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Background and Purpose: HER-MES was the first head-to-head study of erenumab against topiramate (standard of care). This post hoc analysis of the HER-MES study evaluated the effect of erenumab versus topiramate on patient-reported outcomes at week 24., Methods: Adult patients with episodic or chronic migraine (n = 777) were randomized (1:1) to monthly subcutaneous erenumab (n = 389) or daily oral topiramate (n = 388). Migraine-related disability, as measured by the Headache Impact Test 6 (HIT-6) and Short Form 36 Health Survey version 2 (SF-36v2), was analysed in the entire study cohort and true completers., Results: In the erenumab group (vs. topiramate), significant improvements were reported in Headache Impact Test 6 total scores (composite populations, -10.88 vs. -7.72; true completers, -11.92 vs. -10.61) and a higher proportion of patients achieved a ≥5-point reduction from baseline with erenumab (composite populations, 72.2% vs. 53.9%; true completers, 79.64% vs. 71.43%). The adjusted mean change from baseline in the SF-36v2 score was greater with erenumab for both physical component summary (composite population, 5.48 vs. 3.63; true completers, 5.95 vs. 5.23) and mental component summary (composite populations, 1.00 vs. -1.18; true completers, 1.74 vs. -0.33). A higher proportion of patients on erenumab versus topiramate had a ≥5-point improvement in SF-36v2 for the physical component summary (composite populations, 47.7% vs. 37.4%; true completers, 52.1% vs. 48.9%) and mental component summary (composite populations, 25.3% vs. 16.8%; true completers, 27.3% vs. 17.7%)., Conclusions: This post hoc analysis demonstrated that patients treated with erenumab had significant improvements in headache impact and quality of life as measured by patient-reported outcomes versus patients treated with topiramate., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: To develop machine learning models using patient and migraine features that can predict treatment responses to commonly used migraine preventive medications., Background: Currently, there is no accurate way to predict response to migraine preventive medications, and the standard trial-and-error approach is inefficient., Methods: In this cohort study, we analyzed data from the Mayo Clinic Headache database prospectively collected from 2001 to December 2023. Adult patients with migraine completed questionnaires during their initial headache consultation to record detailed clinical features and then at each follow-up to track preventive medication changes and monthly headache days. We included patients treated with at least one of the following migraine preventive medications: topiramate, beta-blockers (propranolol, metoprolol, atenolol, nadolol, timolol), tricyclic antidepressants (amitriptyline, nortriptyline), verapamil, gabapentin, onabotulinumtoxinA, and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) (erenumab, fremanezumab, galcanezumab, eptinezumab). We pre-trained a deep neural network, "TabNet," using 145 variables, then employed TabNet-embedded data to construct prediction models for each medication to predict binary outcomes (responder vs. non-responder). A treatment responder was defined as having at least a 30% reduction in monthly headache days from baseline. All model performances were evaluated, and metrics were reported in the held-out test set (train 85%, test 15%). SHapley Additive exPlanations (SHAP) were conducted to determine variable importance., Results: Our final analysis included 4260 patients. The responder rate for each medication ranged from 28.7% to 34.9%, and the mean time to treatment outcome for each medication ranged from 151.3 to 209.5 days. The CGRP mAb prediction model achieved a high area under the receiver operating characteristics curve (AUC) of 0.825 (95% confidence interval [CI] 0.726, 0.920) and an accuracy of 0.80 (95% CI 0.70, 0.88). The AUCs of prediction models for beta-blockers, tricyclic antidepressants, topiramate, verapamil, gabapentin, and onabotulinumtoxinA were: 0.664 (95% CI 0.579, 0.745), 0.611 (95% CI 0.562, 0.682), 0.605 (95% CI 0.520, 0.688), 0.673 (95% CI 0.569, 0.724), 0.628 (0.533, 0.661), and 0.581 (95% CI 0.550, 0.632), respectively. Baseline monthly headache days, age, body mass index (BMI), duration of migraine attacks, responses to previous medication trials, cranial autonomic symptoms, family history of headache, and migraine attack triggers were among the most important variables across all models. A variable could have different contributions; for example, lower BMI predicts responsiveness to CGRP mAbs and beta-blockers, while higher BMI predicts responsiveness to onabotulinumtoxinA, topiramate, and gabapentin., Conclusion: We developed an accurate prediction model for CGRP mAbs treatment response, leveraging detailed migraine features gathered from a headache questionnaire before starting treatment. Employing the same methods, the model performances for other medications were less impressive, though similar to the machine learning models reported in the literature for other diseases. This may be due to CGRP mAbs being migraine-specific. Incorporating medical comorbidities, genomic, and imaging factors might enhance the model performance. We demonstrated that migraine characteristics are important in predicting treatment responses and identified the most crucial predictors for each of the seven types of preventive medications. Our results suggest that precision migraine treatment is feasible., (© 2024 American Headache Society.)

Objective: To compare calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) versus nonspecific oral migraine preventives (NOEPs)., Background: Insurers mandate step therapy with NOEPs before approving CGRP mAbs., Methods: Databases were searched for class I or II randomized controlled trials (RCTs) comparing CGRP mAbs or NOEPs versus placebo for migraine prevention in adults. The primary outcome measure was monthly migraine days (MMD) or moderate to severe headache days., Results: Twelve RCTs for CGRP mAbs, 5 RCTs for topiramate, and 3 RCTs for divalproex were included in the meta-analysis. There was high certainty that CGRP mAbs are more effective than placebo, with weighted mean difference (WMD; 95% confidence interval) of -1.64 (-1.99 to -1.28) MMD, which is compatible with small effect size (Cohen's d -0.25 [-0.34 to -0.16]). Certainty of evidence that topiramate or divalproex is more effective than placebo was very low and low, respectively (WMD -1.45 [-1.52 to -1.38] and -1.65 [-2.30 to -1.00], respectively; Cohen's d -1.25 [-2.47 to -0.03] and -0.48 [-0.67 to -0.29], respectively). Trial sequential analysis showed that information size was adequate and that CGRP mAbs had clear benefit versus placebo. Network meta-analysis showed no statistically significant difference between CGRP mAbs and topiramate (WMD -0.19 [-0.56 to 0.17]) or divalproex (0.01 [-0.73 to 0.75]). No significant difference was seen between topiramate or divalproex (0.21 [-0.45 to 0.86])., Conclusions: There is high certainty that CGRP mAbs are more effective than placebo, but the effect size is small. When feasible, CGRP mAbs may be prescribed as first-line preventives; topiramate or divalproex could be as effective but are less well tolerated. The findings of this study support the recently published 2024 position of the American Headache Society on the use of CGRP mAbs as the first-line treatment., (© 2024 American Headache Society.)

Background: Cortical spreading depolarization, the cause of migraine aura, is a short-lasting depolarization wave that moves across the brain cortex, transiently suppressing neuronal activity. Prophylactic treatments for migraine, such as topiramate or valproate, reduce the number of cortical spreading depression events in rodents., Objective: To investigate whether cortical spreading depolarization with and without chronic treatment with topiramate or valproate affect the DNA methylation of the cortex., Methods: Sprague-Dawley rats were intraperitoneally injected with saline, topiramate or valproate for four weeks when cortical spreading depolarization were induced and genome-wide DNA methylation was performed in the cortex of six rats per group., Results: The DNA methylation profile of the cortex was significantly modified after cortical spreading depolarization, with and without topiramate or valproate. Interestingly, topiramate reduced by almost 50% the number of differentially methylated regions, whereas valproate increased them by 17%, when comparing to the non-treated group after cortical spreading depolarization induction. The majority of the differentially methylated regions lay within intragenic regions, and the analyses of functional group over-representation retrieved several enriched functions, including functions related to protein processing in the cortical spreading depolarization without treatment group; functions related to metabolic processes in the cortical spreading depolarization with topiramate group; and functions related to synapse and ErbB, MAPK or retrograde endocannabinoid signaling in the cortical spreading depolarization with valproate group., Conclusions: Our results may provide insights into the underlying physiological mechanisms of migraine with aura and emphasize the role of epigenetics in migraine susceptibility.

Topiramate has multiple pharmacological mechanisms that are efficient in treating epilepsy and migraine. Ginger has been established to have gingerols and shogaols that cause migraine relief. Moreover, Topiramate has many off-label uses. Thus, it was necessary to explore the possible neurotoxicity of Topiramate and the role of ginger oil in attenuating the Topiramate neurotoxicity. Male albino mice were orally gavaged with Topiramate, ginger oil (400 mg/kg), and Topiramate plus ginger oil with the same pattern for 28 days. Oxidative stress markers, acetylcholinesterase (AchE), gamma-aminobutyric acid (GABA), and tumor necrosis factor-alpha (TNF-α) were examined. Histopathological examination, immunohistochemical glial fibrillary acidic protein (GFAP), and Bax expression analysis were detected. The GABAAR subunits, Gabra1, Gabra3, and Gabra5 expression, were assessed by RT-qPCR. The investigation showed that Topiramate raised oxidative stress markers levels, neurotransmitters, TNF-α, and diminished glutathione (GSH). In addition, Topiramate exhibited various neuropathological alterations, strong Bax, and GFAP immune-reactivity in the cerebral cortex. At the same time, the results indicated that ginger oil had no neurotoxicity. The effect of Topiramate plus ginger oil alleviated the changes induced by Topiramate in the tested parameters. Both Topiramate and ginger oil upregulated the mRNA expression of gabra1 and gabra3, while their interaction markedly downregulated them. Therefore, it could be concluded that the Topiramate overdose could cause neurotoxicity, but the interaction with ginger oil may reduce Topiramate-induced neurotoxicity and should be taken in parallel., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: HER-MES was the first head-to-head, phase 4 trial to assess the tolerability and effectiveness of erenumab against standard of care treatment (topiramate). This post hoc analysis compared the efficacy of erenumab with topiramate in patients who completed the trial on study medication., Methods: Post hoc sensitivity analysis was performed using the full analysis set. Outcomes assessed included the proportion of patients with a ≥50% reduction in monthly migraine days (MMD) from baseline (50% responder rate), over the last 3 months (months 4, 5, and 6) of the double-blind treatment phase (DBTP), the 50% responder rate during the first month of the DBTP, and change from baseline in MMD during the DBTP. Multiple imputation was done for efficacy values of patients who discontinued study treatment., Results: Patients (N = 777) were randomly assigned (1:1) to either 70 or 140 mg/month erenumab (N = 389) or 50-100 mg/day topiramate (N = 388). Of these, 334 patients (85.9%) receiving erenumab, and 231 patients (59.5%) receiving topiramate completed the DBTP on study medication. Patients on study medication until the end of the DBTP received a mean dose of 119 mg/month for erenumab and 92 mg/day for topiramate. At month 1, a significantly greater proportion of patients receiving erenumab (39.2%) reported ≥50% reduction in MMD from baseline compared with those receiving topiramate (24.0%; p < 0.001). In the last 3 months, a significantly larger proportion of patients receiving erenumab (60.3%) achieved ≥50% reduction in MMD from baseline compared with those receiving topiramate (43.3%; p < 0.001). Patients receiving erenumab demonstrated significantly greater reductions in MMD during the last 3 months from baseline versus those receiving topiramate (- 6.13 vs - 4.90; 95% CI: - 1.87 to - 0.61; p < 0.001)., Conclusions: This post hoc analysis demonstrated significantly superior efficacy of erenumab versus topiramate in achieving a ≥50% reduction in MMD with an early onset of efficacy., Trial Registration: ClinicalTrials.gov NCT03828539 ., (© 2022. The Author(s).)

Background: Head-to-head comparator trials between first-line oral migraine preventatives and the new monoclonal antibodies (mAbs) blocking the calcitonin gene-related peptide (CGRP) pathway have not been published to date., Objectives: This study aimed to indirectly compare the clinical efficacy and safety of mAbs against CGRP or its receptor (CGRPR) and topiramate in episodic migraine prophylaxis using meta-analysis., Methods: We included controlled trials testing efficacy and safety of erenumab, galcanezumab, fremanezumab, eptinezumab, and topiramate in adults diagnosed with episodic migraine. We searched PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from January 2000 to November 2020. We used the Risk of Bias 2 (RoB2) tool to assess the risk of bias and report pooled mean effects (mean difference and risk ratio) as estimated in a random effect model. For efficacy analysis, we determined the reduction of monthly migraine days (MMDs), reduction of days with acute medication (AMDs), and 50% responder rates (50% RR). For safety, we determined adverse events (AEs) occurring in ≥ 2% of study participants and the number of patients who discontinue treatment due to AEs (DAEs). The number needed to treat (NNT) and to harm (NNH) were estimated as well as the likelihood to help or harm (LLH)., Results: We included 13 trials involving 7557 patients: three trials with erenumab, two trials with galcanezumab, two trials with fremanezumab, one trial with eptinezumab, and five trials with topiramate, for the prophylaxis of episodic migraine in adults. The placebo-subtracted reduction (pooled mean difference) of MMDs were - 1.55 (95% CI - 1.86 to - 1.24; active drug n = 3326 vs placebo n = 2219, 8 studies) for the CGRP(R) mAb and - 1.11 (95% CI - 1.62 to - 0.59; active drug n = 1032 vs placebo n = 543, 4 studies) for topiramate (p for subgroup difference = 0.15). 'Cognitive' and 'sensory & pain'-related adverse events occurred more often in patients treated with topiramate compared with those treated with a CGRP(R) mAb (p for subgroup difference 0.03 and < 0.001, respectively). Based on the 50% RR and DAE, the NNT, NNH, and LHH for the CGRP(R) mAbs were 6, 130, and 24.3:1, respectively. For topiramate, these values were 7, 9, and 1.8:1, respectively., Conclusion: The efficacy of CGRP(R) mAbs to reduce migraine days does not differ from topiramate. However, the safety profile is in favor of the CGRP(R) mAbs, with a higher likelihood to help than to harm compared with topiramate. The diversity of endpoint determination and the heterogeneity between studies for some endpoints cause some limitations for this study., (© 2021. The Author(s).)