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Background: Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP mAb) and is used for migraine prophylaxis. Efficacy data are mainly from clinical trials, real-world data are hardly available yet. Reimbursement policy in Germany leads to eptinezumab mainly being used in patients having failed pre-treatment with other CGRP mAb. To date, it is unclear whether eptinezumab is efficacious and well tolerated in this population and how the treatment response differs from patients who are naive to CGRP mAbs., Methods: We analysed clinical routine data of 79 patients (episodic migraine (EM): n = 19; chronic migraine (CM): n = 60) from four different centres in Germany. All patients were treated with eptinezumab (100mg). Differences in monthly headache (MHD), migraine (MMD) and acute medication days (AMD) after three months were analysed. The correlation of response with the number of CGRP mAb failures was evaluated. Significance level has been corrected (alpha = 0.017)., Results: After three months MHD, MMD and AMD were significantly reduced. In EM, the median reduction for MHD was 4.0 days (IQR: -6.5 to -1.0; p = 0.001), for MMD 3.0 days (IQR: -5.5 to -1.5; p < 0.001) and for AMD 2.0 days (IQR: -5.0 to -0.5; p = 0.006). In CM, median reduction of MHD was 4 days (IQR: -8.0 to 0.0; p < 0.001), 3.0 days (IQR: -6.0 to-1.0; p < 0.001) for MMD and 1.0 day (IQR: -5.0 to 0.0; p < 0.001) for AMD. All patients were resistant to conventional preventive therapies and most to CGRP mAbs. Fourteen patients had never received a CGRP mAb and 65 patients had received at least one mAb without sufficient effectiveness and/or intolerability (one: n = 20, two: n = 28, three: n = 17). There was a significant association between the number of prior therapies and the 30% MHD responder rate (none: 78.6%, one: 45.0%, two: 32.1%, three: 23.5%, p = 0.010). Regarding tolerability, 10.4% (8/77) reported mild side effects., Conclusions: The effectiveness of eptinezumab is significantly reduced in patients who have not previously responded to other CGRP mAbs. However, limitations such as the retrospective nature of the analysis, the small sample size and the short treatment period with only the lower dose of eptinezumab must be considered when interpreting the results., (© 2024. The Author(s).)

Background: Neuroinflammation and maladaptive neuroplasticity play pivotal roles in migraine (MIG), trigeminal autonomic cephalalgias (TAC), and complex regional pain syndrome (CRPS). Notably, CRPS shares connections with calcitonin gene-related peptide (CGRP) in its pathophysiology. This study aims to assess if the documented links between CRPS and MIG/TAC in literature align with clinical phenotypes and disease progressions. This assessment may bolster the hypothesis of shared pathophysiological mechanisms., Methods: Patients with CRPS (n = 184) and an age-/gender-matched control group with trauma but without CRPS (n = 148) participated in this case-control study. Participant answered well-established questionnaires for the definition of CRPS symptoms, any headache complaints, headache entity, and clinical management., Results: Patients with CRPS were significantly more likely to suffer from migraine (OR: 3.23, 95% CI 1.82-5.85), TAC (OR: 8.07, 95% CI 1.33-154.79), or non-classified headaches (OR: 3.68, 95% CI 1.88-7.49) compared to the control group. Patients with MIG/TAC developed CRPS earlier in life (37.2 ± 11.1 vs 46.8 ± 13.5 years), had more often a central CRPS phenotype (60.6% vs. 37.0% overall) and were three times more likely to report allodynia compared to CRPS patients with other types of headaches. Additionally, these patients experienced higher pain levels and more severe CRPS, which intensified with an increasing number of headache days. Patients receiving monoclonal antibody treatment targeting the CGRP pathway for headaches reported positive effects on CRPS symptoms., Conclusion: This study identified clinically relevant associations of MIG/TAC and CRPS not explained by chance. Further longitudinal investigations exploring potentially mutual pathomechanisms may improve the clinical management of both CRPS and primary headache disorders., Trial Registration: German Clinical Trials Register (DRKS00022961)., (© 2023. The Author(s).)

Background: Numerous but inconclusive findings have sparked an ongoing debate about whether the arteries of migraine patients undergo vascular alterations. The outlet angle of the superior cerebellar artery (SUCA) and the lateral displacement of basilar arteries are good surrogate parameters for determining elongation of the vertebrobasilar arteries., Methods: We retrospectively determined the SUCA outlet angle and the lateral displacement of the basilar artery in 63 patients with migraine (30.6 ± 8.9 years, 84% women, 16% chronic migraine, 60% migraine with aura) and compared these with 126 age- and sex-matched control subjects., Results: In patients with migraine, the SUCA outlet angle was lower (159 ± 26° vs. 169 ± 29°, p = 0.020) and the lateral displacement of the basilar artery was greater (3.7 ± 2.7 mm vs. 2.8 ± 2.4 mm, p = 0.020) than in the control subjects. Age, gender, migraine characteristics and presence of any cardiovascular risk factors did not affect the SUCA outlet angle or lateral displacement of the basilar artery., Conclusion: Migraine patients exhibited a lower SUCA outlet angle and greater lateral displacement of the basilar arteries. Both may be attributable to the elongation of the vertebrobasilar arteries, which is an indication of arterial wall pathology in migraine., (© 2022. The Author(s).)

Background & Objectives: Calcitonin gene-related peptide ligand/receptor (CGRP) antibodies effectively reduce headache frequency in migraine. It is understood that they act peripherally, which raises the question whether treatment merely interferes with the last stage of headache generation or, alternatively, causes secondary adaptations in the central nervous system and might thus possess disease modifying potential. This study addresses this question by investigating the nociceptive blink reflex (nBR), which is closely tied to central disease activity, before and after treatment with CGRP antibodies., Methods: We enrolled 22 patients suffering episodic migraine (21 female, 46.2 ± 13.8 years of age) and 22 age-/gender-matched controls. Patients received assessments of the nBR (R2 component, 10 trials, 6 stimuli/trial) before (V0) and three months (V3) after treatment with CGRP antibodies started, controls were assessed once. The R2 area (R2a) and habituation (R2h; gradient of R2a against stimulus order) of the stimulated/non-stimulated side (&#95;s/&#95;ns) following repeated supraorbital stimulation provide a direct readout of brainstem excitability and habituation as key mechanisms in migraine., Results: All patients showed a substantial reduction of headache days/month (V0: 12.4±3.3, V3: 6.6 ± 4.9). R2a&#95;s (F global =5.86, p<0.001; block 1: R2a&#95;s: -28%, p<0.001) and R2a&#95;ns (F global =8.22, p<0.001, block 1: R2a&#95;ns: -22%, p=0.003) were significantly decreased, and R2h&#95;ns was significantly enhanced (F global =3.07, p<0.001; block 6: R2h&#95;ns: r=-1.36, p=0.007) from V0 to V3. The global test for changes of R2h&#95;s was non-significant (F global =1.46, p=0.095). Changes of R2h significantly correlated with improvement of headache frequency (R2h&#95;s, r=0.56, p=0.010; R2h&#95;ns: r=0.45, p=0.045). None of the nBR parameters assessed at baseline predicted treatment response., Discussion: We provide evidence that three months of treatment with CGRP antibodies restores brain stem responses to painful stimuli and thus might be considered disease modifying. The nociceptive blink reflex may provide a biomarker to monitor central disease activity. Future studies should evaluate the blink reflex as a clinical biomarker to predict treatment response at baseline and to establish the risk of relapse after treatment discontinuation., Trial Registration: This trial was prospectively registered at clinicaltrials.gov (ID: NCT04019496, date of registration: July 15, 2019)., (© 2021. The Author(s).)

Background: Although migraine is less common in older people, preventive treatment of migraine in these individuals may be more challenging due to the presence of multiple comorbidities and polypharmacy. Additionally, evidence for migraine treatment efficacy, safety, and tolerability is limited in this population. We evaluated efficacy, safety, and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), in clinical trial participants aged ≥60 years with episodic migraine (EM) or chronic migraine (CM)., Methods: This analysis included data from 3 randomized, double-blind, placebo-controlled phase 3 studies: the HALO EM study, HALO CM study, and FOCUS study in participants with EM or CM and prior inadequate response to 2-4 migraine preventive medication classes. Participants in all studies were randomized 1:1:1 to receive 12 weeks of subcutaneous treatment with quarterly fremanezumab (Months 1/2/3: EM/CM, 675 mg/placebo/placebo), monthly fremanezumab (Months 1/2/3: EM, 225 mg/225 mg/225 mg; CM, 675 mg/225 mg/225 mg), or matched monthly placebo., Results: These pooled analyses included 246 participants aged ≥60 years. Reductions in monthly migraine days from baseline over 12 weeks were significantly greater with fremanezumab (least-squares mean change from baseline [standard error]: quarterly fremanezumab, - 4.3 [0.59]; monthly fremanezumab, - 4.6 [0.54]) versus placebo (placebo, - 2.3 [0.57]; both P < 0.01 vs placebo). As early as Week 1, significant reductions from baseline in weekly migraine days were observed with fremanezumab versus placebo (both P < 0.01). With fremanezumab treatment versus placebo, a significantly higher proportion of participants achieved ≥50% reduction in monthly migraine days, and significant improvements in disability and quality-of-life outcomes were observed (P < 0.05). Proportions of participants experiencing serious adverse events and adverse events leading to discontinuation were low and similar in the fremanezumab and placebo groups. Efficacy and safety results were comparable to the overall pooled population (N = 2843)., Conclusions: This pooled subgroup analysis demonstrates that fremanezumab treatment is efficacious and well-tolerated over 12 weeks in participants aged ≥60 years with EM or CM. These data may help healthcare providers with clinical decision making and preventive treatment selection for older patients with migraine., Trial Registration: ClinicalTrials.gov identifiers: HALO CM: NCT02621931 ; HALO EM: NCT02629861 ; FOCUS: NCT03308968 ., (© 2021. The Author(s).)

Headache is frequent in patients with mitochondrial disorders. Previous studies point to a higher prevalence of headache in these patients than in the general population. As mitochondrial disorders often present a variety of other symptoms, the question arises how much the presence of headache really influences daily life. We performed a cross-sectional, questionnaire-based study investigation with 61 patients with a genetically proved mitochondrial disease mainly composed of CPEO phenotype. Headache was examined using a standardized questionnaire, and classified according to ICHD-2. Headache-related disability was evaluated by the Headache-Impact-Test-6 (HIT-6). Additionally, depression and anxiety were examined using the Hospital Anxiety and Depression Scale (HADS) and Short-Form-Health Survey (SF-12) was used to investigate the health-related quality of life. Headache was reported by 43/61 (70.5%) of the patients. 35/61 patients (57.4%) described a Tension-type headache (TTH) and 26 patients (42.6%) a migraine. Patients reporting headache had a significantly higher HIT-6 score than those without (mean: 54.47 vs. 38.47, p < 0.001). The HIT-6 score was significantly higher in patients reporting a migraine compared to those with a tension-type headache (mean: 62.13 vs. 46.18, p < 0.001). In the HADS score and in the SF-12 were not significantly influenced by the occurrence of headache. This study confirms the previously reported frequent occurrence of headache in a large cohort of patients with a confirmed mitochondrial disease. Migraine had the greatest impact on daily living, which appeared not to be confounded by depression and anxiety. Thus, we conclude that Migraine may be a substantial contributor for burden of disease in patients with mitochondrial diseases., (© 2021. The Author(s).)

Mitochondrial processes may play a role in the pathophysiology of migraine. Serum levels of two biomarkers, Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15), are typically elevated in patients with mitochondrial disorders. The study investigated whether the presence of migraine may influence FGF-21 and GDF-15 serum levels considering vascular and metabolic disorders as possible confounders. A cross-sectional study in two headache centers was conducted analyzing GDF-15 and FGF-21 serum concentration in 230 patients with episodic and chronic migraine compared to a control group. Key clinical features of headache were evaluated, as well as health-related life quality, anxiety and depression using SF-12 and HADS-questionnaires. Elevated GDF-15 values were detected in the migraine group compared to the control group (506.65 ± 275.87 pg/mL vs. 403.34 ± 173.29 pg/mL, p < 0.001, Mann-Whitney U test). A strong correlation between increasing age and higher GDF-15 levels was identified ( p < 0.001, 95%-CI elevation of GDF-15 per year 5.246-10.850 pg/mL, multiple linear regression). Mean age was different between the groups, and this represents a confounding factor of the measurements. FGF-21 levels did not differ between migraine patients and controls ( p = 0.635, Mann-Whitney U test) but were significantly influenced by increasing BMI ( p = 0.030, multiple linear regression). Neither biomarker showed correlation with headache frequency. Higher FGF-21 levels were associated with a higher mean intensity of headache attacks, reduced health-related life quality and anxiety. When confounding factors were considered, increased serum levels of FGF-21 and GDF-15 were not detected in migraine patients. However, the results show an age-dependence of GDF-15 in migraine patients, and this should be considered in future studies. Similar findings apply to the relationship between FGF-21 and BMI. Previous studies that did not adjust for these factors should be interpreted with caution.

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., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Key structures for the pathophysiology of primary headache disorders such as migraine, cluster headache, and other trigeminal autonomic cephalalgias were identified by imaging in the past years., Objective: Available data on functional imaging in primary headache disorders are summarized in this review., Material and Methods: We performed a MEDLINE search on December 27 th , 2020 using the search terms "primary headache" AND "imaging" that returned 453 results in English, out of which 137 were labeled reviews. All articles were evaluated for content and relevance for this narrative review., Results: The structure depicted most consistently using functional imaging in different states of primary headaches (without and with pain) was the posterior hypothalamus. Whole-brain imaging techniques such as resting-state functional resonance imaging showed a wide-ranging association of cortical and subcortical areas with human nociceptive processing in the pathophysiological mechanisms underlying the different TACs. Similarities of distinct groups of primary headache disorders, as well as their differences in brain activation across these disorders, were highlighted., Conclusion: The importance of neuroimaging research from clinical practice point of view remains the reliable and objective distinction of each individual pain syndrome from one another. This will help to make the correct clinical diagnosis and pave the way for better and effective treatment in the future. More research will be necessary to fulfill this unmet need., Competing Interests: None

Background: Calcitonin gene related peptide (CGRP) monoclonal antibodies (mAB) are the first specific migraine prophylactic medication. Erenumab is the only CGRP mAB targeting the CGRP receptor. Clinical data regarding efficacy and tolerability of erenumab in highly therapy-refractory patients are not available, yet, although many patients treated with CGRP mAB under real world conditions can be considered as highly therapy-refractory., Methods: Clinical routine data of highly therapy-refractory migraine patients treated with erenumab 70 mg for 3 months between November 2018 and December 2019 in the West German Headache Center, University Hospital Essen, Germany, were analysed. Monthly migraine days (MMD), monthly headache days (MHD) and days of acute medication intake (AMD) were assessed. Statistical analysis was performed using the Wilcoxon test. Descriptive statistics were performed to evaluate changes of vegetative symptoms, acute medication response, side effects, as well as treatment satisfaction., Results: Complete clinical data were available for 26 episodic (EM) and 74 chronic (CM) migraineurs. Sixty-six % (n = 49) of CM patients had an additional medication overuse headache (MOH). After 3 months 57.7% of EM patients and 41.9% of CM patients had a 50% or greater reduction of MMD. The mean number of MMD was reduced by 3.43 (SE 1.26) in EM, and by 4.72 (SE 0.87) in CM. Thirty-nine patients (52.7%) returned from chronic to episodic course of migraine. After 3 months, 23 patients (46.9%) were not suffering from a MOH anymore., Conclusions: Erenumab seems to be a promising therapeutic option in highly therapy-refractory migraine patients., Trial Registration: Retrospective registered.

Background: The combination of vertigo, dizziness and balance disturbance with migraine is called vestibular migraine. Although it is estimated that up to 1% of the population suffers from this disease, it is still widely unknown and often underdiagnosed. Recently, the International Headache Society and the Báràny Society published the first joint document with mutually accepted diagnostic criteria for vestibular migraine., Method: This review summarizes current knowledge on vestibular migraine with regard to epidemiology, clinical presentation, pathophysiology, differential diagnosis and therapeutic options., Results: Approximately 30-50% of patients with migraine report vertigo, dizziness or balance disturbances with at least one migraine attack. Vestibular migraine often appears in a temporal delay to the first onset of migraine headache. In some patients the symptom of sudden onset disequilibrium was the main complaint and more worrisome than the accompanying migraine headache. The duration of attacks varies from a few seconds up to few days. The underlying pathophysiology of vestibular migraine is still widely unknown. As an important differential diagnosis, Ménière's disease has to be considered and excluded., Conclusion: As randomized controlled treatment trials are still missing in vestibular migraine, the therapeutic recommendations for vestibular migraine are currently based on the guidelines of migraine., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Background: Vestibular migraine affects 1% of the general population, and 30%-50% of all migraine patients describe occasionally associated vertigo or dizziness. We aimed to identify brain regions altered in vestibular migraine in order to evaluate the connection between migraine and the vestibular system., Methods: Seventeen patients with definite vestibular migraine were compared to 17 controls using magnetic resonance imaging-based voxel-based morphometry., Results: We found grey matter (GM) volume reduction in the superior, inferior and middle (MT/V5) temporal gyrus as well as in the mid. cingulate, dorsolateral prefontal, insula, parietal and occipital cortex. A negative correlation of disease duration and GM volume was observed in areas associated with pain and vestibular processing. Moreover, there was a negative correlation between headache severity and prefrontal cortex volume., Conclusion: Alterations identified in vestibular migraine resemble those previously described for migraine, but also extend to areas involved in multisensory vestibular control and central vestibular compensation possibly representing the pathoanatomic connection between migraine and the vestibular system., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)