receptor-)antibodies. OBJECTIVES: Status of pharmacologic and nonpharmacologic preventive treatment in migraine therapy. METHODS: Analysis and evaluation of internationally published articles concerning preventive treatment of episodic and chronic migraine. RESULTS: There are many approved medications for migraine prophylaxis with different evidence. The possibilities were further expanded with CGRP antibodies. Comparative studies of the new antibodies with previous prophylactic drugs have not yet been published, so it's unclear whether the antibodies are therapeutically superior. What should be emphasized is their rapid onset of action and their good tolerance. Basically, an individual choice of prophylaxis, which is based on affectedness, comorbidities and comedication, makes sense. In addition, a combination with nondrug measures is always mandatory. CONCLUSIONS: A variety of medicinal and non-medicinal measures are available for the treatment of migraine, which should be used multimodally.

[Drug-induced reversible cerebral vasoconstriction syndrome : Ustekinumab as possible trigger?] / Medikamenteninduziertes reversibles zerebrales Vasokonstriktionssyndrom : Ustekinumab als möglicher Auslöser?

The reversible cerebral vasoconstriction syndrome (RCVS) is a common cause of thunderclap headache. Many trigger factors, such as the intake of vasoactive and less commonly immunosuppressive medication have previously been described. This article reports the first case of the occurrence of RCVS after the intake of ustekinumab in a female patient with a history of Crohn's disease.

Calcitonin gene-related peptide levels in tear fluid are elevated in migraine patients compared to healthy controls.

BACKGROUND: Calcitonin gene-related peptide (CGRP) released from trigeminal nerve fibres indicates trigeminal activation and has a key role in migraine pathophysiology. The trigeminal nerve directly innervates the eye. Therefore, in this study, we compared Calcitonin gene-related peptide in tear fluid of migraine patients and healthy controls. METHODS: Calcitonin gene-related peptide concentrations in tear fluid and plasma of 48 episodic and 45 chronic migraine patients and 48 controls were assessed using ELISA. RESULTS: Calcitonin gene-related peptide levels in tear fluid (0.94 ± 1.11 ng/ml) were ∼140 times higher than plasma concentrations (6.81 ± 4.12 pg/ml). Tear fluid CGRP concentrations were elevated in interictal migraine patients (1.10 ± 1.27 ng/ml, n = 49) compared to controls (0.75 ± 0.80 ng/ml, p = 0.022). There was no difference in tear fluid CGRP levels between interictal episodic and chronic migraine patients (episodic: 1.09 ± 1.47 ng/ml, n = 30 and chronic: 1.10 ± 0.89 ng/ml, n = 19) and no correlation of tear fluid CGRP levels with headache frequency in interictal patients (rho = 0.062, p = 0.674). Unmedicated ictal migraine patients had even more elevated tear fluid CGRP levels than interictal migraine patients (1.92 ± 1.84 ng/ml, n = 13, p = 0.102), while medicated ictal migraine patients had lower levels (0.56 ± 0.47 ng/ml, n = 25, p = 0.011 compared to interictal patients), which were undistinguishable from controls (p = 0.609). In contrast to tear fluid, no significant group differences were found in plasma CGRP levels. CONCLUSION: To the best of our knowledge, this study shows, for the first time, increased CGRP tear fluid levels in migraine patients compared to healthy subjects. Detection of calcitonin gene-related peptide in tear fluid is non-invasive, and likely allows a more direct access to CGRP released from the trigeminal nerve than plasma sampling.

PACAP38 and PAC1 receptor blockade: a new target for headache?

Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is a widely distributed neuropeptide involved in neuroprotection, neurodevelopment, nociception and inflammation. Moreover, PACAP38 is a potent inducer of migraine-like attacks, but the mechanism behind this has not been fully elucidated.Migraine is a neurovascular disorder, recognized as the second most disabling disease. Nevertheless, the antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor are the only prophylactic treatment developed specifically for migraine. These antibodies have displayed positive results in clinical trials, but are not effective for all patients; therefore, new pharmacological targets need to be identified.Due to the ability of PACAP38 to induce migraine-like attacks, its location in structures previously associated with migraine pathophysiology and the 100-fold selectivity for the PAC1 receptor when compared to VIP, new attention has been drawn to this pathway and its potential role as a novel target for migraine treatment. In accordance with this, antibodies against PACAP38 (ALD 1910) and PAC1 receptor (AMG 301) are being developed, with AMG 301 already in Phase II clinical trials. No results have been published so far, but in preclinical studies, AMG 301 has shown responses comparable to those observed with triptans. If these antibodies prove to be effective for the treatment of migraine, several considerations should be addressed, for instance, the potential side effects of long-term blockade of the PACAP (receptor) pathway. Moreover, it is important to investigate whether these antibodies will indeed represent a therapeutic advantage for the patients that do not respond the CGRP (receptor)-antibodies.In conclusion, the data presented in this review indicate that PACAP38 and PAC1 receptor blockade are promising antimigraine therapies, but results from clinical trials are needed in order to confirm their efficacy and side effect profile.

Blocking CGRP in migraine patients - a review of pros and cons.

Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patients exceeds the cons.

Diagnostic accuracy and confounders of vagus nerve ultrasound in amyotrophic lateral sclerosis-a single-center case series and pooled individual patient data meta-analysis.

BACKGROUND: Several single-center studies proposed utility of vagus nerve (VN) ultrasound for detecting disease severity, autonomic dysfunction, and bulbar phenotype in amyotrophic lateral sclerosis (ALS). However, the resulting body of literature shows opposing results, leaving considerable uncertainty on the clinical benefits of VN ultrasound in ALS. METHODS: Relevant studies were identified up to 04/2024 and individual patient data (IPD) obtained from the respective authors were pooled with a so far unpublished cohort (from Munich). An IPD meta-analysis of 109 patients with probable or definite ALS (El Escorial criteria) and available VN cross-sectional area (CSA) was performed, with age, sex, ALS Functional Rating Scale-revised (ALSFRS-R), disease duration, and bulbar phenotype as independent variables. RESULTS: Mean age was 65 years (± 12) and 47% of patients (± 12) had bulbar ALS. Mean ALSFRS-R was 38 (± 7), and mean duration was 18 months (± 18). VN atrophy was highly prevalent [left: 67% (± 5), mean CSA 1.6mm2 (± 0.6); right: 78% (± 21), mean CSA 1.8 mm2 (± 0.7)]. VN CSA correlated with disease duration (mean slope: left - 0.01; right - 0.01), but not with ALSFRS-R (mean slope: left 0.004; mean slope: right - 0.002). Test accuracy for phenotyping bulbar vs. non-bulbar ALS was poor (summary receiver operating characteristic area under the curve: left 0.496; right 0.572). CONCLUSION: VN atrophy in ALS is highly prevalent and correlates with disease duration, but not with ALSFRS-R. VN CSA is insufficient to differentiate bulbar from non-bulbar ALS phenotypes. Further studies are warranted to analyze the link between VN atrophy, autonomic impairment, and survival in ALS.