Restless legs-like syndrome as an emergent adverse event of CGRP monoclonal antibodies: A report of two cases

Background One of the advantages of CGRP monoclonal antibodies is their excellent safety and tolerability. However, postmarketing surveillance, is essential to detect potential rare emergent adverse events. Objectives To report two patients who developed restless legs syndrome symptoms after treatment with CGRP antibodies. Methods and results Two women with chronic refractory migraine, with no significant medical antecedents, developed typical restless legs syndrome symptoms 1.5 and 4 months after starting erenumab 140 mg, respectively. In case 1 symptoms resolved when erenumab was stopped for two months but reappeared on galcanezumab. In both patients migraine attacks had dramatically decreased and no iron deficiency was found. Conclusions Even though caution is needed before establishing a causal relationship, these cases suggest that restless legs-like symptoms might be an emergent adverse event of CGRP antibodies, regardless of the mechanism of action. We propose that plastic changes in CGRP sensory fibers, which are very abundant in legs, induced by CGRP monoclonal antibodies could be the reason for restless legs syndrome development.

Burden and attitude to resistant and refractory migraine: a survey from the European Headache Federation with the endorsement of the European Migraine & Headache Alliance

Background New treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions. Methods We conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care. Results There were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care. Conclusions This report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.

Additive Interaction Between Onabotulinumtoxin-A and Erenumab in Patients With Refractory Migraine

In the last decade, notable progresses have been observed in chronic migraine preventive treatments. According to the European Headache Federation and national provisions, onabotulinumtoxin-A (BTX-A) and monoclonal antibodies acting on the pathway of calcitonin gene–related peptide (CGRP-mAbs) should not be administered in combination due to supposed superimposable mechanism of action and high costs. On the other hand, preclinical observations demonstrated that these therapeutic classes, although operating directly or indirectly on the CGRP pathway, act on different fibers. Specifically, the CGRP-mAbs prevent the activation of the Aδ-fibers, whereas BTX-A acts on C-fibers. Therefore, it can be argued that a combined therapy may provide an additive or synergistic effect on the trigeminal nociceptive pathway. In the present study, we report a case series of 10 patients with chronic migraine who experienced significant benefits with the combination of both erenumab and BTX-A compared to each therapeutic strategy alone. A reduction in frequency and intensity of headache attacks (although not statistically significant probably due to the low sample size) was observed in migraine patients treated with a combined therapy with BTX-A and erenumab compared to both BTX-A and erenumab alone. Moreover, the combined therapy with BTX-A and erenumab resulted in a statistically significant reduction in the symptomatic drug intake and in migraine-related disability probably related to a reduced necessity or also to a better responsiveness to rescue treatments. Present data suggest a remodulation of current provisions depriving patients of an effective therapeutic strategy in peculiar migraine endophenotypes.

Randomized Controlled Study to Evaluate Prophylactic Properties of Ayurvedic Treatment Protocol in Refractory and Chronic Migraine Patients

Background: Migraine is a disorder marked by recurrent episodes of headache. There is a subset of migraine patients who remain refractory to the conventional prophylactic and abortive therapies. This study aimed to assess the therapeutic role of an ayurvedic treatment protocol in patients who had chronic/ refractory migraine. Methods: This single-center, open label, randomized, controlled clinical trial compared the efficacy of ayurvedic treatment protocol to conventional treatment. Included patients were 18-65 years of age and met the diagnostic criteria for chronic/ refractory migraine. The patients were randomized in a 1:1 ratio to the ayurvedic treatment or conventional therapy at the baseline and were followed at regular intervals for 360 days. The primary outcome was reduction in the number of headache days in the last 3 months and the secondary outcomes were a reduction in the visual analog scale (VAS) score and migraine disability assessment score (MIDAS) as compared to the baseline. Results: Patients (n=154) were randomized to the two treatment groups with similar baseline demographic and clinical characteristics. The patients in ayurvedic treatment group had a greater reduction in the number of headache days, VAS score and MIDAS score at day 360 (p<0.05). Further, there were no reported medication-related adverse effects in either group. Conclusion: Ayurvedic treatment protocol is well tolerated and is associated with significant improvement in symptoms of chronic refractory migraine.

Burden and Attitude to Resistant and Refractory Migraine A Survey From the European Headache Federation With the Endorsement of the European Migraine & Headache Alliance

BackgroundNew treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions. MethodsWe conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care. ResultsThere were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care. ConclusionsThis report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.

A trial of antithrombotic therapy in patients with refractory migraine and antiphospholipid antibodies: A retrospective study of 75 patients

Objective It has been reported that patients with antiphospholipid antibodies (aPL) and refractory migraine may experience symptomatic improvement with antithrombotic therapy, but this phenomenon has not been well studied. This study was undertaken to detail the response to trials of antithrombotic therapy in these patients. Methods This is a retrospective study of 75 patients with refractory migraine and aPL who were given a 2–4 week trial of aspirin, clopidogrel and/or anticoagulation. Major response was defined as 50–100% improvement in frequency and/or severity of migraine; minor response: 25–49% improvement; no response: <25% improvement. Results 66 patients were given a trial of aspirin: 47% responded (21% major); 60 patients were given a trial of clopidogrel: 83% responded (67% major); and 34 patients were given a trial of anticoagulation (usually apixaban): 94% responded (85% major). The response rate to any anti-thrombotic therapy was 89% (83% major). Many patients also noted improvement in non-headache symptoms. No patient experienced stroke. There was no major bleeding during any 2–4 week treatment trial and only 3 of 69 patients maintained on an antithrombotic regimen for a median follow up of 29.9 months (5–100) experienced major bleeding. Conclusions There was a high rate of symptomatic response to antithrombotic therapy in this context and long-term follow up suggested an individualized symptom-derived antithrombotic regimen may be associated with a low bleeding risk. Our data support consideration of a 2–4 week trial of antithrombotic therapy, usually starting with antiplatelet therapy, in aPL-positive patients with refractory migraine, particularly if other treatment options have been exhausted. As a retrospective study, our data provide only Class IV level of evidence, but they suggest randomized controlled trials are warranted to validate these encouraging findings.

Identification of predictors of response to Erenumab in a cohort of patients with migraine

Background: The migraine-specific monoclonal antibody Erenumab targeting the calcitonin gene related peptide receptor is an effective and well tolerated preventive treatment of episodic and chronic migraine. However, its price limits its use as a first line therapy against migraine. Therefore, identifying patients who will adequately respond to such treatment is paramount. Methods: In this retrospective, real-life cohort study, 172 adult patients with refractory episodic or chronic migraine treated with Erenumab were included. To identify the predictors of response to Erenumab, bivariate subgroup analysis of several potential factors was performed, and multivariate logistic regression modeling was done to obtain Odds Ratio (OR). Results: Of the 172 patients, 57.0% achieved a successful treatment response (reduction of monthly migraine days by ≥50%). Statistically significant predictors of a treatment response were the presence of chronic migraine, tension-type headache, and a positive response to triptan with an odd ratio of 0.473 (95% CI, 0.235–0.952), 0.485 (95% CI, 0.245–0.962) and 3.985 (95% CI, 1.811–8.770), respectively (P < 0.05). Conclusions: Successful Erenumab treatment response rate was 57.0% in this retrospective cohort. As chronic migraine and tension-type headache were negative predictors of Erenumab response while triptan response was a positive predictor, this data suggests the potential for Erenumab monotherapy without the need for traditional preventive treatment in refractory migraine sufferers improving side effect profile and treatment adherence for a cohort of patients difficult to treat.