Publications by authors named "David Garcia-Azorin"

65 Publications

Acute and post-acute neurological manifestations of COVID-19: present findings, critical appraisal, and future directions.

J Neurol 2021 Oct 21. Epub 2021 Oct 21.

Department of Neurology, Centre for Global Health, Technical University of Munich, Munich, Germany.

Acute and post-acute neurological symptoms, signs and diagnoses have been documented in an increasing number of patients infected by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19). In this review, we aimed to summarize the current literature addressing neurological events following SARS-CoV-2 infection, discuss limitations in the existing literature and suggest future directions that would strengthen our understanding of the neurological sequelae of COVID-19. The presence of neurological manifestations (symptoms, signs or diagnoses) both at the onset or during SARS-CoV-2 infection is associated with a more severe disease, as demonstrated by a longer hospital stay, higher in-hospital death rate or the continued presence of sequelae at discharge. Although biological mechanisms have been postulated for these findings, evidence-based data are still lacking to clearly define the incidence, range of characteristics and outcomes of these manifestations, particularly in non-hospitalized patients. In addition, data from low- and middle-income countries are scarce, leading to uncertainties in the measure of neurological findings of COVID-19, with reference to geography, ethnicity, socio-cultural settings, and health care arrangements. As a consequence, at present a specific phenotype that would specify a post-COVID (or long-COVID) neurological syndrome has not yet been identified.
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http://dx.doi.org/10.1007/s00415-021-10848-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528941PMC
October 2021

Delayed headache after COVID-19 vaccination: a red flag for vaccine induced cerebral venous thrombosis.

J Headache Pain 2021 Sep 17;22(1):108. Epub 2021 Sep 17.

Department of Neurology, Akershus University Hospital, Lørenskog, Norway.

Background: Headache is a frequent symptom following COVID-19 immunization with a typical onset within days post-vaccination. Cases of cerebral venous thrombosis (CVT) have been reported in adenovirus vector-based COVID-19 vaccine recipients.

Findings: We reviewed all vaccine related CVT published cases by April 30, 2021. We assessed demographic, clinical variables and the interval between the vaccination and onset of headache. We assessed whether the presence of headache was associated with higher probability of death or intracranial hemorrhage. We identified 77 cases of CVT after COVID-19 vaccination. Patients' age was below 60 years in 74/77 (95.8%) cases and 61/68 (89.7%) were women. Headache was described in 38/77 (49.4%) cases, and in 35/38 (92.1%) was associated with other symptoms. Multiple organ thrombosis was reported in 19/77 (24.7%) cases, intracranial hemorrhage in 33/77 (42.9%) cases and 19/77 (24.7%) patients died. The median time between vaccination and CVT-related headache onset was 8 (interquartile range 7.0-9.7) days. The presence of headache was associated with a higher odd of intracranial hemorrhage (OR 7.4; 95% CI: 2.7-20.8, p < 0.001), but not with death (OR: 0.51, 95% CI: 0.18-1.47, p = 0.213).

Conclusion: Delayed onset of headache following an adenovirus vector-based COVID-19 vaccine is associated with development of CVT. Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vaccine, should receive a thorough clinical evaluation and CVT must be ruled out.
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http://dx.doi.org/10.1186/s10194-021-01324-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446734PMC
September 2021

The cognitive impact of guard shifts in physicians: a before-after study.

Neurol Sci 2021 Aug 18. Epub 2021 Aug 18.

Department of Neurology, Hospital Clínico Universitario San Carlos, Madrid, Spain.

Objective: We intend to evaluate the change of different cognitive functions after a guard shift in physicians.

Methods: A descriptive observational study was performed. The study population included Spanish physicians who were asked to complete before and immediately after their guard shift the following tests: Digit Span, TMT-A, TMT-B, Symbol Digit, Stroop, Free and Cued Selective Reminding, creep and formal fluency, Visual Orientation and Space Perception tests, and the Leeds Sleep Questionnaire.

Results: Thirty subjects were included in the study among which 43.3% were female. The mean subjective impression of the guard shift was 4.47/10 (2.57) and was correlated with the number of sleep hours during the guard shift (r = 0.72, p < 0.001). Statistically significant differences in the comparison between pre- and post-guard period results were found for the Symbol Digit test (88.27 vs. 81.47, p = 0.005), Digit Span test (7.43 vs. 7.00, p = 0.025), Free and Cued Selective Reminding Test (22.73 vs. 21.20, p = 0.002), categorical fluency (39.03 vs. 34.53, p = 0.008), and phonemic fluency (19.57 vs. 16.13, p = 0.001).

Conclusions: The realization of guard shift was associated with a lower yield in several cognitive functions, especially in tasks related to executive function and attention.
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http://dx.doi.org/10.1007/s10072-021-05501-xDOI Listing
August 2021

Understanding the diagnoses and medical care experience of patients with new daily persistent headache: a qualitative study in Spain.

BMJ Open 2021 08 17;11(8):e048552. Epub 2021 Aug 17.

Department of Neurology, Hospital Clínico Universitario de Valladolid, Valladolid, Spain.

Objective: To explore the experiences of patients suffering from new daily persistent headache (NDPH) regarding the diagnostic process, treatment and medical care.

Design: A qualitative phenomenological study was conducted.

Setting: A specialised headache unit at two university hospitals in Spain between February 2017 and December 2018.

Participants: Patients diagnosed with NDPH according to the International Classification of Headache disorders (third beta edition).

Methods: Purposeful sampling was performed. Data were collected using unstructured and semistructured interviews, researchers' field notes and patients' drawings. An inductive thematic analysis was used to identify significant emerging themes from interviews, field notes and descriptions of patients' drawings. Also, Guillemin's proposal was used to analyse the contents of drawings.

Results: Nineteen patients with a mean age of 45.3 were recruited. Four main themes emerged: (1) Seeking a diagnosis, patients visit many doctors without receiving a clear answer and their diagnosis is delayed; (2) Self-medication-minimising pill intake, medication is ineffective, and therefore, some patients discontinue treatment, or are flexible with how they take medication; (3) Trying other non-pharmacological options, many patients turn to other therapies and complementary and/or alternative therapies as a second option, however these are ineffective and (4) Medical care, with two subthemes, referrals and lacking continuity of care, and building the doctor-patient relationship. Patients describe how the referral breaks the continuity of care, and how they identify the traits of a doctor who is approachable and which behaviours the doctor should avoid when caring for patients.

Conclusions: An in-depth knowledge of the beliefs and expectations of patients with NDPH will allow the professional to establish a relationship of trust, which will improve the patients' knowledge of which therapies are the most appropriate, and to establish expectations based on the relationship with the doctor, and not only on patients' beliefs.
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http://dx.doi.org/10.1136/bmjopen-2020-048552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372810PMC
August 2021

Headache as an acute and post-COVID-19 symptom in COVID-19 survivors: A meta-analysis of the current literature.

Eur J Neurol 2021 11 8;28(11):3820-3825. Epub 2021 Aug 8.

Department of Radiology, Rehabilitation and Physiotherapy, Universidad Complutense de Madrid, Madrid, Spain.

Background: Headache is identified as a common post-COVID sequela experienced by COVID-19 survivors. The aim of this pooled analysis was to synthesize the prevalence of post-COVID headache in hospitalized and non-hospitalized patients recovering from SARS-CoV-2 infection.

Methods: MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers, were searched up to 31 May 2021. Studies or preprints providing data on post-COVID headache were included. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. Random effects models were used for meta-analytical pooled prevalence of post-COVID headache. Data synthesis was categorized at hospital admission/symptoms' onset, and at 30, 60, 90, and ≥180 days afterwards.

Results: From 9573 studies identified, 28 peer-reviewed studies and 7 preprints were included. The sample was 28,438 COVID-19 survivors (12,307 females; mean age: 46.6, SD: 17.45 years). The methodological quality was high in 45% of the studies. The overall prevalence of post-COVID headache was 47.1% (95% CI 35.8-58.6) at onset or hospital admission, 10.2% (95% CI 5.4-18.5) at 30 days, 16.5% (95% CI 5.6-39.7) at 60 days, 10.6% (95% CI 4.7-22.3) at 90 days, and 8.4% (95% CI 4.6-14.8) at ≥180 days after onset/hospital discharge. Headache as a symptom at the acute phase was more prevalent in non-hospitalized (57.97%) than in hospitalized (31.11%) patients. Time trend analysis showed a decreased prevalence from the acute symptoms' onset to all post-COVID follow-up periods which was maintained afterwards.

Conclusion: This meta-analysis found that the prevalence of post-COVID headache ranged from 8% to 15% during the first 6 months after SARS-CoV-2 infection.
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http://dx.doi.org/10.1111/ene.15040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444899PMC
November 2021

Previous History of Migraine Is Associated With Fatigue, but Not Headache, as Long-Term Post-COVID Symptom After Severe Acute Respiratory SARS-CoV-2 Infection: A Case-Control Study.

Front Hum Neurosci 2021 28;15:678472. Epub 2021 Jun 28.

Department of Neurology, Hospital Clínico San Carlos, Madrid, Spain.

Objective: To investigate the association of pre-existing migraine in patients hospitalised and who recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with the presence of post-coronavirus disease (COVID) symptoms.

Background: No study has investigated the role of migraine as a risk factor for development of post-COVID symptoms.

Methods: A case-control study including individuals hospitalised during the first wave of the pandemic (from February 20 to May 31, 2020) was conducted. Patients with confirmed previous diagnosis of migraine were considered cases. Two age- and sex-matched individuals without a history of headache per case were also recruited as controls. Hospitalisation/clinical data were collected from hospital medical records. Patients were scheduled for a telephone interview. A list of post-COVID symptoms was systematically evaluated, but participants were invited to freely report any symptom. The Hospital Anxiety and Depression Scale and the Pittsburgh Sleep Quality Index were used to assess anxiety/depressive symptoms and sleep quality. Multivariable conditional logistic regression models were constructed.

Results: Overall, 57 patients with confirmed diagnosis of migraine and 144 non-migraine controls who had recovered from COVID-19 were assessed at 7.3 months (SD 0.6) after hospital discharge. The number of post-COVID symptoms in the migraine group was significantly greater (OR 1.70, 95% CI 1.29-2.25, < 0.001) than in the non-migraine group. Fatigue was significantly more prevalent (OR 2.89, 95% CI 1.32-6.32, = 0.008) in the migraine group. However, no between-groups difference in the prevalence of headache as a post-COVID symptom was detected.

Conclusion: Patients with a history of migraine who recovered from COVID-19 exhibited more long-term fatigue as post-COVID sequelae than those without migraine. Some of the pathophysiological changes associated with migraine could predispose to the occurrence of post-COVID symptoms.
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http://dx.doi.org/10.3389/fnhum.2021.678472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290894PMC
June 2021

Frequency and phenotype of headache in covid-19: a study of 2194 patients.

Sci Rep 2021 07 19;11(1):14674. Epub 2021 Jul 19.

Headache Unit, Department of Neurology, Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal N° 3, 47003, Valladolid, Spain.

To estimate the frequency of headache in patients with confirmed COVID-19 and characterize the phenotype of headache attributed to COVID-19, comparing patients depending on the need of hospitalization and sex, an observational study was done. We systematically screened all eligible patients from a reference population of 261,431 between March 8 (first case) and April 11, 2020. A physician administered a survey assessing demographic and clinical data and the phenotype of the headache. During the study period, 2194 patients out of the population at risk were diagnosed with COVID-19. Headache was described by 514/2194 patients (23.4%, 95% CI 21.7-25.3%), including 383/1614 (23.7%) outpatients and 131/580 (22.6%) inpatients. The headache phenotype was studied in detail in 458 patients (mean age, 51 years; 72% female; prior history of headache, 49%). Headache was the most frequent first symptom of COVID-19. Median headache onset was within 24 h, median duration was 7 days and persisted after 1 month in 13% of patients. Pain was bilateral (80%), predominantly frontal (71%), with pressing quality (75%), of severe intensity. Systemic symptoms were present in 98% of patients. Headache frequency and phenotype was similar in patients with and without need for hospitalization and when comparing male and female patients, being more intense in females.Trial registration: This study was supported by the Institute of Health Carlos III (ISCIII), code 07.04.467804.74011 and Regional Health Administration, Gerencia Regional de Salud, Castilla y Leon (GRS: 2289/A/2020).
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http://dx.doi.org/10.1038/s41598-021-94220-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290038PMC
July 2021

Patients and general practitioners assessment of the main outcomes employed in the acute and preventive treatment of migraine: a cross sectional study.

BMC Neurol 2021 Jul 15;21(1):279. Epub 2021 Jul 15.

Headache Unit, Neurology Department, Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal 3, 47005, Valladolid, Spain.

Background: We aim to describe and compare patients and general practitioners' opinions about the different variables related to acute and preventive treatment for migraine.

Patients And Methods: An observational descriptive study was performed. Patients with episodic migraine and general practitioners, from our healthcare area, were invited to answer a survey about the different variables related to migraine treatment. They were asked for their opinions on the different variables, and to consider the desired efficacy in percentage terms and the desired action times of treatment.

Results: Fifty-five patients and fifty-five general practitioners were selected. Effectiveness was considered the most important variable for symptomatic and preventive treatment. Cost was considered the least important variable. Patients desired percentage of efficacy was 84.0% (±16.7%) for symptomatic treatment and 79.9% (±17.1%) for preventive treatment. General practitioners desired percentage of efficacy was 75.0% (±14.0) for symptomatic treatment and 70.4% (±14.3) for preventive treatment. For symptomatic treatment the desired action time for pain cessation was selected as 27.5 min (±13.8) for patients and 24.0 min (±18.3) for GPs. For preventive treatment the desired action time for effect was 7.1 days (±4.5) for patients and 13.9 days (±8.9) for general practitioners.

Conclusion: The most important endpoints were, for acute: effectiveness, a short action time and a persistent effect. For prophylactic: effectiveness, sustained effect and tolerability. Both patients and general practitioners agreed on the most and least preferred endpoints. Desired percentage of efficacy was above 75% for both symptomatic and preventive treatment; and the desired action time was below 30 min for acute treatment and 2 weeks for preventive treatment.
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http://dx.doi.org/10.1186/s12883-021-02220-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281698PMC
July 2021

Daily Headache in Chronic Migraine Is a Predictive Factor of Response in Patients Who Had Completed Three Sessions of OnabotulinumtoxinA.

Toxins (Basel) 2021 06 21;13(6). Epub 2021 Jun 21.

Headache Unit, Neurology Department, Hospital Clínico Universitario de Valladolid, 47003 Valladolid, Spain.

OnabotulinumtoxinA is one of the main preventive treatments for chronic migraine. Despite that up to one third of patients with chronic migraine suffer from daily headache, these individuals have hardly been studied. We conducted a prospective cohort study, including patients with chronic migraine and treated with OnabotulinumtoxinA according to the PREEMPT paradigm. The primary endpoint was to assess whether patients with chronic migraine and daily headache had a different response after three sessions of OnabotulinutoxinA than patients without daily headache. The secondary endpoint was to analyse the presence of predictive factors that could be associated with a higher response to OnabotulinumtoxinA. Patients with daily headache had a reduction of 14.9 (SD: 9.7) headache days per month, patients with 22-29 headache days a reduction of 10.6 (SD: 9.9) days, and patients with 15-21 headache days a reduction of 8.6 (SD: 7.1) days ( < 0.001). In the univariate regression analysis, a higher number of headache days per month at baseline was associated with higher odds of reduction in the number of headache days per month after OnabotulinumtoxinaA treatment (OR: 0.474, 95% CI: 0.278-0.670, < 0.001). This association was maintained in the multivariate regression analysis (OR: 0.540, 95% CI: 0.333-0.746, < 0.001). In our sample, daily headache was not associated with a worse response to OnabotulinumtoxinA treatment. A higher frequency of headache at baseline was a predictor of better response to OnabotulinumtoxinA treatment.
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http://dx.doi.org/10.3390/toxins13060432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234385PMC
June 2021

Nerve block as neuropathic pain treatment for the great auricular nerve neuropathy: A case report.

Headache 2021 06 29;61(6):963-968. Epub 2021 Jun 29.

Headache Unit, Department of Neurology, Hospital Clínico Universitario de Valladolid, Valladolid, Spain.

Objective/background: The great auricular nerve (GAN) is a major sensory branch of the cervical plexus. Painful great auricular neuropathy causes pain circumscribed to the inferior preauricular region, the jaw angle, the ventral pinna, and the mastoid region.

Methods: We present a 46-year-old woman experiencing facial pain in the bilateral preauricular and infra-auricular region, constant, of abrasive quality without any other associated symptomatology that is triggered or aggravated with cephalic movements, cervical turn, mandibular movement, and palpation on the affected area.

Results: Symptomatic treatment with analgesics, anti-inflammatories, and neuropathic preventive medications was ineffective. However, nerve block anesthetic treatment resulted in complete pain remission.

Conclusion: Great auricular neuropathy is an uncommon cause of facial pain; our case report is the first bilateral occurrence reported to date. It should be suspected in patients with circumscribed shooting or lancinating paroxysmal pain in the territory of the GAN. It is characterized by the aggravation of pain with cervical movements and complete relief after anesthetic blockade.
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http://dx.doi.org/10.1111/head.14142DOI Listing
June 2021

The presence of headache at onset in SARS-CoV-2 infection is associated with long-term post-COVID headache and fatigue: A case-control study.

Cephalalgia 2021 11 16;41(13):1332-1341. Epub 2021 Jun 16.

CNAP, Center for Sensory-Motor Interaction, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark.

Objective: To investigate the association of headache during the acute phase of SARS-CoV-2 infection with long-term post-COVID headache and other post-COVID symptoms in hospitalised survivors.

Methods: A case-control study including patients hospitalised during the first wave of the pandemic in Spain was conducted. Patients reporting headache as a symptom during the acute phase and age- and sex-matched patients without headache during the acute phase participated. Hospitalisation and clinical data were collected from medical records. Patients were scheduled for a telephone interview 7 months after hospital discharge. Participants were asked about a list of post-COVID symptoms and were also invited to report any additional symptom they might have. Anxiety/depressive symptoms and sleep quality were assessed with the Hospital Anxiety and Depression Scale and the Pittsburgh Sleep Quality Index.

Results: Overall, 205 patients reporting headache and 410 patients without headache at hospitalisation were assessed 7.3 months (Standard Deviation 0.6) after hospital discharge. Patients with headache at onset presented a higher number of post-COVID symptoms (Incident Rate Ratio: 1.16, 95% CI: 1.03-1.30). Headache at onset was associated with a previous history of migraine (Odd Ratio: 2.90, 95% Confidence Interval: 1.41-5.98) and with the development of persistent tension-type like headache as a new post-COVID symptom (Odd Ratio: 2.65, 95% CI: 1.66-4.24). Fatigue as a long-term symptom was also more prevalent in patients with headache at onset (Odd Ratio: 1.55, 95% CI: 1.07-2.24). No between-group differences in the prevalence of anxiety/depressive symptoms or sleep quality were seen.

Conclusion: Headache in the acute phase of SARS-CoV-2 infection was associated with higher prevalence of headache and fatigue as long-term post-COVID symptoms. Monitoring headache during the acute phase could help to identify patients at risk of developing long-term post-COVID symptoms, including post-COVID headache.
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http://dx.doi.org/10.1177/03331024211020404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212025PMC
November 2021

Clinical review of cerebral venous thrombosis in the context of COVID-19 vaccinations: Evaluation, management, and scientific questions.

J Neurol Sci 2021 08 5;427:117532. Epub 2021 Jun 5.

Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York, NY, USA.

Background: Vaccine induced immune mediated thrombocytopenia or VITT, is a recent and rare phenomenon of thrombosis with thrombocytopenia, frequently including cerebral venous thromboses (CVT), that has been described following vaccination with adenovirus vaccines ChAdOx1 nCOV-19 (AstraZeneca) and Ad26.COV2·S Johnson and Johnson (Janssen/J&J). The evaluation and management of suspected cases of CVT post COVID-19 vaccination are critical skills for a broad range of healthcare providers.

Methods: A collaborative comprehensive review of literature was conducted among a global group of expert neurologists and hematologists.

Findings: Strategies for rapid evaluation and treatment of the CVT in the context of possible VITT exist, including inflammatory marker measurements, PF4 assays, and non-heparin anticoagulation.
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http://dx.doi.org/10.1016/j.jns.2021.117532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178065PMC
August 2021

Global survey on disruption and mitigation of neurological services during COVID-19: the perspective of global international neurological patients and scientific associations.

J Neurol 2022 Jan 11;269(1):26-38. Epub 2021 Jun 11.

Department of Neurology, Hospital Clínico Universitario de Valladolid, Valladolid, Spain.

Background: The COVID-19 pandemic outbreak has dramatically disrupted healthcare systems. Two rapid WHO pulse surveys studied disruptions in mental health services, but did not particularly focus on neurology. Here, a global survey was conducted and addresses the impact of the pandemic on neurology services.

Methods: A cross-sectional study was carried out in which 34 international neurological associations were asked to distribute the survey to national associations. The responses represented the national situation, in November-December 2020, with regard to the main disrupted neurological services, reasons and the mitigation strategies implemented as well as the disruption on training of residents and on neurological research. A comparison with the situation in February-April 2020, first pandemic wave, was also requested.

Findings: 54 completed surveys came from 43 countries covering all the 6 WHO regions. Overall, neurological services disruption was reported as mild by 26%, moderate by 30%, complete by 13% of associations. The most affected services were cross-sectoral neurological services (57%) and neurorehabilitation (56%). The second wave of the pandemic, however, was associated with the improvement of service provision for diagnostics services (44%) and for neurorehabilitation (41%). Governmental directives were the major cause of services' disruption (56%). Mitigation strategies were mostly established through telemedicine (48%). Almost half of respondents reported a significant impact on neurological research (48%) and educational activities (60%). Most associations (67%) were not involved in decision making for neurological patients' issues by their national government.

Interpretation: The COVID-19 pandemic affects neurological services and raises the universal need for the development of neurological health care at the policy, systems and services levels. A global national plan on mitigation strategies for disruption of neurological services during pandemic situations should be established and neurological scientific and patients associations should get involved in decision making.
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http://dx.doi.org/10.1007/s00415-021-10641-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195244PMC
January 2022

Cytokine and interleukin profile in patients with headache and COVID-19: A pilot, CASE-control, study on 104 patients.

J Headache Pain 2021 Jun 4;22(1):51. Epub 2021 Jun 4.

Institute of Health Sciences of Castile and Leon (ICSCYL), Santa Clara Square, 42002, Soria, Spain.

Background: The presence of headache during the acute phase of COVID-19 could be associated with the innate response and the cytokine release. We aim to compare the cytokine and interleukin profile in hospitalized COVID-19 patients at the moment of admission with and without headache during the course of the disease.

Methods: An observational analytic study with a case control design was performed. Hospitalized patients from a tertiary hospital with confirmed COVID-19 disease were included. Patients were classified into the headache or the control group depending on whether they presented headache not better accounted for by another headache disorder other than acute headache attributed to systemic viral infection. Several demographic and clinical variables were studies in both groups. We determined the plasmatic levels of 45 different cytokines and interleukins from the first hospitalization plasma extraction in both groups.

Results: One hundred and four patients were included in the study, aged 67.4 (12.8), 43.3% female. Among them, 29 (27.9%) had headache. Patients with headache were younger (61.8 vs. 69.5 years, p = 0.005) and had higher frequency of fever (96.6 vs. 78.7%, p = 0.036) and anosmia (48.3% vs. 22.7%, p = 0.016). In the comparison of the crude median values of cytokines, many cytokines were different between both groups. In the comparison of the central and dispersion parameters between the two groups, GROa, IL-10, IL1RA, IL-21, IL-22 remained statistically significant. After adjusting the values for age, sex, baseline situation and COVID-19 severity, IL-10 remained statistically significant (3.3 vs. 2.2 ng/dL, p = 0.042), with a trend towards significance in IL-23 (11.9 vs. 8.6 ng/dL, p = 0.082) and PIGF1 (1621.8 vs. 110.6 ng/dL, p = 0.071).

Conclusions: The higher levels of IL-10 -an anti-inflammatory cytokine- found in our sample in patients with headache may be explained as a counteract of cytokine release, reflecting a more intense immune response in these patients.
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http://dx.doi.org/10.1186/s10194-021-01268-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177251PMC
June 2021

Secondary Nummular Headache: A New Case Series and Review of the Literature.

Pain Med 2021 Nov;22(11):2718-2727

Headache Unit, Neurology Department, Hospital Clínico Universitario, Valladolid, Spain.

Background: Nummular headache (NH) is defined in the International Classification of Headache Disorders (ICHD) by the presence of localized pain circumscribed to a small round area of the scalp, not better accounted by any other diagnosis. As in many other primary headache disorders, secondary cases might occur. To date, 13 secondary cases have been published. We aim to present a long series of secondary NH and review the literature of symptomatic NH.

Patients And Methods: Retrospective analysis of an observational prospective cohort in a headache unit located in a tertiary hospital. We included patients that fulfilled ICHD criteria and were attributed to a secondary cause. We describe the clinical characteristics, the underlying causes, and the response to treatment.

Results: We included 274 NH patients; eight of them (2.9%) were considered secondary. In one patient the underlying cause was subcutaneous, as for six cases the lesion was located in the bone (two hemangiomas, one osteoma, three different types of cysts), and in one was intracranial but closely related with internal diploe (cavernoma). Among our patients with secondary NH, a preventive therapy was not always needed and, when required, gabapentin or onabotulinumtoxinA were used with positive response.

Conclusions: Secondary NH phenotype overlaps primary NH. Therefore, we recommend routine imaging study in every NH patient. Concerning treatment, it was not necessary to remove the underlying lesion to control the pain and many cases responded to the same prophylactics as primary NH cases.
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http://dx.doi.org/10.1093/pm/pnab174DOI Listing
November 2021

Disruptions of neurological services, its causes and mitigation strategies during COVID-19: a global review.

J Neurol 2021 Nov 22;268(11):3947-3960. Epub 2021 May 22.

Neurology, Public Health, Disability Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Background: The COVID-19 pandemic leads to disruptions of health services worldwide. To evaluate the particular impact on neurological services a rapid review was conducted.

Methods: Studies reporting the provision of neurological services during the pandemic and/or adopted mitigation strategies were included in this review. PubMed and World Health Organization's (WHO) COVID-19 database were searched. Data extraction followed categories used by WHO COVID-19 pulse surveys and operational guidelines on maintaining essential health services during COVID-19.

Findings: The search yielded 1101 articles, of which 369 fulfilled eligibility criteria, describing data from 210,419 participants, being adults (81%), children (11.4%) or both (7.3%). Included articles reported data from 105 countries and territories covering all WHO regions and World Bank income levels (low income: 1.9%, lower middle: 24.7%, upper middle: 29.5% and high income; 44.8%). Cross-sectoral services for neurological disorders were most frequently disrupted (62.9%), followed by emergency/acute care (47.1%). The degree of disruption was at least moderate for 75% of studies. Travel restrictions due to lockdowns (81.7%) and regulatory closure of services (65.4%) were the most commonly reported causes of disruption. Authors most frequently described telemedicine (82.1%) and novel dispensing approaches for medicines (51.8%) as mitigation strategies. Evidence for the effectiveness of these measures is largely missing.

Interpretation: The COVID-19 pandemic affects all aspects of neurological care. Given the worldwide prevalence of neurological disorders and the potential long-term neurological consequences of COVID-19, service disruptions are devastating. Different strategies such as telemedicine might mitigate the negative effects of the pandemic, but their efficacy and acceptability remain to be seen.
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http://dx.doi.org/10.1007/s00415-021-10588-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140556PMC
November 2021

Time lost due to an attack - a novel patient-reported outcome measure for acute migraine treatments.

Cephalalgia 2021 08 19;41(9):1027-1032. Epub 2021 Apr 19.

Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.

Objective: We propose a new outcome measure to assess the efficacy of migraine treatments translating the approach of the Global Burden of Disease studies from a societal to an individual level: Instead of calculating "years lived with disability", we suggest estimating "time lost due to an attack".

Methods: Time lost due to an attack is calculated by multiplying the duration and the degree of impaired functioning during an attack.

Results: Time lost due to an attack, different from other outcome measures, does not just focus on the short-term analgesic effects of treatments, but rather on the improvement of all migraine symptoms and restoration of functioning, also considering therapy-related impairment. Importantly, time lost due to an attack measures the entire time patients are not functioning normally, from onset to complete resolution.

Conclusions: Time lost due to an attack represents a new paradigm to assess migraine burden in single patients for a patient-centered evaluation of both acute and prophylactic treatments.
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http://dx.doi.org/10.1177/03331024211006048DOI Listing
August 2021

Effects of the onabotulinumtoxinA follow-up delay in migraine course during the COVID-19 lockdown.

Neurol Sci 2021 Dec 26;42(12):5087-5092. Epub 2021 Mar 26.

Headache Unit, Department of Neurology, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria de La Princesa, Madrid, Spain.

Background: Face-to-face procedures have been postponed during COVID-19 pandemic. We aim to evaluate the impact of onabotulinumtoxinA follow-up delay in migraine during COVID-19 pandemic.

Methods: Subjective worsening, intensity of migraine attacks, and frequency of headache and migraine were retrospectively compared between patients with unmodified and interrupted onabotulinumtoxinA follow-up in Headache Units.

Results: We included 67 patients with chronic migraine or high-frequency episodic migraine under onabotulinumtoxinA treatment, 65 (97.0%) female, 44.5 ± 12.1 years old. Treatment administration was voluntarily delayed in 14 (20.9%) patients and nine (13.4%) were unable to continue follow-up. Patients with uninterrupted follow-up during lockdown presented 7.6 and 8.1 less monthly days with headache (adjusted p = 0.017) and migraine attacks (adjusted p = 0.009) compared to patients whose follow-up was interrupted, respectively.

Conclusion: Involuntary delay of onabotulinumtoxinA follow-up in patients with migraine due to COVID-19 pandemic was associated with a higher frequency of headache and migraine attacks. Safe administration of onabotulinumtoxinA during lockdown should be promoted.
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http://dx.doi.org/10.1007/s10072-021-05180-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994064PMC
December 2021

Temporal distribution of emergency room visits in patients with migraine and other headaches.

Expert Rev Neurother 2021 May 1;21(5):599-605. Epub 2021 Apr 1.

Emergency Department, Hospital Clínico San Carlos, Madrid, Spain.

Headache is a leading reason for presentation to the emergency department (ED) with migraine being the most frequently headache. To ensure the adequate staffing of healthcare providers during peak times of headache visits, we analyzed the temporal distribution of emergency department visits in patients presenting with headache and/or migraine. The authors conducted an ecological study, including all consecutive visits to the ED for headache. Patients were classified according to the IHS Classification. We analyzed circadian, circaseptan and circannual patterns for number of visits, comparing migraine patients with other headache patients. There were 2132 ED visits for headache, including primary headache in 1367 (64.1%) cases; migraine in 963 (45.2%); secondary headache in 404 (18.9%); and unspecified headache in 366 (17.1%). The circadian pattern showed peaks around 11:00-13:00 and 17:00-19:00, with visits during the night shift 45% less frequent (p < 0.001). The circaseptan pattern showed a peak on Monday-Tuesday and a low point on Sunday (p < 0.007). The circannual pattern peaked in March and decreased in June. ED visits for headache showed specific circadian, circaseptan and circannual variations. No differences were found in these patterns when comparing migraine patients to other headache patients.
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http://dx.doi.org/10.1080/14737175.2021.1906222DOI Listing
May 2021

Linear Headache: A Novel Entity or a Variant of Nummular Headache? Clinical Characteristics and Treatment Response in a Series of 16 Patients.

Pain Med 2021 05;22(5):1158-1166

Headache Unit, Neurology Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain.

Objective: Linear headache has been recently described as an episodic or chronic unilateral pain distributed along a fixed linear trajectory, which combines some characteristics of epicrania fugax and nummular headache. The aim of this study was to describe the clinical characteristics and therapeutic response of a series of 16 new patients.

Design: This is an observational study with a series of cases.

Setting: The study period encompassed June 2014 to June 2019. Demographic, clinical, and therapeutic response data were recorded.

Methods: We included all consecutive patients who presented pain with the following characteristics: sharply contoured, fixed in size and shape, with linear shape, without movement along a trajectory, and not circumscribed to the territory of any nerve.

Results: Twelve patients were women, and four were men. The mean age at onset was 40.1 years. Pain was described as pressing in seven patients, burning in five, and electric or stabbing in two each. Symptomatic treatment had been used by 13 patients (81.2%), with analgesics being the most frequent treatment used. Thirteen patients received preventive treatment. The response to oral medications and anesthetic blockade was insufficient. OnabotulinumtoxinA was used in six cases, with an optimal (>75%) response observed in half.

Conclusion: Linear headache appears to be a distinct headache syndrome from epicrania fugax or nummular headache. Preventive treatment is often required. The drug with the best response was onabotulinumtoxinA.
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http://dx.doi.org/10.1093/pm/pnaa436DOI Listing
May 2021

Evaluation of the Impact of the COVID-19 Lockdown in the Clinical Course of Migraine.

Pain Med 2021 09;22(9):2079-2091

Headache Unit, Department of Neurology, Hospital Universitario de La Princesa & Instituto de Investigación Sanitaria de La Princesa, Madrid, Spain.

Objective: Previous studies have demonstrated that emotional stress, changes in lifestyle habits and infections can worsen the clinical course of migraine. We hypothesize that changes in habits and medical care during coronavirus disease 2019 (COVID-19) lockdown might have worsened the clinical course of migraine.

Design: Retrospective survey study collecting online responses from migraine patients followed-up by neurologists at three tertiary hospitals between June and July 2020.

Methods: We used a web-based survey that included demographic data, clinical variables related with any headache (frequency) and migraine (subjective worsening, frequency, and intensity), lockdown, and symptoms of post-traumatic stress.

Results: The response rate of the survey was 239/324 (73.8%). The final analysis included 222 subjects. Among them, 201/222 (90.5%) were women, aged 42.5 ± 12.0 (mean±SD). Subjective improvement of migraine during lockdown was reported in 31/222 participants (14.0%), while worsening in 105/222 (47.3%) and was associated with changes in migraine triggers such as stress related to going outdoors and intake of specific foods or drinks. Intensity of attacks increased in 67/222 patients (30.2%), and it was associated with the subjective worsening, female sex, recent insomnia, and use of acute medication during a headache. An increase in monthly days with any headache was observed in 105/222 patients (47.3%) and was related to symptoms of post-traumatic stress, older age and living with five or more people.

Conclusions: Approximately half the migraine patients reported worsening of their usual pain during the lockdown. Worse clinical course in migraine patients was related to changes in triggers and the emotional impact of the lockdown.
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http://dx.doi.org/10.1093/pm/pnaa449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108628PMC
September 2021

Neurological presentations of COVID-19: Findings from the Spanish Society of Neurology neuroCOVID-19 registry.

J Neurol Sci 2021 04 19;423:117283. Epub 2020 Dec 19.

Hospital Universitario Quirónsalud Madrid, Madrid, Spain.

Objective: We report the findings from the Spanish Society of Neurology's NeuroCOVID-19 Registry.

Methods: We performed a multicentre study of patients with neurological manifestations of COVID-19. Participating physicians reported demographic, clinical, and paraclinical data and judged the involvement of COVID-19 in causing neurological symptoms.

Results: A total of 233 cases were submitted, including 74 different combinations of manifestations. The most frequently reported were stroke (27%), neuromuscular symptoms (23.6%), altered mental status (23.6%), anosmia (17.6%), headache (12.9%), and seizures (11.6%). The mean age of patients was 61.1 years, with 42.1% being women; a higher proportion of women was recorded among patients with altered mental status, anosmia, and headache. The onset of symptoms differed within categories. Onset of anosmia occurred a mean (standard deviation) of 2.9 (2.5) days after the first general symptom, whereas neuromuscular symptoms appeared after 13.9 (10.1) days. Neurological symptoms were persistent in 33% of patients. General symptoms were present in 97.7% of patients, and results from general laboratory studies were abnormal in 99.4% of patients. Cerebrospinal fluid analysis findings were abnormal in 62.7% of the cases in which this test was performed (n = 51), but positive results for SARS-CoV-2 were only found in one case.

Conclusions: The neurological manifestations of COVID-19 are diverse. Anosmia, myalgia, and headache occur earlier in the course of the disease. Altered mental status, neuromuscular symptoms, and stroke are associated with greater severity. COVID-19 must be incorporated into most clinical and radiological differential diagnoses. COVID-19 may cause persistent and disabling neurological symptoms.
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http://dx.doi.org/10.1016/j.jns.2020.117283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749644PMC
April 2021

Neurological symptoms in Covid-19 patients in the emergency department.

Brain Behav 2021 04 22;11(4):e02058. Epub 2021 Feb 22.

Department of Neurology. Hospital, Clínico Universitario de Valladolid, Valladolid, Spain.

Background: Coronavirus disease 2019 (Covid-19) might present neurological symptoms. We aimed to evaluate the frequency of them at the moment of emergency department (ED) visit and their impact in the prognosis.

Methods: Retrospective cohort study including all consecutive hospitalized cases between March 8th and April 11th, 2020. Covid-19 diagnosis was confirmed by polymerase chain reaction test and/or serology. We compared, in patients with and without neurological symptoms on admission, demographic, clinical presentation, and frequency and type of abnormal laboratory values. We analyzed the variables that were associated with in-hospital all-cause mortality by Cox-regression log-rank test.

Results: We included 576 hospitalized patients, 250 (43.3%) female, aged 67.2 years. At the moment of ED visit, 320 (55.6%) described neurological symptoms, including anosmia (146, 25.3%), myalgia (139, 24.1%), headache (137, 23.8%), and altered mental status (98, 17.0%). Neurological symptoms started the first symptomatic day in 198 (54.2%) cases. Patients with neurological symptoms presented later to the ED (7.9 versus. 6.6 days, p = .019). Only four (0.6%) cases had no typical Covid-19 general symptoms, and only six (1.9%) had a normal laboratory results, for a sensitivity of 98.7% (95% confidence interval (CI): 96.6%-99.6%) and 98.1% (95% CI: 95.7%-99.2%), respectively. In the multivariate Cox-regression of mortality predictors, anosmia (HR: 0.358, 95%CI: 0.140-0.916) and altered mental status (HR: 1.867, 95%CI: 1.162-3.001) were significant.

Conclusion: Neurological symptoms were the most frequent extrapulmonary symptoms. They were present in half of the Covid-19 patients at the time of the ED visit. Anosmia on admission was an independent predictor of lower in-hospital mortality and altered mental status on admission predicted in-hospital mortality.
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http://dx.doi.org/10.1002/brb3.2058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994975PMC
April 2021

Real world effectiveness and tolerability of candesartan in the treatment of migraine: a retrospective cohort study.

Sci Rep 2021 02 15;11(1):3846. Epub 2021 Feb 15.

Headache Unit, Department of Neurology, Hospital Clínico Universitario de Valladolid, Avenida Ramón y Cajal 3, 47003, Valladolid, Spain.

To date, two randomized, controlled studies support the use of candesartan for migraine prophylaxis but with limited external validity. We aim to evaluate the effectiveness and tolerability of candesartan in clinical practice and to explore predictors of patient response. Retrospective cohort study including all patients with migraine who received candesartan between April 2008-February 2019. The primary endpoint was the number of monthly headache days during weeks 8-12 of treatment compared to baseline. Additionally, we evaluated the frequency during weeks 20-24. We analysed the percentage of patients with 50% and 75% response rates and the retention rates after three and 6 months of treatment. 120/4121 patients were eligible, aged 45.9 [11.5]; 100 (83.3%) female. Eighty-four patients (70%) had chronic migraine and 53 (42.7%) had medication-overuse headache. The median number of prior prophylactics was 3 (Inter-quartile range 2-5). At baseline, patients had 20.5 ± 8.5 headache days per month, decreasing 4.3 ± 8.4 days by 3 months (weeks 12-16) and by 4.7 ± 8.7 days by 6 months (paired Student's t-test, p < 0.001). The percentage of patients with a 50% response was 32.5% at 3 months and 31.7% at 6 months, while the retention rate was 85.0% and 58.3%. The number of prior treatments (Odds ratio 0.79, 95% CI 0.64-0.97) and the presence of daily headache (Odds ratio 0.39, 95% CI 0.16-0.97) were associated with a lower probability of response. Candesartan showed beneficial effects in the preventive treatment of migraine in clinical practice, including patients with chronic migraine, medication-overuse headache and resistance to prior prophylactics.
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http://dx.doi.org/10.1038/s41598-021-83508-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884682PMC
February 2021

Headache education and management in Cameroon: a healthcare provider study.

Acta Neurol Belg 2021 Feb 10. Epub 2021 Feb 10.

HM CINAC, Hospital Universitario HM Puerta del Sur, Universidad CEU San Pablo, Móstoles, Madrid, Spain.

Headache disorders are the most prevalent neurological conditions in the Sub-Saharan Africa and the second cause of disability. In this study, we analyze the knowledge about headache disorders and their management among Cameroonian healthcare providers. We conducted an interventional study with a prospective cohort design. Cameroonian health care providers from the whole country were invited. The evaluation was based on a questionnaire that was done before and after a 4-day educational course. The study included 42 participants, 52.4% female, aged 36.8 years. Participants treated a median of 240 monthly patients. Headache was reported as the most frequent neurological condition in their clinics (34%). Mean number of neurological patients seen per week was 69.3, among them 20 were headache patients. At baseline, only 35.8% correctly mentioned at least one primary headache, increasing to 78.6% after the course (p = 0.002). Secondary headaches were correctly identified by 19.0% at baseline and 40.5% after the course (p = 0.01). Clinical history was considered sufficient for headache diagnosis by 57.1% before and 78.6% after (p = 0.5). Correct red flags were mentioned at baseline by only 14.3% of participants, increasing to 40.5% after the course (p = 0.005). At baseline, the preferred symptomatic was paracetamol (47.6%) and Non-Steroidal Anti-Inflammatory Drugs (9.5%), changing to 23.8 and 66.7% after the course (p = 0.05 and < 0.001). Headache was reported as the most frequent neurological disorders. Knowledge about primary headache disorders and their etiology was scarce, and the clinical concept of red flags was limited. The acute drug of choice was paracetamol.
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http://dx.doi.org/10.1007/s13760-021-01620-6DOI Listing
February 2021

Management of thunderclap headache in the emergency room: A retrospective cohort study.

Cephalalgia 2021 05 7;41(6):711-720. Epub 2021 Jan 7.

Headache Unit, Department of Neurology, Institute of Neurosciences, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain.

Introduction: The evaluation of red flags is crucial for the accurate the diagnosis of headache disorders, especially for thunderclap headache. We analysed if secondary headache disorders were adequately ruled out in patients that presented to the emergency room with thunderclap headache.

Methods: In this retrospective cohort study, we screened all patients that visited the emergency room for headache, including those that described thunderclap headache. We measured the frequency with which secondary causes were not adequately ruled out. We analysed the order of the exams, the final diagnosis, and the time elapsed between arrival, initial request for imaging, and the completion of the imaging.

Results: We screened 2132 patients, and 42 (1.9%) fulfilled eligibility criteria. Mean age was 43.1 ± 17.1 years, and 57% of patients were female. For 22 (52.4%) patients, the work-up was incomplete. Vascular study was missing in 16 (38.1%) patients, cerebrospinal fluid evaluation in nine (21.4%), and magnetic resonance imaging in seven (16.7%), with multiple assessments missing in six (14.3%). There were ten different combinations in which the exams were performed, with the most frequent being the second exam's cerebral spinal fluid evaluation in 18 (52.9%) and the computed tomography angiogram in 10 (29.4%). A secondary cause of thunderclap headache was found in 16 (38.1%) patients, and four (9.5%) had a primary headache diagnosis after an adequate and complete study.

Conclusions: Thunderclap onset was described in one of every 50 patients that visited the emergency room for headache. More than half of these patients were not adequately managed. More than a third of thunderclap headache patients had a secondary cause.
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http://dx.doi.org/10.1177/0333102420981721DOI Listing
May 2021

Green Flags and headache: A concept study using the Delphi method.

Headache 2021 02 6;61(2):300-309. Epub 2021 Jan 6.

Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

Objective: The aim of this study was to collect and rate Green Flags, that is, symptoms or pieces of information indicating that a patient is more likely to suffer from a primary than from a secondary headache.

Background: When assessing headaches, a central question to be answered is whether the pain is primary or secondary to another disorder. To maximize the likelihood of a correct diagnosis, relevant signs and symptoms must be sought, identified, and weighed against each other.

Methods: The project was designed as a Delphi study. In the first round, an expert panel proposed green flags that were rated anonymously in two subsequent rounds. Proposals with an average rating of 4.0 and higher on a scale from 0 to 5 reached consensus.

Results: Five Green Flags reached consensus: (i) "The current headache has already been present during childhood"; (ii) "The headache occurs in temporal relationship with the menstrual cycle"; (iii) "The patient has headache-free days"; (iv) "Close family members have the same headache phenotype"; and (v) "Headache occurred or stopped more than one week ago."

Conclusions: We propose five Green Flags for primary headache disorders. None being a pathognomonic sign, we recommend searching for both Green Flags and Red Flags. If both are present, a secondary headache should be suspected. Overall, the application of the Green Flag concept in clinical practice is likely to increase diagnostic accuracy and improve diagnostic resource allocation. Prospective studies in clinical populations should be conducted to validate these Green Flags.
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http://dx.doi.org/10.1111/head.14054DOI Listing
February 2021
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