First Report of Symmetrical Drug-related Intertriginous and Flexural Exanthema (SDRIFE or Baboon Syndrome) After Erenumab Application for Migraine Prevention.

INTRODUCTION: Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), formerly also called baboon syndrome, is characterized by symmetrical erythematous rash with typical localization in the gluteal and intertriginous areas. A type IV delayed hypersensitivity immune response is thought to be responsible for its development. CGRP monoclonal antibodies (CGRP mAbs) are a new class of drugs for the prevention of migraine. We present the first case of SDRIFE occurring in temporal relation to the use of erenumab for migraine prevention. CASE: A 48-year-old female patient with migraine received erenumab 140 mg subcutaneously in the thigh area for the prevention of migraine in repetitive cycles, each 1 month apart. Initially, the patient experienced no side effects. After the third cycle, a masseuse incidentally noticed a reddish, circular rash in the buttock area during a back massage. There were no other symptoms. The skin changes resolved spontaneously. Two years later, approximately 40 h after reapplication of erenumab 140 mg, the patient experienced a severe pain in the buttock area centered over the anal crease. The area of pain extended in a circular pattern with approximately 20 cm in diameter. The pain started abruptly and reached a severe intensity within about 30 min. Sitting on the buttocks was no longer possible for the patient. There was marked allodynia and hyperpathia in the entire buttocks region. A flat, broad-based blister-like skin swelling developed in this region. The blisters began opening up on the fourth day after the onset of the skin reaction. In addition, there was a pronounced redness in the entire buttock area. Here, the patient felt a strong burning pain, similar to a scald. RESULTS: The symptoms lasted for a period of 10 days. From this point on, they fully subsided under concomitant therapy with prednisolone. CONCLUSION: SDRIFE as a rare dermatological side effect should be considered in the monitoring of skin lesions during migraine prophylaxis. In view of the high migraine prevalence, knowledge of this uncommon syndrome is important. It is crucial to recognize the relationship between the medication and the circumscribed exanthema occurring distant from the injection site.

Clinical characteristics of headache after vaccination against COVID-19 (coronavirus SARS-CoV-2) with the BNT162b2 mRNA vaccine: a multicentre observational cohort study.

The novel coronavirus SARS-CoV-2 causes the infectious disease COVID-19. Newly developed mRNA vaccines can prevent the spread of the virus. Headache is the most common neurological symptom in over 50% of those vaccinated. Detailed information about the clinical characteristics of this form of headache has not yet been described. The aim of the study is to examine in detail the clinical characteristics of headaches occurring after vaccination against COVID-19 with the BNT162b2 mRNA COVID-19 vaccine for the first time. In a multicentre observational cohort study, data on the clinical features and corresponding variables were recorded using a standardized online questionnaire. The questionnaire was circulated to 12 000 residential care homes of the elderly as well as tertiary university hospitals in Germany and the United Arab Emirates. The primary outcomes of this study are the clinical features of headache after vaccination. Comorbidities, treatment with medication and sociodemographic variables are also analysed. A total of 2349 participants reported headaches after vaccination with the BNT162b2 mRNA COVID-19 vaccine. Headaches occur an average of 18.0 ± 27.0 h after vaccination and last an average duration of 14.2 ± 21.3 h. Only 9.7% of those affected also report headaches resulting from previous vaccinations. In 66.6% of the participants, headache occurs as a single episode. A bilateral location is indicated by 73.1% of the participants. This is most often found on the forehead (38.0%) and temples (32.1%). A pressing pain character is indicated by 49.2% and 40.7% report a dull pain character. The pain intensity is most often moderate (46.2%), severe (32.1%) or very severe (8.2%). The most common accompanying symptoms are fatigue (38.8%), exhaustion (25.7%) and muscle pain (23.4%). Headaches after COVID-19 vaccination show an extensive complex of symptoms. The constellation of accompanying symptoms together with the temporal and spatial headache characteristics delimit a distinctive headache phenotype.

Headache Attributed to Vaccination Against COVID-19 (Coronavirus SARS-CoV-2) with the ChAdOx1 nCoV-19 (AZD1222) Vaccine: A Multicenter Observational Cohort Study.

INTRODUCTION: The most frequently reported neurological adverse event of ChAdOx1 nCoV-19 (AZD1222) vaccine is headache in 57.5%. Several cases of cerebral venous thrombosis (CVT) have developed after vaccination. Headache is the leading symptom of CVT. For the differential diagnosis of headaches attributed to this vaccine and headaches attributed to CVT, it is of central clinical importance whether and, if so, how the phenotypes and course of these headaches can be differentiated. The study aims to examine in detail the phenotype of headache attributed to this vaccine. METHODS: Data on the clinical features and corresponding variables were recorded using a standardized online questionnaire in this multicenter observational cohort study. The primary outcomes of this study are the clinical features of headaches after vaccination. FINDINGS: A total of 2464 participants reported headaches after vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine. On average, headaches occurred 14.5 ± 21.6 h after vaccination and lasted 16.3 ± 30.4 h. A bilateral location was described by 75.8% of participants. This is most often found on the forehead (40.0%) and temples (31.4%); 50.4% reported a pressing and 37.7% a dull pain character. Headache intensity was most often severe (38.7%), moderate (35.2%), or very severe (15.5%). Accompanying symptoms were most commonly fatigue (44.8%), chills (36.1%), exhaustion (34.9%), and fever (30.4%). CONCLUSION: Headaches attributed to COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine demonstrate an extensive and characteristic complex of symptoms. The findings have several important clinical implications for the differentiation of post-vaccinal headache and other primary as well as secondary headaches.

Phenotype of Cluster Headache: Clinical Variability, Persisting Pain Between Attacks, and Comorbidities-An Observational Cohort Study in 825 Patients.

INTRODUCTION: Cluster headaches can occur with considerable clinical variability. The inter- and intra-individual variability could contribute to the fact that the clinical headache phenotype is not captured by too strict diagnostic criteria, and that the diagnosis and the effective therapy are thereby delayed. The aim of the study was to analyze the severity and extent of the clinical symptoms of episodic and chronic cluster headaches with regard to their variability and to compare them with the requirements of the International Classification of Headache Disorders 3rd edition (ICHD-3) diagnostic criteria. METHODS: The study was carried out as a cross-sectional analysis of 825 patients who had been diagnosed with cluster headaches by their physician. Using an online questionnaire, standardized questions on sociodemographic variables, clinical features of the cluster headache according to ICHD-3, and accompanying clinical symptoms were recorded. RESULTS: The majority of patients with cluster headaches have clinical features that are mapped by the diagnostic criteria of ICHD-3. However, due to the variability of the symptoms, there is a significant proportion of clinical phenotypes that are not captured by the ICHD-3 criteria for cluster headaches. In addition, change in the side of the pain between the cluster episodes, pain location, as well as persisting pain between the attacks is not addressed in the ICHD-3 criteria. In the foreground of the comorbidities are psychological consequences in the form of depression, sleep disorders, and anxiety. CONCLUSIONS: The variability of the phenotype of cluster headaches can preclude some patients from receiving an appropriate diagnosis and effective therapy if the diagnostic criteria applied are too strict. The occurrence of persisting pain between attacks should also be diagnostically evaluated due to its high prevalence and severity as well as psychological strain. When treating patients with cluster headaches, accompanying psychological illnesses should carefully be taken into account.

Effect of Occipital Nerve Stimulation (ONS) on the Orbicularis Oculi Reflex Triggered by a Standardized Air Flow in Patients with Chronic Migraine-A Prospective, Randomized, Interventional Study.

INTRODUCTION: Occipital nerve stimulation (ONS) is a specific form of peripheral neuromodulation used in the treatment of chronic pain disorders. A particular field of application is in the therapy of treatment-refractory headaches, especially of chronic migraine. The precise mode of action is unknown. It is presumed that central and peripheral sensitization are reduced in patients with chronic headache. The aim of this study was to examine the effect of ONS on pain-modulatory mechanisms in the trigeminocervical area in patients with chronic migraine. METHODS: In a balanced repeated measurements design in eight patients with chronic migraine with and without active ONS, we analyzed which effects ONS had on the orbicularis oculi reflex dynamically elicited by corneal air flow. RESULTS: The orbicularis oculi reflex in active ONS (7.38 ± 20.14 eyelid closures/minute) compared to inactive ONS (18.73 ± 14.30 eyelid closures/minute) is significantly reduced (p = 0.021). CONCLUSIONS: The results show that under active ONS compared to inactive ONS in patients with chronic migraine, the orbicularis oculi reflex, dynamically triggered by a standardized air flow, is significantly reduced. This suggests that ONS is able to directly counteract the trigeminally mediated central sensitization in chronic migraine and protectively reduce the effects of aversive peripheral stimulation.

Explicit Diagnostic Criteria for Transient Ischemic Attacks Used in the Emergency Department Are Highly Sensitive and Specific.

BACKGROUND: Making a correct diagnosis of a transient ischemic attack (TIA) is prone to errors because numerous TIA mimics exist and there is a shortage of evidence-based diagnostic criteria for TIAs. In this study, we applied for the first time the recently proposed explicit diagnostic criteria for transient ischemic attacks (EDCT) to a group of patients presenting to the emergency department of a large German tertiary care hospital with a suspected TIA. The aim was to determine the sensitivity and specificity of the EDCT in its clinical application. METHODS: A total of 128 patients consecutively presenting to the emergency department of the University Hospital of Lübeck, Germany, under the suspicion of a TIA were prospectively interviewed about their clinical symptoms at the time of presentation. The diagnosis resulting from applying the EDCT was compared to the diagnosis made independently by the senior physicians performing the usual diagnostic work-up ("gold standard"), allowing calculation of sensitivity and specificity of the EDCT. RESULTS: EDCT achieved a sensitivity of 96% and a specificity of 88%. When adding the additional criterion F ("the symptoms may not be better explained by another medical or mental disorder"), specificity significantly increased to 98%. CONCLUSIONS: The data show that the EDCT in its modified version as proposed by us are a highly useful tool for clinicians. They display a high sensitivity and specificity to accurately diagnose TIAs in patients referred to the emergency department with a suspected TIA.

Occipital Nerve Stimulation in Chronic Migraine: The Relationship Between Perceived Sensory Quality, Perceived Sensory Location, and Clinical Efficacy-A Prospective, Observational, Non-Interventional Study.

INTRODUCTION: Occipital nerve stimulation (ONS) is used to treat therapy-resistant chronic migraine. Clinical use has resulted in a wide intraindividual and interindividual variation of clinical efficacy. The aim of this study was to analyze a potential relationship between sociodemographic variables, headache parameters, perceived sensory quality, perceived sensory location, as well as clinical efficacy. METHODS: Thirty-two subjects (21.9% male, mean age 45.77 years) suffering from chronic migraine refractory to other treatment and therefore treated with ONS were included in this study. We used a computer-based imaging method for mapping the ONS-induced perceived sensory location, the perceived spatial sensory field size, as well as the perceived sensory quality in a long-term course over 21 months in weekly time intervals. Additionally, the effect of ONS on the migraine headache was documented weekly by the participants using a verbal rating scale. Over the observation period, a total of 808 individual weekly data sets were recorded and a potential relationship between ONS-induced perceptions and headache parameters could be analyzed. RESULTS: We found that 48.9% of stimulation intervals were reported as effective by patients. Women displayed a significantly higher responder rate than men. The reported effectiveness did not differ depending on age, the average number of migraine days per month, the MIDAS score, or the duration of the migraine disorder prior to ONS treatment. Implantation with trial period led to significantly lower responder rates than without the trial period. The most frequently perceived sensory quality of "tingling" was found significantly more frequently in non-responders than in responders. Responders displayed significantly lower pleasantness scores for their reported perceptions than non-responders. Sensations that were spatially perceived above the line connecting the external acoustic meati with the external occipital protuberance (MOP line) led to patients reporting a positive clinical effect significantly more frequently than sensations spatially perceived below the MOP line. Spatially small fields of sensory perception were correlated with a higher responder rate than those covering broader areas. CONCLUSIONS: The ONS-induced sensory location, the size of the spatial sensory field, as well as the sensory quality are significantly correlated with the reported clinical effectiveness. The results suggest that besides surgical technique, the individual and continuous programming of the stimulation parameters is clinically relevant in increasing the therapeutic effectiveness.

Efficacy and safety of erenumab in women with a history of menstrual migraine.

BACKGROUND: We performed a post hoc, subgroup analysis of a phase 3, randomized, double-blind, placebo-controlled study of erenumab for prevention of episodic migraine (STRIVE) to determine the efficacy and safety of erenumab in women with self-reported menstrual migraine. METHODS: Patients received placebo, erenumab 70 mg, or erenumab 140 mg subcutaneously once monthly during the 6-month double-blind treatment phase of STRIVE. Women who reported history of menstrual migraine and who were ≤ 50 years old were included in the analysis. Endpoints were change from baseline in monthly migraine days (MMD) and monthly acute migraine-specific medication days (MSMD; among patients who took acute migraine-specific medications at baseline), proportion of patients achieving ≥ 50% reduction from baseline in MMD, and incidence of adverse events. RESULTS: Among 814 women enrolled in STRIVE, 232 (28.5%) reported a history of menstrual migraine and were ≤ 50 years old. Of the 232 patients, 214 (92%) had a baseline MMD > 5, suggesting a high proportion of women with attacks outside of the 5-day perimenstrual window (2 days before and 3 days after the start of menstruation). Information on "migraine days" includes (and does not discriminate between) perimenstrual and intermenstrual migraine attacks. Between-group differences from placebo over months 4-6 for erenumab 70 mg and 140 mg were - 1.8 (P = 0.001) and - 2.1 (P < 0.001) days for MMD and - 1.6 (P = 0.002) and - 2.4 (P < 0.001) days for acute MSMD, respectively. The odds of having a ≥ 50% reduction from baseline in MMD over months 4-6 were 2.2 (P = 0.024) and 2.8 (P = 0.002) times greater for erenumab 70 mg and 140 mg, respectively, than for placebo. Erenumab had an overall safety profile comparable to placebo. CONCLUSION: Data from this subgroup analysis of women with menstrual migraine are consistent with data from the overall STRIVE episodic migraine population, supporting the efficacy and safety of erenumab in women who experience menstrual migraine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02456740. Registered 28 May 2015.

Peripheral nerve stimulation registry for intractable migraine headache (RELIEF): a real-life perspective on the utility of occipital nerve stimulation for chronic migraine.

BACKGROUND: Migraine is common and ranked as the first cause of disability in people under fifty. Despite significant advances in its pharmacological treatment, it often remains intractable. Neuromodulation is one option considered in the management of those patients. OBJECTIVE: To assess the safety and efficacy of neuromodulation in the treatment of intractable chronic migraine using the Abbott occipital nerve stimulator. METHODS: Recruitment took place in 18 centres in 6 countries. Patients over the age of 18 who had failed three or more preventative drugs, had at least moderate disability based on MIDAS or HIT-6 score and were implanted with an Abbott neurostimulator were included in the study. Patients were followed up for a maximum of 24 months. Data were collected on adverse events, headache relief, headache days, quality of life, migraine disability, satisfaction and quality of life. RESULTS: One hundred twelve patients were included, 79 female and 33 male, with 45 patients reaching the maximum follow-up of 24 months. At 3 months, 33.7% were satisfied or very satisfied with the procedure with 43.0% reporting improved or greatly improved quality of life. 67.5% indicated that they would undergo the procedure again with satisfaction peaking at 9 months when 49.3% were satisfied or very satisfied with the procedure. At 24 months, 46.7% of available patients were satisfied or very satisfied with the procedure-18% of enrolled patients. The adverse events were however frequent with incidences of 37%, 47% and 31% respectively for hardware-, biological and stimulation-related side effects. CONCLUSION: Neuromodulation can be beneficial for selected patients with intractable chronic migraine although frequent complications have been consistently reported across studies. Further research focusing on development of better hardware and technique optimisation and in particular reliable randomised trials with significantly longer follow-ups are warranted in this field.

[Modern migraine therapy-interdisciplinary long-term care]. / Moderne Migränetherapie ­ fachübergreifende Versorgung im Langzeitverlauf.

Migraine has a very high lifetime prevalence with a severe illness-related burden. As a result, extensive long-term and regular treatment is required, which cannot be covered solely by neurologists. This is particularly the case for the long-term monitoring of migraine, which often takes place over several decades. The diagnosis is made using the diagnostic criteria of the International Headache Society (ICHD-3) based on the clinical phenotype. Owing to often complex neurological symptoms, a detailed weighing up of the differential diagnoses is required, which calls for specialist neurological expertise. The same is true for follow-up appointments of more complex therapy issues. Acute therapy with antiemetics, analgesics, and triptans can, so long as it is effective and is administered not longer than 10 days per month, be carried out by the general practitioner or specialist in internal medicine. This is also true for medical prophylactic treatment with dietary supplements, antihypertensive drugs, and tricyclic antidepressants. If this therapy is unsuccessful, prophylactic substances must be used that require more specialized knowledge, which is also reflected in the formal prescription requirements. Neurologists and pain therapists should then be involved in the treatment. This is particularly true for the use of Onabotulinumtoxin A and monoclonal CGRP-(receptor)-antibodies.

ICHD-3 is significantly more specific than ICHD-3 beta for diagnosis of migraine with aura and with typical aura.

BACKGROUND: In the emergency room, distinguishing between a migraine with aura and a transient ischemic attack (TIA) is often not straightforward and mistakes can be harmful to both the patient and to society. To account for this difficulty, the third edition of the International Classification of Headache disorders (ICHD-3) changed the diagnostic criteria of migraine with aura. METHODS: One hundred twenty-eight patients referred to the emergency room at the University Hospital of Lübeck, Germany with a suspected TIA were prospectively interviewed about their symptoms leading to admission shortly after initial presentation. The diagnosis that resulted from applying the ICHD-3 and ICHD-3 beta diagnostic criteria was compared to the diagnosis made independently by the treating physicians performing the usual diagnostic work-up. RESULTS: The new ICHD-3 diagnostic criteria for migraine with aura and migraine with typical aura display an excellent specificity (96 and 98% respectively), and are significantly more specific than the previous ICHD-3 beta classification system when it comes to diagnosing a first single attack (probable migraine with aura and probable migraine with typical aura). CONCLUSIONS: The ICHD-3 is a highly useful tool for the clinical neurologist in order to distinguish between a migraine with aura and a TIA, already at the first point of patient contact, such as in the emergency department or a TIA clinic.

Percutaneous closure of patent foramen ovale in migraine with aura, a randomized controlled trial.

AIMS: Migraine with aura and patent foramen ovale (PFO) are associated. The Percutaneous Closure of PFO in Migraine with Aura (PRIMA) trial is a multicentre, randomized trial to investigate the effect of percutaneous PFO closure in patients refractory to medical treatment. METHODS: Migraine with aura patients and PFO who were unresponsive to preventive medications were randomized to PFO closure or medical treatment. Both groups were given acetylsalicylic acid 75-100 mg/day for 6 months and clopidogrel 75 mg/day for 3 months. The primary endpoint was reduction in monthly migraine days during months 9-12 after randomization compared with a 3-month baseline phase before randomization. The committee reviewing the headache diaries were blinded to treatment assignment. RESULTS: One hundred and seven patients were randomly allocated to treatment with an Amplatzer PFO Occluder (N = 53) or control with medical management (N = 54). The trial was terminated prematurely because of slow enrolment. Eighty-three patients (40 occluder, 43 control) completed 12-month follow-up. Mean migraine days at baseline were 8 (±4.7 SD) in the closure group and 8.3 (±2.4) in controls. The primary endpoint was negative with -2.9 days after PFO closure vs. -1.7 days in control group (P = 0.17). Patent foramen ovale closure caused five adverse events without permanent sequelae. CONCLUSION: In patients with refractory migraine with aura and PFO, PFO closure did not reduce overall monthly migraine days.

Systematic re-evaluation of genes from candidate gene association studies in migraine using a large genome-wide association data set.

BACKGROUND: Before the genome-wide association (GWA) era, many hypothesis-driven candidate gene association studies were performed that tested whether DNA variants in genes that had been selected based on prior knowledge about migraine pathophysiology were associated with migraine. Most studies involved small sample sets without robust replication, thereby making the risk of false-positive findings high. Genome-wide marker data of thousands of migraine patients and controls from the International Headache Genetics Consortium provide a unique opportunity to re-evaluate key findings from candidate gene association studies (and other non-GWA genetic studies) in a much larger data set. METHODS: We selected 21 genes from published candidate gene association studies and six additional genes from other non-GWA genetic studies in migraine. Single nucleotide polymorphisms (SNPs) in these genes, as well as in the regions 500 kb up- and downstream, were inspected in IHGC GWAS data from 5175 clinic-based migraine patients with and without aura and 13,972 controls. RESULTS: None of the SNPs in or near the 27 genes, including the SNPs that were previously found to be associated with migraine, reached the Bonferroni-corrected significance threshold; neither when analyzing all migraine patients together, nor when analyzing the migraine with and without aura patients or males and females separately. CONCLUSION: The available migraine GWAS data provide no clear evidence for involvement of the previously reported most promising candidate genes in migraine.

Genetic analysis for a shared biological basis between migraine and coronary artery disease.

OBJECTIVE: To apply genetic analysis of genome-wide association data to study the extent and nature of a shared biological basis between migraine and coronary artery disease (CAD). METHODS: Four separate methods for cross-phenotype genetic analysis were applied on data from 2 large-scale genome-wide association studies of migraine (19,981 cases, 56,667 controls) and CAD (21,076 cases, 63,014 controls). The first 2 methods quantified the extent of overlapping risk variants and assessed the load of CAD risk loci in migraineurs. Genomic regions of shared risk were then identified by analysis of covariance patterns between the 2 phenotypes and by querying known genome-wide significant loci. RESULTS: We found a significant overlap of genetic risk loci for migraine and CAD. When stratified by migraine subtype, this was limited to migraine without aura, and the overlap was protective in that patients with migraine had a lower load of CAD risk alleles than controls. Genes indicated by 16 shared risk loci point to mechanisms with potential roles in migraine pathogenesis and CAD, including endothelial dysfunction (PHACTR1) and insulin homeostasis (GIP). CONCLUSIONS: The results suggest that shared biological processes contribute to risk of migraine and CAD, but surprisingly this commonality is restricted to migraine without aura and the impact is in opposite directions. Understanding the mechanisms underlying these processes and their opposite relationship to migraine and CAD may improve our understanding of both disorders.

Imaging sensory effects of occipital nerve stimulation: a new computer-based method in neuromodulation.

BACKGROUND: Within the last years, occipital nerve stimulation (ONS) has proven to be an important method in the treatment of severe therapy-resistant neurological pain disorders. The correspondence between lead placement as well as possible stimulation parameters and the resulting stimulation effects remains unclear. OBJECTIVE: The method aims to directly relate the neuromodulatory mechanisms with the clinical treatment results, to achieve insight in the mode of action of neuromodulation, to identify the most effective stimulation sets and to optimize individual treatment effects. METHODS: We describe a new computer-based imaging method for mapping the spatial, cognitive and affective sensory effects of ONS. The procedure allows a quantitative and qualitative analysis of the relationship between lead positioning, the stimulation settings as well as the sensory and clinical stimulation effects. CONCLUSION: A regular mapping of stimulation and sensory parameters allows a coordinated monitoring. The stimulation results can be reviewed and compared with regards to clinical effectiveness.

Phenotype of migraine headache and migraine aura of Richard Wagner.

BACKGROUND: The headache phenotype and neurological symptoms of the German composer Richard Wagner (1813-1883), whose music dramas count towards the most frequently performed operas across the world, are previously undocumented. METHODS: Richard Wagner's own descriptions of his headache symptoms in his original writings and letters are investigated, as well as the complete diary records of his second wife, Cosima Wagner. RESULTS: There are manifold indications that Richard Wagner suffered from a severe headache disorder, which fulfils most likely the diagnostic criteria of migraine without aura and migraine with aura of ICHD-3 beta. CONCLUSIONS: Richard Wagner's life and opus can help to better understand the burden and suffering caused by migraine with its severe effects on the individual, familial and social life, the culture and community.