Neuromodulation in migraine.

The International Neuromodulation Society defines therapeutic neuromodulation as the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body. Neuromodulation for the treatment of migraine is an evolving field offering further insight into the pathophysiology of migraine as well as advanced therapeutics. Central and peripheral neuronal targets have been explored in the efforts to reduce the frequency and severity of attacks. Invasive and noninvasive techniques have been developed, targeting either the central or peripheral nervous system. Noninvasive central neuromodulation techniques have the benefit of a low side effect profile in addition to higher level of evidence for use thanks to sham-controlled trials; however, these modalities are less clinically available for use. Noninvasive transcutaneous neuromodulation techniques that target the peripheral nervous system have provided devices that are available over the counter or by prescription. Several of these devices are effective for abortive and preventive treatment of migraine. Invasive techniques such as cranial nerve stimulation with implanted stimulator devices or spinal cord stimulation may be used for more aggressive management in patients refractory to other treatments. Overall, neuromodulation techniques can be particularly beneficial for medically complex or refractory patients, those that prefer nonmedication options, and those that have experienced adverse effects from medications.

Temporomandibular Disorders and Fibromyalgia Prevalence: A Systematic Review and Meta-Analysis.

PURPOSE: To evaluate the prevalence of chronic widespread pain (CWP) and fibromyalgia syndrome (FMS) in TMD patients and the prevalence of TMDs in patients with FMS. METHOD: A systematic search was performed in electronic databases. Studies published in English examining the prevalence of comorbid TMDs and CWP/FMS were included. The Newcastle-Ottawa Scale was used to assess study quality, and meta-analyses using defined diagnostic criteria were conducted to generate pooled prevalence estimates. RESULTS: Nineteen studies of moderate to high quality met the selection criteria. Meta-analyses yielded a pooled prevalence rate (95% CI) for TMDs in FMS patients of 76.8% (69.5% to 83.3%). Myogenous TMDs were more prevalent in FMS patients (63.1%, 47.7% to 77.3%) than disc displacement disorders (24.2%, 19.4% to 39.5%), while a little over 40% of FMS patients had comorbid inflammatory degenerative TMDs (41.8%, 21.9% to 63.2%). Almost a third of individuals (32.7%, 4.5% to 71.0%) with TMDs had comorbid FMS, while estimates of comorbid CWP across studies ranged from 30% to 76%. CONCLUSIONS: Despite variable prevalence rates among the included studies, the present review suggests that TMDs and CWP/FMS frequently coexist, especially for individuals with painful myogenous TMDs. The clinical, pathophysiologic, and therapeutic aspects of this association are important for tailoring appropriate treatment strategies.

Hemicrania Continua: An Update.

PURPOSE OF REVIEW: Hemicrania Continua (HC) is a rare and disabling primary headache disorder that is characterized by persistent, unilateral headache with ipsilateral, cranial autonomic symptoms and restlessness or agitation. The diagnosis requires patients to experience an absolute response to therapeutic doses of indomethacin. RECENT FINDINGS: HC is diagnosed in in about 1.8% of adult patients who were evaluated for headache in tertiary care services, albeit this estimate should be interpreted with caution. The most prevalent accompanying symptoms appear to be lacrimation, conjunctival injection and restlessness or agitation. However, the available literature is limited by methodologic issues, and the current diagnostic criteria lack clarity on what defines absolute response to indomethacin. More rigorous studies are thus needed to improve our understanding of HC which, in turn, will facilitate better disease management in clinical practice. Here, we provide a comprehensive overview of HC, including its epidemiology, clinical presentation, diagnostic evaluation, and management.

Long-Term Effect of Switching From an Anti-CGRP Receptor to an Anti-CGRP Ligand Antibody in Treatment-Refractory Chronic Migraine: A Prospective Real-World Analysis.

In migraine patients with a poor response to a calcitonin gene-related peptide monoclonal antibody against the receptor, switching to a calcitonin gene-related peptide monoclonal antibodies against the ligand may be beneficial. This was a long-term real-world prospective analysis conducted in treatment-refractory chronic migraine patients coming from two large tertiary referral headache centres, who did not achieve a meaningful response to erenumab and were switched to fremanezumab. Responders to fremanezumab were considered those who achieved at least 30% reduction in monthly migraine days by month 3, compared to the post-erenumab baseline. Secondary efficacy and disability outcomes were analysed. Thirty-nine patients (female n = 32, 82.1%; median age: 49 years old, IQR = 29.0-56.0) were included. After three months of treatment with fremanezumab, ten out of 39 patients (25.6%) were considered responders. Four of the 11 patients who continued fremanezumab became responders at month 6, increasing the number of responders to 14 patients (35.9%). Responders received a median of 12 injections (IQR = 9.0-18.0) at the time of the analysis. After the last treatment, 13 patients (33.3%) remained responders. The number of mean monthly migraine days significantly decreased from 21.4 at baseline (IQR = 10.7-30.0) to 8.6 (IQR = 3.8-13.9) at the last follow-up. Painkillers intake and HIT-6 score were significantly reduced at the last follow-up. About 1/3 of patients with treatment refractory chronic migraine who have a disappointing response to erenumab and switch to fremanezumab, obtained a meaningful and sustained improvement of their migraine load over time, supporting the appropriateness of this therapeutic approach in clinical practice.

Eptinezumab improved patient-reported outcomes and quality of life in patients with migraine and prior preventive treatment failures.

BACKGROUND AND PURPOSE: In the phase 3b, randomized, double-blind, placebo-controlled DELIVER clinical trial, eptinezumab reduced migraine frequency and headache in adults with two to four prior preventive treatment failures. Here, the effect of eptinezumab on coinciding patient-reported outcomes is reported. METHODS: Adults were randomized to receive eptinezumab 100, 300 mg or placebo intravenously at weeks 12 and 24. The EQ-5D-5L, measuring overall patient health, and the six-item Headache Impact Test were completed every 4 weeks. The Patient Global Impression of Change was completed at weeks 4, 12 and 24. Patient-identified most bothersome symptom and the Migraine-Specific Quality of Life Questionnaire were administered at weeks 12 and 24. RESULTS: Eptinezumab improved patient-reported outcomes more than placebo, starting at week 4 and at all subsequent time points. By week 12, patients' overall health (EQ-5D-5L visual analog scale score) improved with eptinezumab treatment (difference from placebo in change from baseline: 100 mg, 5.1, 95% confidence interval [CI] 2.2, 8.1, p < 0.001; 300 mg, 7.5, 95% CI 4.5, 10.4, p < 0.0001). At week 12, eptinezumab improved headache-related quality of life (difference from placebo in change from baseline in Headache Impact Test total score: 100 mg, -3.8, 95% CI -5.0, -2.5, p < 0.0001; 300 mg, -5.4, 95% CI -6.7, -4.2, p < 0.0001), including each Migraine-Specific Quality of Life Questionnaire domain (p ≤ 0.0001, all comparisons). Over twice as many patients receiving eptinezumab than placebo reported much or very much improvement on the Patient Global Impression of Change and patient-identified most bothersome symptom. CONCLUSION: Patients with two to four prior preventive treatment failures receiving eptinezumab versus placebo reported greater improvements in well-being, quality of life and most bothersome symptoms compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04418765; EudraCT identifier: 2019-004497-25.

Effects of eptinezumab on self-reported work productivity in adults with migraine and prior preventive treatment failure in the randomized, double-blind, placebo-controlled DELIVER study.

BACKGROUND: The multinational phase 3b DELIVER trial was designed to evaluate the efficacy and safety of eptinezumab for migraine prevention in patients with prior preventive treatment failures across 17 countries. In the placebo-controlled portion, eptinezumab relative to placebo demonstrated greater reductions in migraine and headache frequency, migraine and headache severity, and acute medication use. The objective of this report is to describe the effects of eptinezumab on self-reported work productivity in the placebo-controlled portion of DELIVER. METHODS: Adults 18-75 years of age with migraine and documented evidence of 2 to 4 prior preventive treatment failures in the past 10 years were randomized to receive eptinezumab 100 mg, 300 mg, or placebo intravenously (IV) every 12 weeks. The Work Productivity and Activity Impairment questionnaire specific to migraine (WPAI:M), which comprises 6 items (4 of which are completed by currently employed patients only), was administered every 4 weeks. Changes from baseline in subscores (absenteeism, presenteeism, work productivity loss, and activity impairment) were calculated based on item responses. A mixed model for repeated measures was used to analyze changes from baseline in WPAI:M subscores. RESULTS: A total of 890 adults (mean age, 43.8 years) were included in the full analysis set (eptinezumab 100 mg, n = 299; eptinezumab 300 mg, n = 293; placebo, n = 298). Mean WPAI:M subscores at baseline indicated a negative impact of migraine attacks on work productivity and ability to complete normal daily activities. Eptinezumab improved WPAI:M subscores more than placebo at all assessment points throughout the study. Mean changes from baseline in self-reported work productivity loss were -19.5, -24.0, and -9.7 at Week 12; and -22.6, -20.2, and -7.2 at Week 24 (all P < 0.001 vs placebo) for eptinezumab 100 mg, eptinezumab 300 mg, and placebo, respectively. Mean changes from baseline in activity impairment were -21.3, -23.8, and -11.2 at Week 12; and -24.7, -22.6, and -10.1 at Week 24 (all P < 0.0001 vs placebo). Similarly, mean improvements in absenteeism and presenteeism were greater in the eptinezumab groups than in the groups receiving placebo at all timepoints (P < 0.05). CONCLUSION: In adults with migraine and prior preventive treatment failure, eptinezumab 100 mg and 300 mg IV every 12 weeks improved absenteeism, presenteeism, work productivity loss, and activity impairment more than placebo. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765 ); EudraCT (Identifier: 2019-004497-25) ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004497-25/PL ). Eptinezumab improves self-reported work productivity in patients with migraine and prior preventive treatment failures.

Two-year effectiveness of erenumab in resistant chronic migraine: a prospective real-world analysis.

BACKGROUND: Controlled and real-world evidence have demonstrated the efficacy of calcitonin gene related peptide (CGRP) monoclonal antibodies (MABs) in migraine. However, data on the over-one-year sustained effectiveness of CGRP MABs in resistant chronic migraine (CM) is sparse.  METHODS: This is a two-year real-world prospective analysis of an ongoing single centre audit conducted in patients with resistant CM. Patients received monthly erenumab for six months before assessing its effectiveness. Responders were considered those who achieved at least 30% reduction in monthly migraine days (MMD) by month 6, compared to baseline. Secondary outcomes were also analysed, including changes of the Headache Impact Test version 6 (HIT-6). RESULTS: One hundred sixty-four patients [135 (82.3%) females; mean age 46 SD 14) years] were included in the audit and 160 patients analysed. Patients had failed a mean of 8.4 preventive treatments at baseline. At month 6, 76 patients (48%) were 30% responders to erenumab, 50 patients (31%) were 50% responders and 25 (15%) were 75% responders. The mean reduction in MMD at month 6 was 7.5 days compared to baseline (P < 0.001). At month 12 and month 18, 61 patients (38%) and 52 patients (33%) remained 30% responders respectively. At month 24, 36 patients (23%) remained 30% responders, 25 patients (16%) and 13 patients (8%) were respectively 50% and 75% responders. Compared to 95% of patients at baseline, at months 6, 12 and 24, 46%, 29% and 16% of responders respectively had severe disability. At least one adverse event at month 6, 12, 18 and 24 was reported by 49%, 19%, 11% and 3% of patients. By month 6, 13% of patients discontinued the treatment because of side effects, often constipation. CONCLUSIONS: Long-term sustained effectiveness of erenumab was reported only by a minority of resistant CM patients. Although more research in resistant migraine is needed, Erenumab can provide long-term meaningful reduction in migraine load and migraine-related disability in some patients.

Excellent Response to OnabotulinumtoxinA: Different Definitions, Different Predictors.

The identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with <4 monthly headache days (frequency-based excellent responders). The characteristics of excellent responders at the baseline were compared with the ones of patients with a <30% decrease in monthly headache days. Percent-based excellent responders represented about 10% of the sample, whilst frequency-based excellent responders were about 5% of the sample. Compared with non-responders, percent-based excellent responders had a higher prevalence of medication overuse and a higher excellent response rate even after the 1st and the 2nd injection. Females were less like to be frequency-based excellent responders. Chronic migraine sufferers without medication overuse and of female sex may find fewer benefits with onabotulinumtoxinA. Additionally, the excellent response status is identifiable after the first cycle.

Fully Endoscopic Microvascular Decompression for Trigeminal Neuralgia: Technical Note Describing a Single-Center Experience.

BACKGROUND: Microscopic microvascular decompression (MVD) of the trigeminal nerve is the gold standard surgical treatment for medically refractory classical trigeminal neuralgia. Endoscopy has significantly advanced surgery and provides enhanced visualization of the cerebellopontine angle and its critical neurovascular structures. We present our initial experience of fully endoscopic microvascular decompression (e-MVD). METHODS: This retrospective case series investigated e-MVD performed from September 2016 to February 2020 at a single institution. Clinical data including presenting symptoms, medications, operative findings, postoperative complications, and outcomes were recorded. The 5-point Barrow Neurological Institute (BNI) pain intensity score was used to quantify patients' pain relief. RESULTS: During the study period, 25 patients with trigeminal neuralgia (10 males, 15 females; mean [SD] age = 63 [10.4] years) underwent e-MVD. All patients had a preoperative BNI score of V. The left side was affected in 15 patients. Complications occurred in 2 patients: both experienced hearing loss, and one experienced transient facial weakness 7 days after surgery. The facial weakness had resolved by the last follow-up. All patients were completely pain-free (BNI score I) immediately postoperatively. On latest follow-up, 22 patients have remained pain-free, and 3 patients have recurrent pain that is being controlled with medication (BNI score III). CONCLUSIONS: Our study demonstrated that e-MVD is a safe, possibly effective method of performing MVD with the added benefit of improved visualization of the operative field for the operating surgeon and the surgical team. Larger prospective studies are required to evaluate whether performing e-MVD confers any additional benefits in long-term clinical outcome of patients with trigeminal neuralgia.

Trigeminal microvascular decompression for short-lasting unilateral neuralgiform headache attacks.

A significant proportion of patients with short-lasting unilateral neuralgiform headache attacks are refractory to medical treatments. Neuroimaging studies have suggested a role for ipsilateral trigeminal neurovascular conflict with morphological changes in the pathophysiology of this disorder. We present the outcome of an uncontrolled open-label prospective single-centre study conducted between 2012 and 2020, to evaluate the efficacy and safety of trigeminal microvascular decompression in refractory chronic short-lasting unilateral neuralgiform headache attacks with MRI evidence of trigeminal neurovascular conflict ipsilateral to the pain side. Primary endpoint was the proportion of patients who achieved an 'excellent response', defined as 90-100% weekly reduction in attack frequency, or 'good response', defined as a reduction in weekly headache attack frequency between 75% and 89% at final follow-up, compared to baseline. These patients were defined as responders. The study group consisted of 47 patients, of whom 31 had short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, and 16 had short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (25 females, mean age ± SD 55.2 years ± 14.8). Participants failed to respond or tolerate a mean of 8.1 (±2.7) preventive treatments pre-surgery. MRI of the trigeminal nerves (n = 47 patients, n = 50 symptomatic trigeminal nerves) demonstrated ipsilateral neurovascular conflict with morphological changes in 39/50 (78.0%) symptomatic nerves and without morphological changes in 11/50 (22.0%) symptomatic nerves. Postoperatively, 37/47 (78.7%) patients obtained either an excellent or a good response. Ten patients (21.3%, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing = 7 and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms = 3) reported no postoperative improvement. The mean post-surgery follow-up was 57.4 ± 24.3 months (range 11-96 months). At final follow-up, 31 patients (66.0%) were excellent/good responders. Six patients experienced a recurrence of headache symptoms. There was no statistically significant difference between short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache attacks in the response to surgery (P = 0.463). Responders at the last follow-up were, however, more likely to not have interictal pain (77.42% versus 22.58%, P = 0.021) and to show morphological changes on the MRI (78.38% versus 21.62%, P = 0.001). The latter outcome was confirmed in the Kaplan-Meyer analysis, where patients with no morphological changes were more likely to relapse overtime compared to those with morphological changes (P = 0.0001). All but one patient, who obtained an excellent response without relapse, discontinued their preventive medications. Twenty-two post-surgery adverse events occurred in 18 patients (46.8%) but no mortality or severe neurological deficit was seen. Trigeminal microvascular decompression may be a safe and effective long-term treatment for patients suffering short-lasting unilateral neuralgiform headache attacks with MRI evidence of neurovascular conflict with morphological changes.

Comparing the relative and absolute effect of erenumab: is a 50% response enough? Results from the ESTEEMen study.

BACKGROUND: Monoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or its receptor have changed migraine preventive treatment. Those treatments have led to reconsidering the outcomes of migraine prevention. Available data mostly considered benefits in terms of relative efficacy (percent or absolute decrease in monthly migraine days [MMDs] or headache days compared with baseline). However, not enough attention has been paid to residual MMDs and/or migraine-related disability in treated patients. In the present study, we aimed at comparing the relative and absolute efficacy of erenumab. METHODS: ESTEEMen was a collaborative project among 16 European headache centers which already performed real-life data collections on patients treated with erenumab for at least 12 weeks. For the present study, we performed a subgroup analysis on patients with complete data on MMDs at baseline and at weeks 9-12 of treatment. Starting from efficacy thresholds proposed by previous literature, we classified patients into 0-29%, 30-49%, 50-74%, and ≥75% responders according to MMD decrease from baseline to weeks 9-12 of treatment. For each response category, we reported the median MMDs and Headache Impact test-6 (HIT-6) scores at baseline and at weeks 9-12. We categorized the number of residual MMDs at weeks 9-12 as follows: 0-3, 4-7, 8-14, ≥15. We classified HIT-6 score into four categories: ≤49, 50-55, 56-59, and ≥60. To keep in line with the original scope of the ESTEEMen study, calculations were performed in men and women. RESULTS: Out of 1215 patients, at weeks 9-12, 381 (31.4%) had a 0-29% response, 186 (15.3%) a 30-49% response, 396 (32.6%) a 50-74% response, and 252 (20.7%) a ≥75% response; 246 patients (20.2%) had 0-3 residual MMDs, 443 (36.5%) had 4-7 MMDs, 299 (24.6%) had 8-14 MMDs, and 227 (18.7%) had ≥15 MMDs. Among patients with 50-74% response, 246 (62.1%) had 4-7 and 94 (23.7%) 8-14 residual MMDs, while among patients with ≥75% response 187 (74.2%) had 0-3 and 65 (25.8%) had 4-7 residual MMDs. CONCLUSIONS: The present study shows that even patients with good relative response to erenumab may have a clinically non-negligible residual migraine burden. Relative measures of efficacy cannot be enough to thoroughly consider the efficacy of migraine prevention.

Safety and Efficacy of 10 kHz Spinal Cord Stimulation for the Treatment of Refractory Chronic Migraine: A Prospective Long-Term Open-Label Study.

BACKGROUND: Refractory chronic migraine (rCM) is a highly disabling condition for which novel safe and effective treatments are needed. Safety and long-term efficacy of paresthesia-free high cervical 10 kHz spinal cord stimulation (SCS) were here prospectively evaluated for the treatment of rCM. MATERIALS AND METHODS: Twenty adults with rCM (mean numbers of preventive treatments failed: 12.2 ± 3.1) were enrolled in this single-center, open-label, prospective study and implanted with a 10 kHz SCS system (Senza™ system, Nevro Corp), with the distal tip of the lead(s) positioned epidurally at the C2 vertebral level. Safety and effectiveness outcomes, such as adverse events, headache and migraine reductions, responder rates, Migraine Disability Assessment (MIDAS), Headache Impact Test-6 (HIT-6), and Migraine-Specific Quality-of-Life (MSQ), were captured up to 52 weeks after implantation. RESULTS: Compared to baseline, at 52 weeks postimplantation, there was a significant reduction of mean monthly migraine days (MMD) by 9.3 days (p < 0.001). Sixty percent and 50% of patients obtained respectively at least 30% and at least 50% reduction in mean MMD. By week 52, 50% of patients' chronic pattern converted to an episodic pattern. The proportion of subjects classified with severe headache-related disability on the HIT-6, decreased from 100% to 60% at week 52. Meaningful improvements of headache-related quality of life measured by the MSQ scale were observed with mean gain of 24.9 ± 23.1 (p < 0.001) points at 52 weeks. No unanticipated adverse device effects occurred. No patients required any additional device surgical revision. CONCLUSION: 10 kHz SCS may a be safe and effective neurostimulation option for rCM patients. The paresthesia-free waveform constitutes an unprecedented advantage for future methodologically sound sham-controlled studies in headache neuromodulation.

Is There a Gender Difference in the Response to onabotulinumtoxinA in Chronic Migraine? Insights from a Real-Life European Multicenter Study on 2879 Patients.

INTRODUCTION: Migraine is mostly a female disorder because of its lower prevalence in men. Less than 20% of patients included in the available studies on migraine treatments are men; hence, the evidence on migraine treatments might not apply to men. The aims of the present study were to provide reliable information on the effectiveness of onabotulinumtoxinA (BT-A) for chronic migraine in men and to compare clinical benefits between men and women. METHODS: We performed a pooled patient-level gender-specific analysis of real-life data on BT-A for chronic migraine of patients followed-up to 9 months. We reported the 50% responder rates during each BT-A cycle, defined as percentage of reduction in monthly headache days (MHDs) compared to baseline, along with 75% and 30% responder rates. We also reported the mean decrease in MHDs and in days of acute medication use (DAMs) during each BT-A cycle as compared to baseline. We also evaluated the reasons for stopping the treatment within the third cycle. RESULTS: We included an overall cohort of 2879 patients, 522 of whom (18.1%) were men. In men, 50% responder rates were 27.7% during the first BT-A cycle, 29.2% during the second, and 35.6% during the third cycle; in women, the corresponding rates were 26.6%, 33.5%, and 41.0%. In the overall cohort, responder rates did not differ between men and women during the first two cycles; during the third cycle, the distribution was different (P < 0.001) mostly because of higher rates of treatment stopping and non-responders in men. In the propensity score matched cohort, the trend was maintained but lost its statistical significance. Both men and women had a significant decrease in MHDs and in DAMs with BT-A treatment (P < 0.001). There were no gender differences in those changes with the only exception of MHD decrease which, during the third cycle, was lower in men than in women (7.4 vs 8.2 days, P = 0.016 in the overall cohort and 9.1 vs 12.5 days, P = 0.009 in the propensity score matched cohort). At the end of follow-up, 152 men and 485 women stopped BT-A treatment (29.1% vs 20.6%; P < 0.001). The relative proportion of patients stopping treatment because of inadequate response (less than 30% decrease in MHDs from baseline) was higher in men than in women (42.8% vs 39.6%), while the proportion of patients stopping because of adverse events was higher in women than in men (5.6% vs 0%; P = 0.031). CONCLUSIONS: Our pooled analysis suggests that the response to BT-A is significant in both men and women with a small gender difference in favor of women. Men tended to stop the treatment more frequently than women. We emphasize the need for more gender-specific data on migraine treatments from randomized controlled trials and observational studies.

Trigeminal neuralgia: a practical guide.

Trigeminal neuralgia (TN) is a highly disabling disorder characterised by very severe, brief and electric shock like recurrent episodes of facial pain. New diagnostic criteria, which subclassify TN on the basis of presence of trigeminal neurovascular conflict or an underlying neurological disorder, should be used as they allow better characterisation of patients and help in decision-making regarding medical and surgical treatments. MR imaging, including high-resolution trigeminal sequences, should be performed as part of the diagnostic work-up. Carbamazepine and oxcarbazepine are drugs of first choice. Lamotrigine, gabapentin, pregabalin, botulinum toxin type A and baclofen can be used either alone or as add-on therapy. Surgery should be considered if the pain is poorly controlled or the medical treatments are poorly tolerated. Trigeminal microvascular decompression is the first-line surgery in patients with trigeminal neurovascular conflict while neuroablative surgical treatments can be offered if MR imaging does not show any neurovascular contact or where patients are considered too frail for microvascular decompression or do not wish to take the risk.

Noninvasive Neuromodulation in Headache: An Update.

Background: Migraine is a common disabling primary headache condition. Although strives have been made in treatment, there remains an unmet need for safe, effective acute, and preventative treatments. The promising concept of neuromodulation of relevant neuronal targets in a noninvasive fashion for the treatment of primary headache disorders has led to the trial of numerous devices over the years. Objective: We aimed to review the evidence on current neuromodulation treatments available for the management of primary headache disorders. Methods: Randomized controlled trial as well as open-label and real-world studies on central and peripheral cephalic and noncephalic neuromodulation modalities in primary headaches were critically reviewed. Results: The current evidence suggests a role of single-pulse transcranial magnetic stimulation, supraorbital nerve stimulation, and remote noncephalic electrical stimulation as migraine abortive treatments, with stronger evidence in episodic rather than in chronic migraine. Single-pulse transcranial magnetic stimulation and supraorbital nerve stimulation also hold promising evidence in episodic migraine prevention and initial positive evidence in chronic migraine prevention. More evidence should clarify the therapeutic role of the external vagus nerve stimulation and transcranial direct current stimulation in migraine. However, external vagus nerve stimulation may be effective in the acute treatment of episodic but not chronic cluster headache, in the prevention of hemicrania continua and paroxysmal hemicrania but not of short-lasting neuralgiform headache attacks. The difficulty in setting up sham-controlled studies has thus far prevented the publication of robust trials. This limitation along with the cost of these therapies has meant that their use is limited in most countries. Conclusion: Neuromodulation is a promising nonpharmacological treatment approach for primary headaches. More studies with appropriate blinding strategies and reduction of device cost may allow more widespread approval of these treatments and in turn increase clinician's experience in neuromodulation.

Early Management of OnabotulinumtoxinA Treatment in Chronic Migraine: Insights from a Real-Life European Multicenter Study.

INTRODUCTION: OnabotulinumtoxinA (BT-A) quarterly was the first treatment approved specifically for chronic migraine (CM). It is unclear whether three cycles are better than two to assess early BT-A response. METHODS: We performed a retrospective analysis on real-life prospectively collected data in 16 European headache centers. All the centers provided data on patients treated with BT-A for CM over the first three cycles of treatment. For each treatment cycle we defined patients as "good responders" if reporting a ≥ 50% reduction in monthly headache days compared with the three months before starting BT-A, "partial responders" if reporting a 30-49% reduction in monthly headache days, and "non-responders" if reporting a < 30% reduction in monthly headache days or stopping the treatment before the third cycle. RESULTS: We included 2879 patients. Seven hundred and eighty-four (64.6%) of the 1213 patients reporting a good response during the first and/or the second cycle had a good response during the third cycle; 309 (49.3%) of the 627 patients reporting a partial response (but no good response) during the first and/or the second cycle had a good response during the third cycle; only 65 (6.3%) of the 1039 patients who did not respond during both the first two cycles achieved a good response during the third cycle. Multivariate analyses showed that partial or good response during the first or the second cycle were independently associated with good response during the third cycle. CONCLUSIONS: Our data suggest that patients with CM responding to BT-A during the first two cycles will likely benefit from the third cycle of treatment, while the probability that non-responders to the first two cycles start responding during the third cycle is low. These results can help guide the individual decision to stop or continue treatment after the second cycle in patients who have not responded to the first two cycles.

Gender Differences in 3-Month Outcomes of Erenumab Treatment-Study on Efficacy and Safety of Treatment With Erenumab in Men.

Objective: We reported gender-specific data on the efficacy and safety of erenumab, a monoclonal antibody antagonizing the calcitonin gene-related peptide (CGRP) receptor. Methods: Our pooled patient-level analysis of real-world data included patients treated with erenumab and followed up for 12 weeks. We considered the following outcomes at weeks 9-12 of treatment compared with baseline: 0-29%, 30-49%, 50-75%, and ≥75% responder rates, according to the decrease in monthly headache days (MHDs), rate of treatment stopping, change in MHDs, monthly migraine days (MMDs), monthly days of acute medication and triptan use, and Headache Impact Test-6 (HIT-6) score from baseline to weeks 9-12. Outcomes were compared between men and women by the chi-squared test or t-test, as appropriate. An analysis of covariance (ANCOVA) was performed to identify factors influencing the efficacy outcomes. Results: We included 1,410 patients from 16 centers, of which 256 (18.2%) were men. Men were older than women and had a lower number of MHDs at baseline. At weeks 9-12, compared with baseline, 46 (18.0%) men had a ≥75% response, 75 (29.3%) had a 50-74% response, 35 (13.7%) had a 30-49% response, and 86 (33.6%) had a 0-29% response, while 14 (5.5%) stopped the treatment. The corresponding numbers for women were 220 (19.1%), 314 (27.2%), 139 (12.0%), 402 (34.8%), and 79 (6.8%). No gender difference was found in any of the outcomes. The ANCOVA showed that gender did not influence the efficacy of outcomes. Conclusion: We found that erenumab is equally safe and effective in men compared with women after 12 weeks.

Position Paper on Post-Traumatic Headache: The Relationship Between Head Trauma, Stress Disorder, and Migraine.

Traumatic brain injury (mTBI) is a major public health concern, with mild TBI (mTBI) constituting the vast majority of the injuries. Post-traumatic headache (PTH) is one of the most frequent symptoms that follow a mTBI, occurring in isolation with a tension-type or migraine phenotype, or more often as part of a complex neurobehavioural array of symptoms. The existence of PTH as a separate entity from the primary headaches is still a matter of debate. Classification issues and a lack of methodologically robust epidemiological and clinical studies have made it difficult to elucidate the mechanisms underlying acute and even more persistent PTH (PPTH). Furthermore, psychiatric comorbidities such as post-traumatic stress disorder (PTSD), previous history of migraine, and legal issues often reported by PPTH patients have complicated the understanding of this condition, hence treatment approaches for PTH remain problematic. Recent findings from structural and functional neuroimaging studies have attempted to describe the brain architecture of PPTH, suggesting the involvement of different networks compared to migraine. It also seems that calcitonin gene-related peptide (CGRP) levels are not particularly raised in PPTH, although CGRP monoclonal antibodies have obtained positive initial open-label evidence of efficacy in PPTH, and more trials assessing the efficacy of this class of treatments are underway. The broad overlap between PTH, migraine, and PTSD suggests that research in this field should start with a re-appraisal of the diagnostic criteria, followed by methodologically sound epidemiological and clinical studies. Preclinical research should strive to create more reliable PTH models to support human neuroimaging, neurochemical, and neurogenetic studies, aiming to underpin new pathophysiological hypotheses that may expand treatment targets and improve the management of PTH patients.

Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine.

With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene-related peptide-targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain-binary toxin-AA (BiTox/AA)-cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ- and C-fiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine.

Medical treatment of SUNCT and SUNA: a prospective open-label study including single-arm meta-analysis.

INTRODUCTION: The management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) remains challenging in view of the paucity of data and evidence-based treatment recommendations are missing. METHODS: In this single-centre, non-randomised, prospective open-label study, we evaluated and compared the efficacy of oral and parenteral treatments for SUNCT and SUNA in a real-world setting. Additionally, single-arm meta-analyses of the available reports of SUNCT and SUNA treatments were conducted. RESULTS: The study cohort comprised 161 patients. Most patients responded to lamotrigine (56%), followed by oxcarbazepine (46%), duloxetine (30%), carbamazepine (26%), topiramate (25%), pregabalin and gabapentin (10%). Mexiletine and lacosamide were effective in a meaningful proportion of patients but poorly tolerated. Intravenous lidocaine given for 7-10 days led to improvement in 90% of patients, whereas only 27% of patients responded to a greater occipital nerve block. No statistically significant differences in responders were observed between SUNCT and SUNA. In the meta-analysis of the pooled data, topiramate was found to be significantly more effective in SUNCT than SUNA patients. However, a higher proportion of SUNA than SUNCT was considered refractory to medications at the time of the topiramate trial, possibly explaining this isolated difference. CONCLUSIONS: We propose a treatment algorithm for SUNCT and SUNA for clinical practice. The response to sodium channel blockers indicates a therapeutic overlap with trigeminal neuralgia, suggesting that sodium channels dysfunction may be a key pathophysiological hallmark in these disorders. Furthermore, the therapeutic similarities between SUNCT and SUNA further support the hypothesis that these conditions are variants of the same disorder.