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Regular or frequent use of analgesics and acute antimigraine drugs can increase the frequency of headache, and induce the transition from episodic to chronic headache or medication overuse headache. The 1-year prevalence of this condition in the general population is between 1% and 2%. Medication overuse headache is more common in women and in people with comorbid depression, anxiety, and other chronic pain conditions. Treatment of medication overuse headache has three components. First, patients need education and counselling to reduce the intake of medication for acute headache attacks. Second, some patients benefit from drug withdrawal (discontinuation of the overused medication). Finally, preventive drug therapy and non-medical prevention might be necessary in patients at onset of treatment or in patients who do not respond to the first two steps. The optimal therapeutic approach requires validation in controlled trials.

The management of patients with migraine is often unsatisfactory because available acute and preventive therapies are either ineffective or poorly tolerated. The acute treatment of migraine attacks has been limited to the use of analgesics, combinations of analgesics with caffeine, ergotamines, and the triptans. Successful new approaches for the treatment of acute migraine target calcitonin gene-related peptide (CGRP) and serotonin (5-hydroxytryptamine, 5-HT1F) receptors. Other approaches targeting the transient receptor potential vanilloid (TRPV1) receptor, glutamate, GABAA receptors, or a combination of 5-HT1B/1D receptors and neuronal nitric oxide synthesis have been investigated but have not been successful in clinical trials thus far. In migraine prevention, the most promising new approaches are humanised antibodies against CGRP or the CGRP receptor. Non-invasive and invasive neuromodulation approaches also show promise as both acute and preventive therapies, although further studies are needed to define appropriate candidates for these therapies and optimum protocols for their use.

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

BackgroundCalcitonin gene-related peptide (CGRP) (receptor) antibodies (erenumab, fremanezumab and galcanezumab) are increasingly used in prophylactic treatment of migraine. In the approval studies, severely affected patients with migraine and chronic daily headache without any headache free days were excluded. Thus, less is known about the effectiveness of CGRP antibody treatment in this cohort.MethodsClinical routine data of 32 patients with migraine and daily headache were analysed after three months of treatment with a CGRP antibody (16 erenumab, 7 galcanezumab, 9 fremanezumab), including changes of monthly headache days (MHD) monthly migraine days (MMD) and monthly acute medication intake (AMD) as well as migraine characteristics. Statistical analysis was performed with the Wilcoxon-Test. Migraine characteristics were analysed descriptively.ResultsThe number of MHD was significantly reduced (mean reduction (standard error), p-value): (-4.2 (1.3), p = 0.009) as well as MMD (-4.3 (1.6), p = 0.033). Four patients (13 %) reached a 50 % reduction regarding MHD and 8 patients (25 %) regarding MMD, migraine duration and intensity improved under therapy.ConclusionsDespite the low responder rate, CGRP antibodies can be effective at least in a few cases of severely affected patients with drug resistant migraine and chronic daily headache.Trial registrationRetrospective registered.

BackgroundErenumab is a monoclonal antibody (mAb) against the calcitonin gene related peptide (CGRP) receptor and is commonly used in migraine prophylaxis. Pivotal and open-label studies show a good safety and tolerability. However, little is known about possible predictors, dose dependence and time course of development of adverse events (AEs) during the treatment under real-world conditions.MethodsClinical routine data of 128 patients with migraine treated in the West German Headache Center Essen were analyzed regarding AEs during a treatment interval of up to 12 months (3mo n = 128, 6mo n = 105, 9mo n = 74, 12mo n = 54). Patients obtained subcutaneous erenumab injections with either 70 mg or 140 mg per month. The occurrence and alterations of AEs were evaluated. All reported AEs, regardless of their severity, were included. AEs were graded using the common terminology criteria for adverse events (CTCAE). Possible parameters that could influence the occurrence of AEs (sex, episodic or chronic migraine, medication overuse headache, aura and the dosage of erenumab) were analyzed using the Chi-squared test, alpha adjustment was done using the Bonferroni’s correction (6 tests, adjusted alpha = 0.0083).ResultsThe proportion of patients who reported at least one AE were stable over the course of 12 months (after 3mo = 37%, 6mo = 36%, 9mo = 32%, 12mo = 35%). All reported AEs were grade 1 according to CTCAE with one exception (grade 2). Throughout the interval, five AEs were mostly reported: constipation, skin reactions, fatigue, sleep disturbances and nausea/emesis. Discontinuation of erenumab therapy was rarely caused by AEs (5/49). Increasing the dosage from 70 mg to 140 mg per month caused no higher frequency of AEs (Chi-squared test, p = 0.57). Significant more AEs were reported by females and by patients with aura (Chi-squared test, p < 0.001, respectively).ConclusionIn general, erenumab is well tolerated up to a treatment interval of 12 months and reported AEs rarely lead to discontinuation of therapy. A higher dosage does not increase the patient reported AEs. Furthermore, no habituation of AEs is observed. Nevertheless, females and patients with aura seem to be more prone to have AEs.Trial registrationNo registration, retrospective analysis.

Trigeminal neuralgia (TN) is supposedly caused by an ectatic blood vessel affecting the trigeminal nerve at the root entry zone of the brain stem. Recent evidence suggests an additional central component within trigeminal pain-processing in the pathophysiology of TN. Therefore, we aimed to identify specific brain regions possibly associated with the development or maintenance of TN using magnetic resonance imaging (MRI) voxel-based morphometry (VBM). Sixty patients with classical TN were compared to 49 healthy controls. Eighteen patients had TN with concomitant constant facial pain, a condition previously described as a predictor of worse treatment outcome. We found gray matter (GM) volume reduction in TN patients compared to healthy controls in the primary somatosensory and orbitofrontal cortices, as well as the in the secondary somatosensory cortex, thalamus, insula, anterior cingulate cortex (ACC), cerebellum, and dorsolateral prefrontal cortex. GM volume decrease within the ACC, parahippocampus, and temporal lobe correlated with increasing disease duration in TN. There were no differences comparing patients with and without concomitant constant facial pain. No GM increase was found comparing patient subgroups with each other and with healthy controls. The observed changes probably reflect the impact of multiple, daily attacks of trigeminal pain in these patients similar to what was previously described in other chronic pain conditions and may be interpreted as adaptation mechanism to chronic pain in regard to neuronal plasticity. The ACC, parahippocampus and temporal lobe volume reduction in parallel with disease duration may point to a pivotal role of these structures in chronic pain. •Evidence for a central component in the pathophysiology of trigeminal neuralgia.•Nerve-vessel conflict should be regarded as risk factor.•Structures identified resemble typical of chronic pain disorders.•Frequent pain attacks lead to changes related to central adaptation mechanisms.•Patients with and without constant facial pain share these morphological changes.

BackgroundMonoclonal 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.MethodsESTEEMen 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.ResultsOut 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.ConclusionsThe 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.

Persistent postural-perceptual dizziness (PPPD) is the most common vestibular disorder in the age group between 30 and 50 years. It is considered to be based on a multisensory maladjustment involving alterations of sensory response pattern including vestibular, visual and motion stimuli. Previous data supported a link between vestibular and pain mechanism. The aim of the study was to investigate whether other sensory inputs such as pain stimuli might be altered in terms of a more widespread central perception dysfunction in this disorder. Nociceptive blink reflex was measured in 27 patients with PPPD and compared with 27 healthy, age and gender matched controls. The habituation of the R2 component of the blink reflex was evaluated as the percentage area-under-the curve (AUC) decrease in ten consecutive blocks of five averaged rectified responses. Additionally, clinical characteristics were evaluated. In patients with PPPD a lack of habituation was observed compared to healthy controls. Relative AUC decreased between the first and the tenth block by 19.48% in PPPD patients and by 31.63% (p = 0.035) in healthy controls. There was no correlation between clinical data (course of disease, comorbid depression, medication, trigger factors) or electrophysiological data (perception threshold, pain threshold, stimulus intensity) and habituation pattern. No trigeminal sensitization in terms of facilitation of absolute values could be detected. Our study results supports the hypothesis of the multisensory dimension of impaired sensory processing in patients with PPPD extends beyond vestibular/visual motion stimuli and reflexive postural/oculomotor control mechanisms to other sensory inputs such as pain perception in terms of a more generalized disturbed habituation pattern.

Drug-associated headache is a quite common phenomenon, e.g. as a side effect of distinct substances such as nitric oxide or as a result of medication overuse of analgesic drugs. A different drug-associated headache entity is headache in drug-induced aseptic meningitis (DIAM). This is a rare disorder and only described in few case reports or smaller case series. One of the main clinical features of DIAM despite fever is headache. Based on the literature, no typical or even pathognomonical clinical presentation of this headache entity can be described. Sometimes, migrainous features might be present, and treatment response to triptans was reported in single case reports. Headache in DIAM seems to be emerging from sterile meningeal inflammation, which is suggested to represent the underlying pathology in DIAM. Headache in DIAM usually ceases when treated sufficiently, mainly through termination or withdrawal of the causing agent. Migraine as a predisposing factor of DIAM has been discussed previously but remains unproven.

Background Current German and European guidelines suggest migraine patients undertake a treatment break after 9 to 12 months of treatment with CGRP (pathway) monoclonal antibodies. Methods Clinical routine data of highly resistant migraine patients were analyzed before treatment with CGRP monoclonal antibodies (baseline), after 12 months of treatment, and following a treatment break between November 2018 and December 2020 in the West German Headache Centre, University Hospital Essen, Germany. Monthly migraine days (MMD), monthly headache days (MHD), and days of acute medication intake (AMD) were assessed. Results Complete clinical data from 46 migraine patients (14 episodic migraine (EM), 32 chronic migraine (CM) patients) treated with erenumab (n = 40), galcanezumab (n = 4), and fremanezumab (n = 2) were analyzed. The mean number of MMDs among EM and CM patients after 12 months of CGRP antibody treatment increased during the treatment break by 5.18 (SE 0.92, p < .001) and 5.06 (SE 1.22, p = .003) days, respectively. There was an increased intake of acute medications among episodic (4.72, SE 0.87, p = .004) and chronic migraine patients (3.01, SE 1.08, p = .013) during treatment break. Eighty‐three percent of patients (n = 38) were dissatisfied with the mandatory treatment break. All patients continued with a CGRP (pathway) monoclonal antibody after the mandatory treatment break. Conclusion A mandatory break in CGRP (pathway) monoclonal antibody therapy had a negative short‐term impact on migraine patients. The manuscript focuses on the relevance of treatment break after twelve months of treatment with the CGRP monoclonal antibodies. Validated data obtained during in depth interviews obtained at the West‐German Headache Center, Essen Germany was analyzed