Effectiveness and tolerability of eptinezumab in treating patients with migraine resistant to conventional preventive medications and CGRP (receptor) antibodies: a multicentre retrospective real-world analysis from Germany.

BACKGROUND: Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP mAb) and is used for migraine prophylaxis. Efficacy data are mainly from clinical trials, real-world data are hardly available yet. Reimbursement policy in Germany leads to eptinezumab mainly being used in patients having failed pre-treatment with other CGRP mAb. To date, it is unclear whether eptinezumab is efficacious and well tolerated in this population and how the treatment response differs from patients who are naive to CGRP mAbs. METHODS: We analysed clinical routine data of 79 patients (episodic migraine (EM): n = 19; chronic migraine (CM): n = 60) from four different centres in Germany. All patients were treated with eptinezumab (100mg). Differences in monthly headache (MHD), migraine (MMD) and acute medication days (AMD) after three months were analysed. The correlation of response with the number of CGRP mAb failures was evaluated. Significance level has been corrected (alpha = 0.017). RESULTS: After three months MHD, MMD and AMD were significantly reduced. In EM, the median reduction for MHD was 4.0 days (IQR: -6.5 to -1.0; p = 0.001), for MMD 3.0 days (IQR: -5.5 to -1.5; p < 0.001) and for AMD 2.0 days (IQR: -5.0 to -0.5; p = 0.006). In CM, median reduction of MHD was 4 days (IQR: -8.0 to 0.0; p < 0.001), 3.0 days (IQR: -6.0 to-1.0; p < 0.001) for MMD and 1.0 day (IQR: -5.0 to 0.0; p < 0.001) for AMD. All patients were resistant to conventional preventive therapies and most to CGRP mAbs. Fourteen patients had never received a CGRP mAb and 65 patients had received at least one mAb without sufficient effectiveness and/or intolerability (one: n = 20, two: n = 28, three: n = 17). There was a significant association between the number of prior therapies and the 30% MHD responder rate (none: 78.6%, one: 45.0%, two: 32.1%, three: 23.5%, p = 0.010). Regarding tolerability, 10.4% (8/77) reported mild side effects. CONCLUSIONS: The effectiveness of eptinezumab is significantly reduced in patients who have not previously responded to other CGRP mAbs. However, limitations such as the retrospective nature of the analysis, the small sample size and the short treatment period with only the lower dose of eptinezumab must be considered when interpreting the results.

Cognitive deficits in patients with peripheral vestibular dysfunction.

BACKGROUND AND PURPOSE: Previous studies demonstrated cognitive deficits in patients with peripheral vestibulopathy (PVP) with dysfunction of spatial navigation and orientation, but also documented cognitive decline in nonspatial abilities. This study evaluates cognitive deficits in patients with unilateral vestibulopathy (UVP) as well as bilateral vestibulopathy (BVP) in multiple cognitive domains using common screening tests to reliably detect these deficits in clinical practice. METHODS: This prospective study compared patients with UVP and BVP to age- and sex-matched healthy controls (HC). Tests included the Alzheimer's Disease Assessment Scale (ADAS), Mini-Mental Status Examination (MMSE), Trail Making Test Part A and B, Clock Drawing Task, Executive Interview-25 (EXIT25), Dementia Detection (DemTect), and the Judgment of Line Orientation (JLO). The Montgomery-Åsberg Depression Rating Scale was used to control for depression. Videonystagmography objectively reconfirmed PVP. The Vertigo Symptoms Scale and the Dizziness Handicap Inventory were used to assess for symptom severity and restrictions of activities of daily living. RESULTS: Eighty-one patients (65 UVP, 16 BVP) were compared to 55 HC. Patients showed impairment in ADAS, MMSE, DemTect, EXIT25, and JLO. No differences between UVP and BVP were detected. The relative risk (RR) estimates of developing cognitive deficits following PVP were increased. The RR for the ADAS was higher in BVP (RR = 4.91, 95% confidence interval [CI] = 1.87-12.9, p = 0.001) than in UVP (RR = 3.75, 95% CI = 1.65-8.51, p = 0.002), but was similar for the MMSE and DemTect between groups. CONCLUSIONS: Patients with PVP showed deficits in multiple cognitive domains including nonspatial cognitive abilities. Vestibulopathy could be a risk factor for the development of cognitive impairment.

Real-world evidence following a mandatory treatment break after a 1-year prophylactic treatment with calcitonin gene-related peptide (pathway) monoclonal antibodies.

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.

Twelve-month safety, tolerability and susceptibility to adverse events of prophylactic migraine therapy with erenumab: a retrospective real-world study.

BACKGROUND: Erenumab 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. METHODS: Clinical 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). RESULTS: The 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). CONCLUSION: In 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 REGISTRATION: No registration, retrospective analysis.

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.

No structural brain alterations in new daily persistent headache - a cross sectional VBM/SBM study.

OBJECTIVE: To identify grey matter alterations in patients suffering new daily persistent headache to enrich the pathophysiological concept of this rare headache disorder characterised by a distinct, clearly remembered onset and its instant chronification. METHOD: Magnetic resonance-based voxel-based and surface-based morphometry was used to investigate 23 patients suffering from new daily persistent headache and 23 age- and gender-matched healthy controls with 1.5 Tesla MRI.Independent statistical analysis was performed at three sites using statistical parametric mapping, as well as FSL(FMRIB Software Library)-based approaches. RESULTS: No grey matter changes were detected using this sophisticated and cross-checked method. CONCLUSION: The absence of structural brain changes in patients with new daily persistent headache contribute to the recent discussion regarding structural alterations in primary headache disorders in general and does not provide evidence for grey matter changes being associated with the pathophysiology of new daily persistent headache. Future research will have to determine the underlying pathophysiological mechanisms of this disorder.

Reduced vestibular perception thresholds in persistent postural-perceptual dizziness- a cross-sectional study.

BACKGROUND: Persistent postural-perceptual dizziness (PPPD) is the most common functional vestibular disorder. A multisensory mismatch altered by psychological influences is considered to be an important pathophysiological mechanism. Increased cortical and subcortical excitability may play a role in the pathophysiology of PPPD. We hypothesized that decreased motion perception thresholds reflect one mechanism of the abnormal vestibular responsiveness in this disorder. We investigated the vestibular perception thresholds and the vestibular ocular reflex with a rotatory chair experiment to gain insights in the processing and adaption to vestibular provocation. METHODS: In this cross-sectional study 26 female PPPD patients and 33 healthy female age matched controls (HC) were investigated sitting in a motorized rotary chair shielded regarding visual and acoustic stimuli. The chair was rotated for 20 minutes with slowly increasing velocity to a maximum of 72°/s. We functionally tested motion perception thresholds and vegetative responses to rotation as well as vestibular-ocular reflex thresholds. We additionally investigated several psychological comorbidities (i.e. depression, anxiety, somatosensory amplification) using validated scores. Conventional dizziness scores were obtained to quantify the experienced dizziness and impact on daily life. RESULTS: PPPD patients showed a significant reduced vestibulo-perceptual threshold (PPPD: 10.9°/s vs. HC: 29.5°/s; p<0.001) with increased motion sensitivity and concomitant vegetative response during and after the chair rotation compared to healthy controls. The extent of increased vestibular sensitivity was in correlation with the duration of the disease (p=0.043). No significant difference was measured regarding nystagmus parameters between both groups. CONCLUSION: PPPD patients showed increased vegetative response as well as decreased vestibulo-perceptual thresholds which are related to disease duration. This is of interest as PPPD might be sustained by increased vestibular excitability leading to motion intolerance and induction of dizziness when exposed to movement.

CGRP antibody therapy in patients with drug resistant migraine and chronic daily headache: a real-world experience.

BACKGROUND: Calcitonin 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. METHODS: Clinical 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. RESULTS: The 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. CONCLUSIONS: Despite 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 REGISTRATION: Retrospective registered.

Sensitized rotatory motion perception and increased susceptibility to motion sickness in vestibular migraine: A cross-sectional study.

BACKGROUND AND PURPOSE: Vestibular migraine (VM) patients are ictally and interictally hypersensitive for self-motion and visual perception. Increased cortical excitability of the vestibular system represented by lowered motion perception thresholds might play an important role in the pathophysiology of VM. We aimed to compare motion perception thresholds and the vegetative response to rotatory motion, as well as the vestibulo-ocular reflex (VOR) during rotation in VM patients compared to healthy controls (HC). METHODS: In this cross-sectional study, 28 female VM patients in the interictal state and 33 age- and gender-matched HC were investigated sitting in a motorized rotary chair shielded regarding visual and acoustic stimuli for 20 min with slowly increasing velocity (maximum = 72°/s). The motion perception threshold was indicated by the participants by pushing a button. During and after rotation, participants rated the presence and extent of motion sickness using a sickness rating scale. RESULTS: We detected lower motion perception thresholds (7.54°/s vs. 23.49°/s; p < 0.001) in VM patients compared to HC but no difference at the basic VOR thresholds. Furthermore, the patients showed enhanced susceptibility to motion sickness during and after the rotation. CONCLUSIONS: We provide evidence for decreased motion perception thresholds and pronounced susceptibility to motion sickness in VM patients in the interictal state, which could indicate alterations in higher levels of vestibular processing. Future studies should determine whether this could be the pathophysiological hallmark of VM either as a unique disease entity or in differentiation from other forms of migraine.

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.

Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Prednisone is commonly used for initial short-term therapy of episodic cluster headaches before preventive medication such as verapamil becomes effective, but this strategy has not been tested in large randomised trials. We aimed to access the safety and efficacy of this treatment approach. METHODS: This study was a multicentre, randomised, double-blind, placebo-controlled trial done in ten specialised headache centres in Germany. Patients with episodic cluster headaches who were aged between 18 and 65 years and within a current pain episode for not more than 30 days, received 100 mg oral prednisone for 5 days followed by tapering of 20 mg every 3 days, or matching placebo (17 days total exposure). All patients received oral verapamil for long-term prevention, starting with 40 mg three times daily and increasing to 120 mg three times daily by day 19; patients then continued with verapamil 120 mg throughout the study. Randomisation was computer-generated at a 1:1 ratio by use of an interactive web-response system, with stratification according to age, sex, and participating site. Participants, investigators, and those assessing outcomes were unaware of treatment allocation. The primary endpoint was the mean number of attacks within the first week of treatment with prednisone compared with placebo. An attack was defined as a unilateral headache with moderate-to-severe intensity of at least five on a numerical rating scale. All efficacy and safety analyses were done in the modified intention-to-treat (mITT) population, which consisted of all patients who had been randomly assigned to a trial group and received at least one dose of prednisone or placebo. The study was stopped early due to slow recruitment and expired funding. The study was registered with EudraCT (2011-006204-13) and with the German Clinical Trials Register (DRKS00004716). FINDINGS: Between April 5, 2013, and Jan 11, 2018, 118 patients were enrolled in the study. Two patients dropped out immediately and 116 patients were randomly assigned (57 patients to prednisone and 59 patients to placebo); 109 patients were included in the mITT analysis (53 patients assigned to prednisone and 56 patients assigned to placebo). Participants in the prednisone group had a mean of 7·1 (SD 6·5) attacks within the first week compared with 9·5 (6·0) attacks in the placebo group (difference -2·4 attacks, 95% CI -4·8 to -0·03; p=0·002). Two serious adverse events occurred, both in the placebo group (inguinal hernia and severe deterioration of cluster headache). A total of 270 adverse events were observed: in the prednisone group, 37 (71%) of 52 patients reported 135 adverse events (most common were headache, palpitations, dizziness, and nausea) and in the placebo group, 39 (71%) of 55 patients had 135 adverse events (most common were nausea, dizziness, and headache). INTERPRETATION: Oral prednisone was an effective short-term preventive therapy in our population of patients with episodic cluster headache. Our findings support the use of prednisone as a first-line treatment in parallel to the up-titration of verapamil, although the efficacy of prednisone alongside other long-term prevention requires additional investigation. FUNDING: German Federal Ministry for Education and Research.

Erenumab in highly therapy-refractory migraine patients: First German real-world evidence.

BACKGROUND: Calcitonin 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. METHODS: Clinical 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. RESULTS: Complete 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. CONCLUSIONS: Erenumab seems to be a promising therapeutic option in highly therapy-refractory migraine patients. TRIAL REGISTRATION: Retrospective registered.

Impaired wound healing in a migraine patient as a possible side effect of calcitonin gene-related peptide receptor antibody treatment: A case report.

INTRODUCTION: Wound healing disturbances as possible side effects of calcitonin gene-related peptide (CGRP) antibody treatment have been discussed previously but not yet described in humans. Basic research suggests that calcitonin gene-related peptide plays an important role in keratinocyte migration, vascularization and immune response and lack of calcitonin gene-related peptide may lead to impaired wound healing. CASE: A 51-year-old female migraine patient was treated with the CGRP receptor antibody erenumab for 6 months, which led to a relevant reduction of migraine days. During the treatment, two periods of severely impaired wound healing occurred after a trivial skin injury without spatial relation to the injection site. Skin biopsy confirmed a deep perivascular and interstitial lymphohistiocytic infiltrate with admixed eosinophils, ulceration of the epithelium, a heavy edema of the papillary dermis and focally thrombosed vessels. CONCLUSION: Impaired wound healing might be relevant side effects of CGRP antibody therapy and anamnesis within the course of treatment should also include possible observation of impaired wound healing or planned surgery.

Pathophysiology, prevention, and treatment of medication overuse headache.

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.

Polarity-specific modulation of pain processing by transcranial direct current stimulation - a blinded longitudinal fMRI study.

BACKGROUND: To enrich the hitherto insufficient understanding regarding the mechanisms of action of transcranial direct current stimulation (tDCS) in pain disorders, we investigated its modulating effects on cerebral pain processing using functional magnetic resonance imaging (fMRI). METHODS: Thirteen right-handed healthy participants received 20 min of 1.5 mA tDCS applied over the primary motor cortex thrice and under three different stimulation pattern (1.anodal-tDCS, 2.cathodal-tDCS, and 3.sham-tDCS) in a blinded cross-over design. After tDCS neural response to electric trigeminal-nociceptive stimulation was investigated using a block designed fMRI. RESULTS: Pain stimulation showed a distinct activation pattern within well-established brain regions associated with pain processing. Following anodal tDCS increased activation was detected in the thalamus, basal ganglia, amygdala, cingulate, precentral, postcentral, and dorsolateral prefrontal cortex, while cathodal t-DCS showed decreased response in these areas (pFWE < 0.05). Interestingly the observed effect was reversed in both control conditions (visual- and motor-stimulation). Behavioral data remained unchanged irrespective of the tDCS stimulation mode. CONCLUSIONS: This study demonstrates polarity-specific modulation of cerebral pain processing, in reconfirmation of previous electrophysiological data. Anodal tDCS leads to an activation of the central pain-network while cathodal tDCS does not. Results contribute to a network-based understanding of tDCS's impact on cerebral pain-processing.

Chronic Headache Due to Overuse of Analgesics and Anti-Migraine Agents.

BACKGROUND: The frequent or regular use of analgesics and anti-migraine drugs can make headache more frequent and induce the transformation of episodic to chronic headache. Chronic headache due to medication overuse is defined as headache that is present on ≥ 15 days per month for at least three months in a patient who previously suffered from primary headaches, and who takes analgesics on ≥ 15 days per month or anti-migraine drugs (triptans or ergot alkaloids), opioid drugs, or combined analgesics on ≥ 10 days per month. METHODS: This review is based on pertinent articles published up to December 2017 that were retrieved by a selective search in PubMed employing the terms "medication overuse AND headache" and "medication overuse headache." RESULTS: The prevalence of medication overuse headache in the general population in Germany is 0.7% -1%. This disorder is more common in women and in persons suffering from comorbid mental disorders or other painful conditions. The treatment of medication overuse headache consists of three steps. Patient education and counseling are given with the goal of reducing the intake of medication for acute headache treatment. The ensuing headache prophylaxis is with topiramate, amitriptyline, or onabotulinum toxin A. If these treatment strategies fail, a drug holiday is recommended. This can be in the outpatient, day clinic, or inpatient setting, depending on the severity of the condition and its comorbidities. CONCLUSION: Patients who frequently take acute medication to treat headache episodes must be identified early in order to avoid headache chronification and medication overuse headache. The suggested treatment algorithm is still in need of validation by randomized trials.

Functional Neuroimaging in Trigeminal Autonomic Cephalalgias.

Functional neuroimaging was able to identify key structures for the pathophysiology of trigeminal autonomic cephalalgias (TACs) including cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing or cranial autonomic features and hemicrania continua. The posterior hypothalamus was the structure most consistently depicted with functional imaging in different states of disease with and without pain. Network-oriented imaging techniques such as resting-state functional resonance imaging were able to show a broader involvement of human trigeminal pain processing in the underlying pathophysiological mechanisms of the different TACs, highlighting similarities between this distinct group of primary headache disorders, while also demonstrating the differences in brain activation across these disorders. The most important clinical assignment for neuroimaging research from the treating physician remains the objective and reliable distinction of each individual TAC syndrome from one another, to make the correct clinical diagnosis as the foundation for proper treatment. More research will be necessary to fulfill this unmet need.

Cerebral gray matter changes in persistent postural perceptual dizziness.

BACKGROUND: Persistent postural perceptual dizziness (PPPD) is the most common vestibular syndrome in middle-aged patients. Multisensory maladjustment involving alterations of sensory response pattern including vestibular, visual and motion stimuli is thought to be a key pathophysiological correlate of this disorder. OBJECTIVE: We aimed to identify regional gray matter changes in PPPD patients that might be involved in the underlying pathophysiology of this disorder. METHODS: 42 PPPD patients and healthy age and gender matched controls were investigated using magnetic resonance imaging-based voxel-based morphometry. All patients fulfilled the current diagnostic criteria for PPPD, established by the Bárány-Society based on previous criteria for chronic subjective dizziness and phobic postural vertigo. RESULTS: PPPD patients showed gray matter volume decrease in the temporal cortex, cingulate cortex, precentral gyrus, hippocampus, dorsolateral prefrontal cortex, caudate nucleus and the cerebellum. A negative correlation of disease duration and gray matter volume was observed in the visual cortex, supplementary motor area and somatosensory processing structures. CONCLUSIONS: In patients with PPPD areas involved in multisensory vestibular processing show gray matter volume decrease. These brain regions resemble those previously described for other vestibular disorders. Longer duration of disease leads to a more pronounced gray matter alteration, which might represent maladaptive mechanisms within the course of disease.