Plasma calcitonin gene-related peptide levels in idiopathic intracranial hypertension: an exploratory study.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a debilitating condition characterized by increased intracranial pressure often presenting with chronic migraine-like headache. Calcitonin gene-related peptide (CGRP) plays an important pathophysiological role in primary headaches such as migraine, whilst its role in IIH has not yet been established. METHODS: This longitudinal exploratory study included patients with IIH, episodic migraine (EM) in a headache-free interval and healthy controls (HC). Blood samples were collected from a cubital vein and plasma CGRP (pCGRP) levels were measured by standardized ELISA. RESULTS: A total of 26 patients with IIH (mean age 33.2 years [SD 9.2], 88.5% female, median BMI 34.8 kg/m2 [IQR 30.0-41.4]), 30 patients with EM (mean age 27.6 years [7.5], 66.7% female) and 57 HC (mean age 25.3 years [5.2], 56.1% female) were included. pCGRP levels displayed a wide variation in IIH as well as in EM and HC on a group-level. Within IIH, those with migraine-like headache had significantly higher pCGRP levels than those with non-migraine-like headache (F(2,524) = 84.79; p < 0.001) and headache absence (F(2,524) = 84.79; p < 0.001) throughout the observation period, explaining 14.7% of the variance in pCGRP levels. CGRP measurements showed strong intraindividual agreement in IIH (ICC 0.993, 95% CI 0.987-0.996, p < 0.001). No association was found between pCGRP levels and ophthalmological parameters. CONCLUSIONS: Although interindividual heterogeneity of pCGRP levels is generally high, migraine-like headache seems to be associated with higher pCGRP levels. CGRP may play a role in the headache pathophysiology at least in a subgroup of IIH.

Early Vascular Ageing in adolescents with migraine with aura: a community-based study.

BACKGROUND: Migraine with aura is associated with an increased risk of cardiovascular disease, yet the pathophysiology is unknown. Suggested underlying mechanisms of aura formation point into the direction of an abnormal vasoreactivity that also extends to the extracranial vasculature. METHODS: In the Early Vascular Ageing Tyrol study, a community-based non-randomized controlled trial conducted in 45 schools and companies in Tyrol (Austria) and South-Tyrol (Italy) between May 2015 and September 2018 aiming to increase cardiovascular health in adolescents, headache syndromes were classified according to the International Classification of Headache Disorders in a face-to-face interview. Carotid-femoral pulse-wave-velocity was measured by applanation tonometry and carotid intima-media-thickness by high-resolution ultrasound of the distal common carotid arteries. Differences in pulse-wave-velocity and carotid intima-media-thickness in youngsters with migraine with aura were compared respectively to those without headache and with other headaches by multivariable linear regression analysis. RESULTS: Of the 2102 study participants 1589 were aged 14 to 19 (mean 16.8) years and had complete data. 43 (2.7%) reported migraine with aura and 737 (46.4%) other headaches. Mean pulse-wave-velocity was 6.17 m/s (± 0.85) for migraine with aura, 6.06 m/s (± 0.82) for all other headaches and 6.15 (0.95) m/s for participants without headaches. Carotid intima-media-thickness was 411.3 µm (± 43.5) for migraine with aura, 410.9 µm (± 46.0) for all other headaches and 421.6 µm (± 48.4) for participants without headaches. In multivariable linear regression analysis, we found no differences in carotid-femoral pulse-wave-velocity or carotid intima-media-thickness in young subjects with migraine with aura, all other headaches, or no headaches. CONCLUSIONS: In line with previous large-scale studies in adults, we could not demonstrate relevant associations of migraine with aura with markers of arterial stiffness or subclinical atherosclerosis making early vascular ageing an unlikely pathophysiological link between migraine with aura and cardiovascular diseases. TRIAL REGISTRATION: First registered on ClinicalTrials.gov 29/04/2019 (NCT03929692).

Real-world effectiveness of fremanezumab in patients with migraine switching from another mAb targeting the CGRP pathway: a subgroup analysis of the Finesse Study.

BACKGROUND: Monoclonal antibodies targeting the CGRP pathway are effective and safe for prophylactic treatment of episodic (EM) and chronic migraine (CM). In case of treatment failure of a CGRP pathway targeting mAb, physician has to decide whether using another anti-CGRP pathway mAb is useful. This interim analysis of Finesse Study evaluates effectiveness of the anti-CGRP mAb fremanezumab in patients with a history of other prior anti-CGRP pathway mAb treatments (switch patients). METHODS: FINESSE, a non-interventional, prospective, multicentre, two-country (Germany-Austria) study observing migraine patients receiving fremanezumab in clinical routine. This subgroup analysis presents data on documented effectiveness over 3 months after the first dose of fremanezumab in switch patients. Effectiveness was evaluated based on reduction in average number of migraine days per month (MMDs), MIDAS and HIT-6 scores changes as well as in number of monthly days with acute migraine medication use. RESULTS: One hundred fifty-three out of 867 patients with a history of anti-CGRP pathway mAb treatment prior to initiation of fremanezumab were analysed. Switch to fremanezumab led to ≥ 50% MMD reduction in 42.8% of migraine patients, with higher response rate in EM (48.0%) than in CM patients (36.5%). A ≥ 30% MMD reduction was achieved by 58.7% in CM patients. After three months, monthly number of migraine days decreased by 6.4 ± 5.87 (baseline: 13.6 ± 6.5; p < 0.0001) in all patients, 5.2 ± 4.04 in EM and 7.7 ± 7.45 in CM patients. MIDAS scores decreased from 73.3 ± 56.8 (baseline) to 50.3 ± 52.9 (after 3 months; p = 0.0014), HIT-6 scores decreased from 65.9 ± 5.0 to 60.9 ± 7.2 (p < 0.0001). Concomitant use of acute migraine medication had decreased from 9.7 ± 4.98 (baseline) to 4.9 ± 3.66 (3 months) (p < 0.0001). CONCLUSIONS: Our results show that about 42.8% of anti-CGRP pathway mAb-non-responder benefit from switching to fremanezumab. These results suggest that switching to fremanezumab may be a promising option for patients experiencing poor tolerability or inadequate efficacy with prior other anti-CGRP pathway mAb use. TRIAL REGISTRATION: FINESSE Study is registered on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS44606).

Monoclonal antibodies against CGRP (R): non-responders and switchers: real world data from an austrian case series.

OBJECTIVE: Assessement of the responder and non-responder rate to consecutive monoclonal CGRP-antibody (CGRP-mAb) treatment, the presence of side effects, analysis of predictors of response and loss-of-effectiveness evaluation over time. METHODS: We conducted a retrospective analysis including 171 patients with episodic (EM) or chronic migraine (CM), who received one, two or three different CGRP-mAbs. Non-response was defined as ≤ 50% reduction of monthly migraine days (MMDs) in EM and ≤ 30% reduction of MMDs in CM after 3 months of treatment. RESULTS: 123 (71.9%) responded to the first mAb. Side effects led to treatment discontinuation in 9 (5.3%) patients. Of the 26 patients who did not respond to the first mAb or experienced a loss of efficacy over time, 11 (42.3%) responded to the second and two (28.6%) of 7 to the third monoclonal antibody. Poor response to therapy was associated with a higher monthly migraine frequency (p = 0.028), a higher number of prior preventive migraine therapies (p = 0.011) and medication overuse (p = 0.022). CONCLUSION: Our findings support mAb-class switch in non-responders or in patients experiencing a loss of effectiveness. The use of a third CGRP-mAb could be beneficial for some patients.

Primary headache types in adult epilepsy patients.

BACKGROUND: Headache is among the most common comorbidities in epilepsy. This study examined the distribution of different primary headache disorders in a large cohort of patients with diagnosed epilepsy. Headache types were analysed with regard to gender, type of epilepsy and antiepileptic drugs (AEDs). METHODS: In this prospective single-centre study, 500 patients with epilepsy (250 female, mean age: 45.52 ± 17.26 years) were evaluated with regards to primary headache types using a validated German headache questionnaire categorizing for migraine (MIG), tension-type headache (TTH) or trigeminal autonomic cephalalgias (TAC), their combinations and unclassifiable headache. Data regarding type of epilepsy, seizure-associated headache, AED treatment and seizure freedom were collected. RESULTS: Of 500 patients with epilepsy, 163 (32.6%) patients (108 female and 55 male) reported suffering from headaches at least 1 day per month. MIG (without aura, with aura) and TTH were the most frequent headache type (MIG 33.1%, TTH 33.1%). Female epilepsy patients reported headaches significantly more often than male patients (x2 = 8.20, p = 0.0042). In contrast, the type of epilepsy did not significantly affect headache distribution. Of 163 patients with headache, 66 (40.5%) patients reported seizure-associated headache and AEDs were used by 157 patients. Of importance, patients with AED monotherapy suffered from MIG less often when compared to patients on polytherapy (x2 = 4.79, p = 0.028). CONCLUSION: MIG and TTH are the most common headache types in epilepsy patients and headache is more frequent among female epilepsy patients. Monotherapy in AEDs might have a beneficial effect on the frequency of headache compared to polytherapy.

Is prednisone still a reasonable option in the treatment of withdrawal headache in patients with chronic migraine and medication overuse headache in the age of CGRP antibodies? A narrative review.

OBJECTIVE: Along with the development of novel migraine therapies as the monoclonal antibodies against calcitonin gene-related peptide (CGRP) and its receptor, the question arises if the treatment of chronic migraine (CM) and medication overuse headache (MOH) must be reconsidered. Have previous therapeutic approaches, including glucocorticoids, lost their role in the management of this debilitating disorder? In this narrative review, we present an overview of the available treatment options in CM and MOH in light of CGRP antibodies as well as an evaluation of the role of glucocorticoids in withdrawal therapy. BACKGROUND: Chronic migraine and medication overuse continues to be a difficult to treat condition. To date, potent treatment options are scarce and algorithms for advising patients with MOH are often still based on expert consensus rather than evidence-based medicine. For years and probably due to lack of effective alternatives, glucocorticoids have been used in MOH, especially to alleviate withdrawal symptoms caused by detoxification. Small case series report positive effects of steroids in this respective patient group; however, randomized controlled trials did not show a consistent benefit, although this may be due to methodological limitations. Because of these discrepancies, their role in MOH has been under debate ever since. METHODS: We searched the electronic database PubMed for articles up to June 1, 2022 on the use of glucocorticoids in CM and MOH. CONCLUSION: Despite popular use in clinical practice, there is currently still no scientific evidence for the efficacy of glucocorticoids in patients with CM and MOH. Treatment with monoclonal antibodies achieved high transition rates from medication overuse to non-overuse. However, further research is needed to evaluate the additional benefit of these new agents.

Case report: Monoclonal CGRP-antibody treatment in a migraine patient with a mutation in the mitochondrial single-strand binding protein (SSBP1).

Background: There is a growing body of mitochondrial disorders that are associated with headaches, albeit only one of them is currently listed in the latest International Classification of Headache Disorders, 3rd edition (ICHD-3). Headache frequency and headache presentation can vary widely in this respective patient group. Acute and preventive migraine treatment can be quite challenging-the use of several established medications is often limited due to their side effects in the setting of mitochondrial dysfunction and multi-organ disease. Case presentation: Along with a review of the literature on treatment options in patients with mitochondrial disorders and migraine headaches, we present the case of a 23-year-old male with a homozygous mutation in the mitochondrial single-strand binding protein (SSBP1) with chronic migraine with aura. After failing several standard of care prophylactics due to either side effects or inefficacy, he was successfully treated with a monoclonal anti-CGRP-antibody as a preventive migraine treatment. The monoclonal antibody was well tolerated and showed adequate efficacy with a sustained > 50% reduction in monthly headache days after 3 years of treatment. Conclusion: Migraine is often challenging to treat in patients with mitochondriopathy due to therapy-limiting comorbidities. Monoclonal CGRP-antibodies might be a safe treatment option in the prevention of migraine headaches in patients with a mitochondrial disorder.

Hypoxia-related mechanisms inducing acute mountain sickness and migraine.

Experimental models of human diseases are vital for pathophysiological and therapeutic research. To investigate the initiation, maintenance, pathophysiology and even termination of a migraine/headache attack these models are urgently needed. Results from different studies promote the profound involvement of hypoxia in migraine and other primary/secondary headaches. The possible mechanisms that drive the induction of headaches through hypoxia are still unknown, but several modes of action, such as increased blood flow, dilation of cerebral arteries, the release of nitroglycerin, calcitonin gene-related peptide and adenosine or increased oxygen extraction are discussed intensively. In studies exposing healthy volunteers and people with a history of migraine to controlled normobaric hypoxia, our research group could demonstrate normobaric hypoxia to be an effective trigger of migraine headaches. Furthermore, a longitudinal measurement of calcitonin gene-related peptide (CGRP), during a hypoxic challenge in migraine patients, revealed increasing CGRP levels with prolonged hypoxic challenge. Since GRP has been linked to migraine and other headache disorders, hypoxia could be regarded as initiator for headaches on a neurotransmitter basis. Furthermore, it has been known for more than 2 decades from studies in vitro and in vivo that hypoxia can induce cortical spreading depression, a phenomenon believed to represent aura. Considering the increased prevalence of migraine in altitude populations and the solid pathophysiological changes on cellular and neurotransmitter level-the role of hypoxia should be investigated in greater detail by the headache community.

Short Report of Longitudinal CGRP-Measurements in Migraineurs During a Hypoxic Challenge.

Background: Calcitonin gene related peptide (CGRP) plays a key role in the pathophysiology of migraine and is therefore considered a potential biomarker for primary headache disorders. The challenge remaining is establishing standardized protocols for its assessment in various extracellular compartments and identifying pathological situations associated with an increase in CGRP. Methods: We performed longitudinal measurements of CGRP plasma levels in 30 volunteers with the diagnosis of episodic migraine with and without aura under controlled circumstances during an induced migraine attack under a hypoxic challenge. Blood samples were collected from a cubital vein and CGRP plasma levels measured using ELISA. Results: CGRP levels varied significantly between the subjects at baseline (15.48-1,889.31 pg/ml) but were neither associated with socio-demographic data nor with headache/migraine frequency or intensity collected before hypoxic exposure. CGRP levels during hypoxia fluctuated around baseline and increased with prolonged hypoxia but did not differ significantly in subjects with migraine or headache compared to those without. However, subjects experiencing migraine without aura showed significantly higher levels than those with aura. Ictal CGRP levels were increased in females, in subjects with a negative family history regarding headaches, in those older than 30 years of age or with a recent headache attack before the experiment (p < 0.05). Conclusion: CGRP plasma levels seem to be highly variable even at baseline in migraine patients and increased during hypoxic challenge and migraine attacks. This is the first in human longitudinal measurement of peripheral CGRP levels during induced migraine attacks using a highly standardized protocol.

Investigating the Migraine Cycle over 21 Consecutive Days Using Proton Magnetic Resonance Spectroscopy and Resting-State fMRI: A Pilot Study.

Recent neuroimaging studies have revealed important aspects of the underlying pathophysiological mechanisms of migraine suggesting abnormal brain energy metabolism and altered functional connectivity. Proton magnetic resonance spectroscopy (1H-MRS) studies investigated migraine patients in the interictal or ictal state. This first-of-its-kind study aimed to investigate the whole migraine cycle using 1H-MRS and resting-state functional magnetic resonance imaging (fMRI). A migraine patient underwent 1H-MRS and resting-state fMRI for 21 consecutive days, regardless of whether he was in an interictal or ictal state. Metabolite ratios were assessed and compared to the intrinsic connectivity of subcortical brain areas. Probable migraine phase-dependent changes in N-acetyl aspartate (NAA)/total creatine (tCr) and choline (Cho)/tCr levels are found in the left occipital lobe and left basal ganglia. NAA reflects neuronal integrity and Cho cellular membrane turnover. Such abnormalities may increase the susceptibility to excitatory migraine triggers. Functional connectivity between the right hippocampus and right or left pallidum was strongly correlated to the NAA/Cho ratio in the right thalamus, suggesting neurochemical modulation of these brain areas through thalamic connections. To draw statistically significant conclusions a larger cohort is needed.

Primary headache disorders in adolescents in North- and South-Tyrol: Findings of the EVA-Tyrol-Study.

OBJECTIVE: Assessment of the prevalence of primary headache disorders, associated risk factors and use of acute/preventive medication in a representative large sample of adolescents. METHODS: Within the EVA-Tyrol project, a community-based non-randomized controlled cross-sectional study, data was collected from adolescents aged 14-19 years from 45 sites across North-, East- and South Tyrol. Headaches were classified according to the latest ICHD-3 and assessed by headache specialists in face-to-face interviews. FINDINGS: Of 1923 participants 930 (48.4%) reported having headaches. Female to male ratio was 2:1. Migraine, tension-type headache and other headache were diagnosed in 10%, 30.2% and 8.2% respectively. Medication overuse was diagnosed in 3.4%, increasing up to 21.7% in participants with chronic headache. The use of preventative medication was not reported by any adolescent. Sleep disturbances (p < 0.05), alcohol consumption (p < 0.05), low physical activity (p < 0.01) and high screen time exposure (p < 0.01) were associated with an increased risk of headaches. CONCLUSION: We report high prevalence of primary headache disorders and medication overuse in a large community-based sample of teenagers. Acute and preventive non-drug and pharmacological treatments are not established due to lack of paediatric headache outpatient clinics. Promoting health education in teenagers and encouraging public awareness, including that of health care providers is pivotal.Trial registration: EVA-Tyrol has been retrospectively registered at clinicaltrials.gov under https://clinicaltrials.gov/ct2/show/NCT03929692 since April 29, 2019.

Head/neck pain characteristics after spontaneous cervical artery dissection in the acute phase and on a long-run.

OBJECTIVE: Head/neck pain is one of the primary symptoms associated with spontaneous cervical artery dissection. Still, data on pain quality, intensity, and long-term dynamics are scarce. METHODS: Spontaneous cervical artery dissection subjects were included if mural hematoma was visualised through T1 fat-saturated MRI at baseline. All available medical records were evaluated and patients were invited to standardised clinical follow-up visits at least 1 year after the index event. RESULTS: In total, 279 subjects were included in the ReSect-study with head/neck pain being the most frequent symptom of spontaneous cervical artery dissection (220 of 273, 80.6%). Pain was of pulling nature in 107 of 218 (49.1%), and extended to the neck area in 145 of 218 (66.5%). In those with prior headache history, pain was novel in quality in 75.4% (42 of 55). Median patient-reported pain intensity was 5 out of 10 with thunderclap-type headache being uncommon (12 of 218, 5.5%). Prior to hospital admission, head/neck pain rarely responded to self-medication (32 of 218, 14.7%). Characteristics did not differ between subjects with and without cerebral ischemia. Pain resolved completely in all subjects within a median of 13.5 days (IQR 12). Upon follow-up in 42 of 164 (25.6%) novel recurring headache occurred, heterogeneous in quality, localisation and intensity. CONCLUSION: We present an in-depth analysis of spontaneous cervical artery dissection-related head/neck pain characteristics and its long-term dynamics.

Repetitive T1 Imaging Influences Gray Matter Volume Estimations in Structural Brain Imaging.

Voxel-based morphometry (VBM) is a widely used tool for studying structural patterns of brain plasticity, brain development and disease. The source of the T1-signal changes is not understood. Most of these changes are discussed to represent loss or possibly gain of brain gray matter and recent publications speculate also about non-structural changes affecting T1-signal. We investigated the potential of pain stimulation to ultra-short-term alter gray matter signal changes in pain relevant brain regions in healthy volunteers using a longitudinal design. Immediately following regional nociceptive input, we detected significant gray matter volume (GMV) changes in central pain processing areas, i.e. anterior cingulate and insula cortex. However, similar results were observed in a control group using the identical time intervals but without nociceptive painful input. These GMV changes could be reproduced in almost 100 scanning sessions enrolling 72 healthy individuals comprising repetitive magnetization-prepared rapid gradient-echo (MPRAGE) sequences. These data suggest that short-term longitudinal repetitive MPRAGE may produce significant GMV changes without any intervention. Future studies investigating brain plasticity should focus and specifically report a consistent timing at which time-point during the experiment the T1-weighted scan is conducted. There is a necessity of a control group for longitudinal imaging studies.

CGRP measurements in human plasma - a methodological study.

BACKGROUND: Calcitonin gene-related peptide plasma levels have frequently been determined as a biomarker for primary headaches. However, published data is often inconsistent resulting from different methods that are not precisely described in most studies. METHODS: We applied a well-proven enzyme-linked immunosorbent assay to measure calcitonin gene-related peptide concentrations in human blood plasma, we modified parameters of plasma preparation and protein purification and used calcitonin gene-related peptide-free plasma for standard solutions, which are described in detail. RESULTS: Calcitonin gene-related peptide levels are stable in plasma with peptidase inhibitors and after deep-freezing. Calcitonin gene-related peptide standard solutions based on synthetic intercellular fluid or pooled plasma with pre-absorbed calcitonin gene-related peptide influenced the measurements but yielded both comprehensible results. In a sample of 56 healthy subjects the calcitonin gene-related peptide plasma levels varied considerably from low (<50 pg/mL) to very high (>500 pg/mL) values. After a 12-hour exposure of these subjects to normobaric hypoxia the individual calcitonin gene-related peptide levels remained stable. CONCLUSION: Buffering with peptidase inhibitors and immediate freezing or processing of plasma samples is essential to achieve reliable measurements. Individuals show considerable differences and partly high calcitonin gene-related peptide plasma levels without detectable pathological reason. Thus plasma measurements are suited particularly to follow calcitonin gene-related peptide levels in longitudinal studies.The use of data for this study was approved by the Ethics Committee of the MedicalUniversity of Innsbruck (https://www.i-med.ac.at/ethikkommission/; EK Nr: 1242/2017).

Reduction in acute migraine-specific and non-specific medication use in patients treated with erenumab: post-hoc analyses of episodic and chronic migraine clinical trials.

BACKGROUND: In patients with migraine, overuse of acute medication, including migraine-specific medication (MSM) such as triptans and ergots, can lead to adverse health outcomes, including development of medication overuse headache. Here, we examined the effect of erenumab on reducing acute medication use, in particular MSM, in patients with episodic migraine (EM) and chronic migraine (CM). METHODS: The current post-hoc analyses were based on data from the double-blind treatment phase (DBTP) of two erenumab studies, a pivotal EM (N = 955) and a pivotal CM (N = 667) trial, and their respective extensions. Patients were administered subcutaneous placebo or erenumab (70 or 140 mg) once monthly. Daily acute headache medication use (including MSM and non-MSM) was recorded using an electronic diary during a 4-week pretreatment baseline period until the end of the treatment period. Outcome measures included change in monthly acute headache medication days (HMD) in acute headache medication users at baseline, and changes in monthly MSM days (MSMD) in MSM users at baseline and non-MSMD in non-MSM users at baseline. RESULTS: In total, 60 and 78 % of patients (all acute headache medication users) with EM and CM used MSM at baseline, respectively. For acute headache medication users, the change in mean monthly acute HMD over Months 4, 5 and 6 compared with the pre-DBTP was 1.5, 2.5, and 3.0 for placebo, erenumab 70 mg and 140 mg, respectively for the EM study. The respective change in monthly MSMD in MSM users was 0.5, 2.1 and 2.8, and in monthly non-MSMD in non-MSM users was 2.3, 2.6, and 2.7. In the acute headache medication users at baseline, the change in monthly acute HMD at Month 3 compared with pre-DBTP was 3.4, 5.5, and 6.5 for placebo, erenumab 70 mg and 140 mg, respectively for the CM study. The respective change in monthly MSMD in MSM users was 2.1, 4.5, and 5.4, and in monthly non-MSMD in non-MSM users was 5.9, 6.4, and 6.6. Reductions in MSMD versus placebo were sustained in the extension periods of both studies. Erenumab was also associated with a higher proportion of MSM users achieving ≥ 50 %, ≥ 75 and 100 % reduction from baseline in monthly MSMD versus placebo in both EM and CM. CONCLUSIONS: In both EM and CM, treatment with erenumab is associated with a significant and sustained reduction in the use of acute headache medication, in particular MSM. TRIAL REGISTRATIONS: NCT02456740; NCT02066415; NCT02174861.

CGRP-antibodies, topiramate and botulinum toxin type A in episodic and chronic migraine: A systematic review and meta-analysis.

BACKGROUND: The approval of monoclonal antibodies for prevention of migraine has revolutionized treatment for patients. Oral preventatives are still considered first line treatments as head-to-head trials comparing them with antibodies are lacking. METHODS: The main purpose of this study was to provide a comparative overview of the efficacy of three commonly prescribed migraine preventative medication classes. For this systematic review and meta-analysis, we searched the databases CENTRAL, EMBASE, and MEDLINE until 20 March 2020. We included RCTs reporting the 50% response rates for topiramate, Botulinum Toxin Type A and monoclonal antibodies against CGRP(r). Studies were excluded if response rates were not reported, treatment allocation was unclear, or if study quality was insufficient. Primary outcome measure were the 50% response rates. The pooled odds ratios with 95% confidence intervals were calculated with the random effects model. The study was registered at PROSPERO (CRD42020222880). FINDINGS: We identified 6552 reports. Thirty-two were eligible for our review. Studies assessing monoclonal antibodies included 13,302 patients and yielded pooled odds ratios for the 50% response rate of 2.30 (CI: 2.11-2.50). Topiramate had an overall effect estimate of 2.70 (CI: 1.97-3.69) with 1989 included patients and Botulinum Toxin Type A achieved 1.28 (CI: 0.98-1. 67) with 2472 patients included. INTERPRETATION: Topiramate, botulinum toxin type A and monoclonal antibodies showed higher odds ratios in achieving a 50% response rate compared to placebo. Topiramate numerically demonstrated the greatest effect size but also the highest drop-out rate.

Zonisamide as treatment option in persistent migraine aura.

Persistent migraine aura without infarction is a rare but debilitating condition. Treatment options are mostly anecdotal and limited due to inefficacy and side effects. We present a 16-year-old female patient with triple X syndrome, having persistent aura symptoms for over 2 years, consisting of continuous visual and sensory sensations. Previous treatments with seven different migraine preventatives were not successful. The patient successfully responded to zonisamide against refractory prolonged aura and remained symptom-free under the ongoing treatment without any relevant side effects. Zonisamide may be considered a new and safe treatment option for patients with persistent migraine aura.

Brain temperature regulation in poor-grade subarachnoid hemorrhage patients - A multimodal neuromonitoring study.

Elevated body temperature (Tcore) is associated with poor outcome after subarachnoid hemorrhage (SAH). Brain temperature (Tbrain) is usually higher than Tcore. However, the implication of this difference (Tdelta) remains unclear. We aimed to study factors associated with higher Tdelta and its association with outcome. We included 46 SAH patients undergoing multimodal neuromonitoring, for a total of 7879 h of averaged data of Tcore, Tbrain, cerebral blood flow, cerebral perfusion pressure, intracranial pressure and cerebral metabolism (CMD). Three-months good functional outcome was defined as modified Rankin Scale ≤2. Tbrain was tightly correlated with Tcore (r = 0.948, p < 0.01), and was higher in 73.7% of neuromonitoring time (Tdelta +0.18°C, IQR -0.01 - 0.37°C). A higher Tdelta was associated with better metabolic state, indicated by lower CMD-glutamate (p = 0.003) and CMD-lactate (p < 0.001), and lower risk of mitochondrial dysfunction (MD) (OR = 0.2, p < 0.001). During MD, Tdelta was significantly lower (0°C, IQR -0.2 - 0.1; p < 0.001). A higher Tdelta was associated with improved outcome (OR = 7.7, p = 0.002). Our study suggests that Tbrain is associated with brain metabolic activity and exceeds Tcore when mitochondrial function is preserved. Further studies are needed to understand how Tdelta may serve as a surrogate marker for brain function and predict clinical course and outcome after SAH.

Refractory short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing responsive to anti-calcitonin gene-related peptide monoclonal antibodies: A case report.

BACKGROUND: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is a rare but severely disabling variant within the spectrum of trigeminal autonomic cephalalgia lacking evidence-based treatment. CASE: We report a case of chronic SUNCT in a 67-year-old man refractory to various guideline-conforming treatment attempts responding excellently to galcanezumab. CONCLUSIONS: This case report indicates that monoclonal antibodies against calcitonin gene-related peptide, specifically galcanezumab, might be a treatment option for SUNCT warranting further investigation.

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.