Characteristics and outcomes of cerebral venous thrombosis associated with COVID-19.

INTRODUCTION: Previous reports and meta-analyses derived from small case series reported a mortality rate of up to 40% in patients with coronavirus disease 2019 associated cerebral venous thrombosis (COVID-CVT). We assessed the clinical characteristics and outcomes in an international cohort of patients with COVID-CVT. PATIENTS AND METHODS: This was a registry study of consecutive COVID-CVT patients diagnosed between March 2020 and March 2023. Data collected by the International Cerebral Venous Thrombosis Consortium from patients with CVT diagnosed between 2017 and 2018 served as a comparison. Outcome analyses were adjusted for age and sex. RESULTS: We included 70 patients with COVID-CVT from 23 hospitals in 15 countries and 206 controls from 14 hospitals in 13 countries. The proportion of women was smaller in the COVID-CVT group (50% vs 68%, p < 0.01). A higher proportion of COVID-CVT patients presented with altered mental state (44% vs 25%, p < 0.01), the median thrombus load was higher in COVID-CVT patients (3 [IQR 2-4] vs 2 [1-3], p < 0.01) and the length of hospital stay was longer compared to controls (11 days [IQR 7-20] vs 8 [4-15], p = 0.02). In-hospital mortality did not differ (5/67 [7%, 95% CI 3-16] vs 7/206 [3%, 2-7], aOR 2.6 [95% CI 0.7-9]), nor did the frequency of functional independence after 6 months (modified Rankin Scale 0-2; 45/58 [78%, 95% CI 65-86] vs 161/185 [87%, 81-91], aOR 0.5 [95% CI 0.2-1.02]). CONCLUSION: In contrast to previous studies, the in-hospital mortality rate and functional outcomes during follow-up did not differ between COVID-CVT patients and the pre-COVID-19 controls.

Two-year, real-world erenumab persistence and quality of life data in 82 pooled patients with abrupt onset, unremitting, treatment refractory headache and a migraine phenotype: New daily persistent headache or persistent post-traumatic headache in the majority of cases.

BACKGROUND: Patients diagnosed with New Daily Persistent Headache and Persistent Post-Traumatic Headache belong to a heterogeneous group of primary and secondary headache disorders, with the common clinical feature that these conditions start abruptly, continue unabated, and are refractory to conventional migraine preventive treatments. OBJECTIVE: This is a real-world, medium-term audit to explore whether erenumab improves quality of life in a pooled group of 82 abrupt-onset, unremitting and treatment refractory patients, where the diagnosis is new daily persistent headache and persistent post-traumatic headache in the majority of cases. METHODS: Eighty-two patients were treated with erenumab every 28 days over a two to three-year period, beginning in December 2018. These patients were "longstanding chronic" and refractory with a median of eight (IQR 4-12) prior failed migraine preventive treatments and median duration of disease of seven (IQR 3-11) years. The starting dose of erenumab was 70 mg in 79% of cases and 140 mg in the remaining patients (individuals with a BMI of more than 30). All patients were asked to complete three migraine specific Quality of Life questionnaires or Patient Reported Outcome Measures before starting treatment and typically at 3-12 intervals until the end of June 2021 or cessation of treatment. The Patient Reported Outcome Measures included: Headache Impact Test-6, Migraine Associated Disability Assessment test and Migraine-Specific Quality-of-Life Questionnaire. Patients generally only stayed on treatment after 6-12 months if there was deemed to be an improvement of at least 30% and there were no significant side effects. The longest treated cases have quality of life data for 30 months after starting erenumab. RESULTS: Of the 82 patients, 29 (35%) had improvement in Quality of Life scores, with no significant side effects, and wished to stay on treatment. Fifty-three patients (65%) stopped treatment during the first 6-25 months due to lack of efficacy and/or patient reported side effects (n = 33 and n = 17, respectively) or a combination of both, pregnancy planning (n = 2), and lost to follow up (n = 1). CONCLUSION: Significant improvements in Quality of Life scores were recorded by one-third of patients over a period of 11-30 months, with a 35% persistence after a median of 26 months of treatment. This contrasts with our recently published, treatment resistant, chronic migraine cohort where the persistence with erenumab treatment was almost 55% after a median time of 25 months.

Medium-term real-world data for erenumab in 177 treatment resistant or difficult to treat chronic migraine patients: persistence and patient reported outcome measures after 17-30 months.

BACKGROUND: Many migraine patients do not respond adequately to conventional preventive treatments and are therefore described as treatment/medically resistant or difficult to treat cases. Calcitonin gene-related peptide monoclonal antibodies are a relatively novel molecular treatment for episodic and chronic migraine that have been shown to be effective in short duration clinical trials in approximately 40-50% of all chronic migraine patients. Patient Related Outcome Measures (PROM) or Quality of Life (QoL) questionnaires are used to help measure response to treatment in migraine. Although some open label extension studies have become available for erenumab, there is a lack of real-world data pertaining to quality of life in the medium to long-term for chronic and treatment resistant migraine patients. METHODS: A total of 177 treatment resistant CM patients were started on erenumab (70 mg or 140 mg subcutaneous injection every 4 weeks) in our three specialist Headache Clinics. Of these, 174 had their first injection between December 2018 and October 2019. All patients were evaluated with the following PROM: the Headache Impact Test- 6, Migraine Associated Disability Assessment test and Migraine-Specific QoL Questionnaire, before starting treatment with erenumab and at intervals of 3-12 months after starting treatment. The decision to continue treatment was based on subjective clinical improvement of at least 30% (as reported by the patient), supported with diaries and QoL questionnaires. We present here the QoL measurements for this group of 177 patients. Prior preventive migraine treatments included conventional oral prophylactic medications (such as topiramate, candesartan, propranolol, or amitriptyline), at least two cycles of PREEMPT protocol onabotulinumtoxin A or (in a small number of cases) neuromodulation with single pulse Transcranial Magnetic Stimulation. RESULTS: Of the 177 patients who started treatment with erenumab, 68/177 (38.4%) stopped during the first year, either due to lack of efficacy (no significant benefit or only minimal improvement) and/or possible side effects. 109/177 (61.6%) patients reported clinically significant improvement after 6-12 months and wished to stay on treatment. Twelve of these 109 patients subsequently stopped treatment in the period between 1 year and up to June 2021 (mainly due to a worsening of their migraine). Therefore, a total of 97/177 patients (54.8%) remained on treatment as of June 2021 (duration of treatment 17-30 months, median of 25 months). CONCLUSION: Approximately 55% of treatment resistant or difficult to treat CM patients who trialled erenumab in our clinics reported a subjective benefit and were still on treatment after 17-30 months.

Ischemic stroke with extensive vasculopathy in a patient with neurofibromatosis type 1.

Neurofibromatosis type 1 is an autosomal dominant genetic disorder with multisystem manifestations including vascular abnormalities. The condition is also associated with an increased risk of both ischemic and hemorrhagic stroke. Here we report a case of a 60-year-old male with known neurofibromatosis who presented with right sided hemiparesis. Neuroimaging work-up revealed left internal carotid artery dissection and tandem occlusion of the left internal carotid artery and left middle cerebral artery. There was associated territorial ischemic infarction. The patient was found to have extensive intra and extra cranial vasculopathy including gross basilar dolichoectasia and a right-sided cervical internal carotid artery pseudoaneurysm. This case highlights the clinical significance of neurofibromatosis associated vasculopathy which can result in stroke.

Management of Cerebral Venous Thrombosis Due to Adenoviral COVID-19 Vaccination.

OBJECTIVE: Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality. METHODS: We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis. RESULTS: Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54). CONCLUSIONS: In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022;92:562-573.

Characteristics and Outcomes of Patients With Cerebral Venous Sinus Thrombosis in SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia.

Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson). Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS. Design, Setting, and Participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination. Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria. Main Outcomes and Measures: Clinical characteristics and mortality rate. Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later. Conclusions and Relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.

Raynaud's phenomenon secondary to erenumab in a patient with chronic migraine.

Raynaud's phenomenon is a rare side effect of CGRP monoclonal antibodies. These molecular treatments are a relatively new class of drugs for the prevention of migraine. It is likely that we will see this side effect more often in the future. Patients with a background of Raynaud's phenomenon may experience worsening of their symptoms if started on these treatments.

Perceptions, experiences, and understandings of cluster headache among GPs and neurologists: a qualitative study.

BACKGROUND: Cluster headache is a severe primary headache with a similar prevalence to that of multiple sclerosis. Cluster headache is characterised by unilateral trigeminal distribution of pain, ipsilateral cranial autonomic features, and a tendency to circadian and circannual periodicity. AIM: To explore the perceptions, experiences, and understandings of cluster headache among GPs and neurologists. DESIGN AND SETTING: Qualitative interview study in primary care surgeries and neurology departments in the north of England. METHOD: Semi-structured interviews were conducted with GPs and neurologists, recorded, and transcribed. A thematic analysis was applied to the dataset. RESULTS: Sixteen clinicians participated in this study: eight GPs and eight neurologists. Four main themes were identified following thematic analysis: challenges with the cluster headache diagnosis; impact of cluster headache; challenges with treatment; and appropriateness of referrals to secondary care. Clinicians recognised the delays in the diagnosis of cluster headache, misdiagnosis, and mismanagement, and were aware of the potential impact cluster headache can have on patients' mental health and ability to remain in employment. Findings highlighted tensions between primary and secondary care around the cost of medication and the remit of prescribing treatment regimens. Patients' anxiety, their need for reassurance, and their insistence about seeing a specialist are some of the reasons for referrals. CONCLUSION: Clinicians acknowledged delays in diagnosis, misdiagnosis, and mismanagement of cluster headache. The responsibility of prescribing causes ongoing tensions between primary and secondary care. Clear referral and management pathways for primary headaches are required to improve patient outcomes and healthcare costs.

Development and Evaluation of a Screening Tool to Aid the Diagnosis of a Cluster Headache.

Cluster headache (CH), a severe primary headache, is often misdiagnosed and mismanaged. The aim of this study was to develop and evaluate a screening tool to aid the diagnosis of CH. We developed a novel 12-item screening tool. This was comprised of four components: (1) images depicting headache pain; (2) pain descriptors; (3) key questions that could differentiate between CH and migraine; and (4) a visual analogue pain scale. The total possible questionnaire score ranged from 3-32. Patients with CH and migraines (control group) were recruited prospectively from a headache centre in the North of England, UK. Two-hundred and ninety-six patients were included in the study: 81 CH patients, 36 of which suffer with episodic CH and 45 with chronic CH; 215 migraine patients, 92 of which suffer with episodic migraine and 123 with chronic migraine. The mean questionnaire score was higher in CH patients versus migraine patients (28.4 versus 19.5). At a cut-off score of >25 out of 32, the screening tool had a sensitivity of 86.4% and a specificity of 92.0% in differentiating between CH and migraine. The screening tool could be a useful instrument to aid the diagnosis of a CH. The images depicting headache pain do not clearly discriminate between CH and migraine.

Images depicting headache pain - a tool to aid the diagnosis of cluster headache: a pilot study.

INTRODUCTION AND OBJECTIVE: The diagnosis of primary headaches is based on the International Classification of Headache Disorders (ICHD-3). Cluster headache (CH), a debilitating primary headache, is often misdiagnosed as migraine. In the absence of biological markers, a new visual screening tool with images depicting pain could aid the correct diagnosis of CH. The objective of the study is to test the tool on healthy participants and participants with CH and migraine. METHODS: In phase 1, 6 images portraying people with pain were tested on 150 healthy participants. The healthy participants were asked to rate the images as mild, moderate, severe or excruciating pain. In phase 2, the images were further tested on 116 participants with headache (16 participants with CH, 100 participants with migraine). The participants were recruited prospectively from a tertiary headache center between February and May 2017. The participants were asked to choose which image best illustrated their headache attacks. RESULTS: Phase 1 results showed that the images represent a range of headache pain severities from mild to excruciating as rated by healthy participants. They rated two images as excruciating, one image as severe, one image as moderate/severe, one image as moderate and one image as mild. Phase 2 results showed that two-thirds of participants with CH (69%) and half of the participants with migraine (52%) chose an image described as excruciating by the healthy participants. CONCLUSION: We developed a screening tool with six drawings depicting headache pain severities from mild to excruciating as rated by the healthy participants. Although the images did not differentiate between CH and migraine, the study indicated the potential of using visual aids to assess headache severity.

Update on the pathophysiology of cluster headache: imaging and neuropeptide studies.

OBJECTIVE: Cluster headache (CH) is the most severe primary headache condition. Its pathophysiology is multifaceted and incompletely understood. This review brings together the latest neuroimaging and neuropeptide evidence on the pathophysiology of CH. METHODS: A review of the literature was conducted by searching PubMed and Web of Science. The search was conducted using the following keywords: imaging studies, voxel-based morphometry, diffusion-tensor imaging, diffusion magnetic resonance imaging, tractography, connectivity, cerebral networks, neuromodulation, central modulation, deep brain stimulation, orexin-A, orexin-B, tract-based spatial statistics, single-photon emission computer tomography studies, positron-emission tomography, functional magnetic resonance imaging, magnetic resonance spectroscopy, trigeminovascular system, neuropeptides, calcitonin gene-related peptide, neurokinin A, substance P, nitric oxide synthase, pituitary adenylate cyclase-activating peptide, vasoactive intestinal peptide, neuropeptide Y, acetylcholine, noradrenaline, and ATP. "Cluster headache" was combined with each keyword for more relevant results. All irrelevant and duplicated records were excluded. Search dates were from October 1976 to May 2018. RESULTS: Neuroimaging studies support the role of the hypothalamus in CH, as well as other brain areas involved in the pain matrix. Activation of the trigeminovascular system and the release of neuropeptides play an important role in CH pathophysiology. Among neuropeptides, calcitonin gene-related peptide, vasoactive intestinal peptide, and pituitary adenylate cyclase-activating peptide have been reported to be reliable biomarkers for CH attacks, though not specific for CH. Several other neuropeptides are involved in trigeminovascular activation, but the current evidence does not qualify them as reliable biomarkers in CH. CONCLUSION: CH has a complex pathophysiology and the pain mechanism is not completely understood. Recent neuroimaging studies have provided insight into the functional and structural network bases of CH pathophysiology. Although there has been important progress in neuropeptide studies, a specific biomarker for CH is yet to be found.

Systematic literature review on the delays in the diagnosis and misdiagnosis of cluster headache.

INTRODUCTION: Patients with cluster headache (CH), the most common trigeminal autonomic cephalalgia, often face delayed diagnosis, misdiagnosis and mismanagement. OBJECTIVES: To identify, appraise and synthesise clinical studies on the delays in diagnosis and misdiagnosis of CH in order to determine its causes and help the management of this condition. METHODS: The systematic review was prepared, conducted and reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis. It was registered with International Prospective Register of Systematic Reviews. A systematic search of different electronic databases (Medline, EMBASE, PsycINFO, PubMed, CINAHL, BNI, HMIC, AMED, HBE and Cochrane Library) was carried out in May 2017. Reference lists of relevant articles were hand searched. RESULTS: The search identified 201 unique studies. Fifteen studies met the inclusion criteria of which 13 case series studies and two survey studies. Nine studies assessed the delays in diagnosis and misdiagnosis of CH, five studies the delays in diagnosis and one study the misdiagnosis of CH. The studies included 4661 patients. Delays in diagnosis, misdiagnosis and mismanagement have been reported in many European countries, Japan and in the USA with well-developed health services. The patients with CH often visited many different clinicians, surgeons and dentists and received multiple diagnosis prior to being correctly diagnosed. CONCLUSION: This systematic review shows that the delays in the diagnosis of CH are a widespread problem, the time to diagnosis still vary from country to country and both patients and physicians are responsible for the delays in diagnosis.

Iatrogenic visual aura: a case report and a brief review of the literature.

Iatrogenic migraine aura following transseptal catheterization has only rarely been reported in the literature. We report the case of a 60-year-old female who presented with new onset of migraine with visual aura 1 day after transseptal cryoballoon catheter ablation for atrial fibrillation. The patient had a 5-year history of typical migraine without aura and had never experienced visual aura before the cardiac intervention. The neurological examination, fundoscopy, and blood tests were normal. The magnetic resonance imaging of the brain showed small vessel ischemia without evidence of vessel ischemic changes in the occipital lobes and large blood vessel disease. A change in the characteristics of existing migraine could occur following an iatrogenic episode, which in this case was catheter ablation for atrial fibrillation. A new onset of aura is considered an indication for a brain scan as it may signify underlying new pathology.

Current Understanding on Pain Mechanism in Migraine and Cluster Headache.

CONTEXT: Migraine and cluster headache are undoubtedly painful conditions. The respective pathogenesis of these two conditions is incompletely understood. In both cases, the treatments used have largely been empirical and have relied to a much lesser extent on our understanding of the mechanisms causing pain. We hereby review the pain mechanisms in migraine and cluster headache, two of the commonest primary headache disorders. EVIDENCE ACQUISITION: A review of the English literature was conducted by searching PubMed for studies on pain mechanism in migraine and cluster headache. We entered [migraine] and [pain mechanism] in Pubmed and 488 articles were obtained. Articles were then included according to their relevance to the topic. Similarly, [cluster headache] and [pain mechanism] revealed 79 search results. RESULTS: There is evidence that the trigeminovascular system and neurogenic inflammation play important roles, together with certain areas of the brain, leading to these conditions being termed 'neurovascular headaches'. Functional imaging findings suggest a possible role of the dorsolateral pons in generating migraine attacks while the role of the hypothalamus in cluster headache is more firmly established. CONCLUSIONS: Migraine and cluster headache have complex pathophysiologies. The exact mechanism causing pain in both conditions is incompletely understood and more research needs to be undertaken in this area.

Evidence-based treatments for cluster headache.

Cluster headache (CH), one of the most painful syndromes known to man, is managed with acute and preventive medications. The brief duration and severity of the attacks command the use of rapid-acting pain relievers. Inhalation of oxygen and subcutaneous sumatriptan are the two most effective acute therapeutic options for sufferers of CH. Several preventive medications are available, the most effective of which is verapamil. However, most of these agents are not backed by strong clinical evidence. In some patients, these options can be ineffective, especially in those who develop chronic CH. Surgical procedures for the chronic refractory form of the disorder should then be contemplated, the most promising of which is hypothalamic deep brain stimulation. We hereby review the pathogenesis of CH and the evidence behind the treatment options for this debilitating condition.

Does analgesic overuse matter? Response to OnabotulinumtoxinA in patients with chronic migraine with or without medication overuse.

Chronic migraine affects 2 % of the population and has substantial impact on quality of life and considerable burden on healthcare resources. 50-80 % patients with chronic migraine have excessive consumption of analgesic medications. Withdrawal of analgesics is often advised before commencing preventive treatments. However, some headache experts recommend preventive treatments alongside analgesic withdrawal. 434 patients with chronic migraine attending the Hull Headache Clinic who received OnabotulinumtoxinA as preventive treatment were stratified to those with or without analgesic overuse. Data was collected through a dedicated headache diary and analysed for headache and migraine days reduction and for an increment in headache-free days in the month post treatment. The data shows no difference in the therapeutic outcome in patients with or without analgesic overuse with substantial reduction in headache and migraine days and an increment in headache-free days in both groups in a real-life clinical setting. OnabotulinumtoxinA is equally effective in patients with chronic migraine with or without analgesic overuse.