Red Flags in the evaluation of patients with headache in the emergency department: the good, the bad and the ugly

PROGRAMA DE DOCTORADO EN INVESTIGACIÓN EN CIENCIAS DE LA SALUD TESIS DOCTORAL: RED FLAGS IN THE EVALUATION OF PATIENTS WITH HEADACHE IN THE EMERGENCY DEPARTMENT: THE GOOD, THE BAD AND THE UGLY Presentada por David García Azorín para optar al grado de Doctor/a por la Universidad de Valladolid Dirigida por: Prof. Ángel Luis GUERRERO PERAL Prof. Jesús PORTA ETESSAM Prof. Alberto MARCOS DOLADO 2 3 UNIVERSIDAD DE VALLADOLID FACULTAD DE MEDICINA DEPARTAMENTO DE MEDICINA TESIS DOCTORAL RED FLAGS IN THE EVALUATION OF PATIENTS WITH HEADACHE IN THE EMERGENCY ROOM: THE GOOD, THE BAD AND THE UGLY DOCTORANDO : David GARCÍA AZORÍN DIRECTORES DE TESIS: Prof. Ángel Luis GUERRERO PERAL Prof. Jesús PORTA ETESSAM Prof. Alberto MARCOS DOLADO VALLADOLID, 2021 4 UNIVERSIDAD DE VALLADOLID FACULTAD DE MEDICINA DOCTORADO EN INVESTIGACIÓN EN CIENCIAS DE LA SALUD DEPARTAMENTO DE MEDICINA TESIS DOCTORAL RED FLAGS IN THE EVALUATION OF PATIENTS WITH HEADACHE IN THE EMERGENCY ROOM: THE GOOD, THE BAD AND THE UGLY DOCTORANDO : David GARCÍA AZORÍN DIRECTORES DE TESIS: Prof. Ángel Luis GUERRERO PERAL Prof. Jesús PORTA ETESSAM Prof. Alberto MARCOS DOLADO Departamento de Medicina, Universidad de Valladolid VALLADOLID, enero de 2021 5 6 Nota del autor: El camino hasta estas líneas no ha sido recto ni fácil. No habría sido posible sin la generosidad de quienes dieron sin esperar recibir nada a cambio, empezando por mi familia , siguiendo por mis compañeros y terminando por mis mentores . Por ello, las primeras palabras de agradecimiento deben ser para una familia que ha sacrificado su tiempo y recursos para dar siempre lo mejor. A mis padres, que siempre han dado sin pedir a cambio. A mi hermano, de quien me siento orgulloso y quien pronto seguirá mis pasos y a mi tía Lourdes, quien logró contagiarme su interés por una de sus dos carreras. Y a mi pareja, por su apoyo y comprensión durante tantas jornadas. Quiero destacar también a unos compañeros que han sido el mejor de los ejemplos, convirtiéndose en estímulo para seguir aprendiendo y enseñando, como ellos hicieron conmigo, y para los mentores que han tenido la paciencia de corregir mis errores y transferirme su saber hacer. En este mundo en el que se gratifica tan poco la tradición docente y el aprendizaje, mi máximo agradecimiento para ellos y mis deseos para que sigan creando escuela. El momento en el que concluye esta etapa es harto convulso a nivel sociosanitario. Un virus ha puesto de manifiesto las carencias de nuestro sistema político, económico, sanitario, afectivo e incluso personal y ha causado terribles estragos. Por ello, espero poder corresponder con todos aquellos que tanto me han dado, y seguir su ejemplo de dar sin pensar en el retorno. Valladolid, enero de 2021 David García Azorín 7 8 Quote: [Sergeant Wallace and Tuco – the ugly – are at the train station, handcuffed together] Armed Union soldier: Hey, corporal, afraid he’ll get lost? Where’s the Rebel going? Sergeant Wallace: To hell, with a rope around his neck and a price on his head. Tuco – the ugly: Yeah… three thousand dollars, friend. That’s a lot of money for a head. [He flips the soldier’s empty sleeve] Tuco – the ugly: I bet they didn’t even pay you a penny for your arm. 9 16 • TNF-alpha: tumoral necrosis factor alpha • TTH: tension-type headache • UK: United Kingdom • Univ: univariate • USA: United States of America • VCAM-1: vascular cell adhesion molecule 1 • VEGF-A: vascular endothelial grow factor-A • vWF: von Willebrand factor • YLD: years lived with disability 17 18 INDEX 1. Introduction 20 1.1. Frequency and impact of headache 22 1.1.1. Frequency and impact of headache in the emergency room 23 1.2. Classification of headache disorders 25 1.3. Secondary headache diagnosis 26 1.3.1. Pitfalls in the diagnosis of secondary headache disorders 27 1.3.2. Sub-classification of secondary headache disorders based on the severity 30 1.4. Headache phenotype in secondary headache disorders 31 1.5. Aids in the diagnosis of headache disorders 38 1.5.1. Biomarkers in headache disorders 38 1.5.2. Concept of red flags 43 1.6. Pearls and pitfalls of red flags 55 1.6.1. Problems in secondary headache diagnosis related to the use of red flags 60 2. Rationale 64 3. Hypothesis 68 4. Objectives 72 5. Methods 76 5.1. Study setting 79 5.2. Ethical aspects 79 5.3. Eligibility criteria 80 5.4. Study period and data sources 85 5.5. Study procedures 85 19 5.6. Statistical aspects 86 6. Results 88 6.1. Tension-type headache 90 6.2. Cerebral Venous Sinus Thrombosis 91 6.3. Coronavirus disease 2019 (Covid-19) 92 6.4. Manuscript 1 96 6.5. Manuscript 2 128 6.6. Manuscript 3 154 7. Discussion 188 7.1. Main findings of the studies 190 7.2. Tension-type headache 192 7.2.1. Epidemiology of tension-type headache 193 7.2.2. Diagnostic criteria for tension-type headache 195 7.2.3. Problems with tension-type headache diagnosis 198 7.2.4. Problems with tension-type headache diagnosis in the emergency department 200 7.3. Red flags in cerebral venous sinus thrombosis 202 7.4. Headache in Covid-19 208 7.4.1. Strengths of this series 208 7.4.2. Cerebral venous sinus thrombosis in patients with Covid-19 214 7.5. Lessons and tips for the design of future studies assessing red flags in headache 217 8. Conclusions 220 9. References 224 10. Supplementary appendix 266 20 21 22 I. INTRODUCTION 23 24 1. Introduction 1.1. Frequency and impact of headache Headache is a universal experience, common in all ages, genders and races (Saylor et al, 2018). The lifetime prevalence of headache is 90-99% (Nikiforow, 1981; Rassmussen et al, 1991; Rassmussen et al, 1992; Olofsson et al, 2000; Boardman et al, 2003), and the one-year prevalence is 79% across several different European countries (Steiner et al, 2014; Saylor et al, 2018). Tension-type headache (TTH) and migraine are the second and third most prevalent disorders worldwide (Global Burden of Disease (GBD) 2017 Disease and Injury Incidence and Prevalence collaborators, 2018). When compared with other common neurological disorders, the prevalence of migraine is ten times higher than the combined prevalence of Alzheimer’s disease, Parkinson’s disease, idiopathic epilepsy, and multiple sclerosis (Global Burden of Disease 2016 Neurology collaborators, 2019). Due to their prevalence, headache disorders are an important cause of disability. They are the second leading cause of years lived with disability (YLD) worldwide (Global Burden of Disease 2016 Headache collaborators, 2018, Global Burden of Disease 2017 Disease and Injury Incidence and Prevalence collaborators, 2018, Global Burden of Disease 2019 Diseases and Injury Incidence and prevalence collaborators, 2020). Migraine is the first cause of YLD in adults between 15 and 49 years old (Global Burden of Disease 2017 Disability-adjusted life-years and Healthy Life Expectancy Collaborators, 2018; Steiner et al, 2020). This negatively affects the personal and professional development of people who suffer from headache. 25 1.1.1. Frequency and impact of headache in the Emergency Room Headache is also a leading complaint in the Emergency Room (ER). It is the most common neurological reason for an ER visit and the fourth most common reason for the visit when including all causes (Goldstein et al, 2006; Burch et al, 2018; Godwin et al, 2019). Data from the Centers for Disease Control and Prevention, which include 138,977 visits during 2017, showed that headache was within the top 10 reasons for an ER visit, accounting for 2.5% of all the visits and being the third leading reason in female patients aged between 15 and 64 (Centers for Disease Control and Prevention, National Hospital Ambulatory Medical Care Survey, 2017). In studies analysing the reasons for on-call neurologist consults, headache is within the main reasons but is less frequent than stroke or seizures (Table 1). Those studies that specifically analysed the proportion of headache patients in which neurologists are summoned showed that they evaluate 23%-28% of the patients (Matías-Guiu et al, 2016; García Azorín et al, 2020). According to the World Health Organization protocols, headache patients should be managed during first-level (i.e. primary) care whenever possible (Thakkur et al, 2015). In the ER setting, the main priority of clinicians is the detection of potential life-threatening causes of headache (Davenport 2002; Bo et al, 2008; Friedman et al, 2011). 32 1.3.2. Sub-classification of secondary headache disorders based on the severity Headache disorders, in general, are more associated with disability rather than mortality (Global Burden of Disease 2017 Disease and Injury Incidence and Prevalence collaborators, 2018; Global Burden of Disease 2017 DALY and HALE Collaborators, 2018). Primary headache disorders cause disability mainly during the acute phase of attacks, while secondary headache disorders might cause persistent disability due to sequelae, e.g., persistent visual loss, cognitive impairment, or weakness, among others (Goffaux et al, 2010). In addition, primary headache disorders should never be a cause of headacherelated mortality (Chou, 2018). The severity of the different secondary headache disorders is highly variable. Certain secondary causes could be considered mild or relatively benign, while others might cause death or long-term sequelae (Nye et al, 2015). Those that may cause death can be subclassified as high-risk headaches or life-threatening secondary headache disorders (Filler et al, 2019, García-Azorín et al, 2020). High-risk headaches can be defined as headache disorders whose cause may be associated with significant mortality or morbidity or whose cause may be a primary headache disorder that mimic a secondary cause. This last statement is particularly relevant, since some diagnoses should be made only when other causes have been properly ruled out, as in the cases of 1.2.3 Hemiplegic migraine, 1.4.2 Persistent aura without infarction or 4.4 Primary thunderclap headache. In other primary headache disorders, the clinical presentation might be completely “typical,” but the headaches of these groups are associated with secondary causes at a 33 higher frequency than would be expected by chance (de Coo et al, 2015; Burish et al, 2019). For that reason, symptomatic causes should be ruled out with imaging before confirming the diagnosis, as in the case of trigeminal autonomic cephalalgias (Gago-Veiga et al, 2020; Pareja et al, 2020) or nummular headache (García-Iglesias et al, 2020). 1.4. Headache phenotype in secondary headache disorders The ICHD-3 includes 118 causes of varying life-threatening secondary headache disorders (Headache Classification committee, 2018) (Figure 1). However, the total number of causes of secondary headache might be even higher. A systematic review found 119 total causes of thunderclap headache alone, spanning 1224 articles (Devenney et al, 2014). Table 5 shows the main groups and/or subgroups of secondary causes of lifethreatening headache disorders. Since the number of possible clinical phenotypes for a headache is limited, many secondary causes may mimic a primary headache phenotype (Taylor 2014, Goffaux et al, 2010). Figure 1: The cover of the International Classification of Headache Disorders, 1st edition, 1988 (left), first page of the International Classification of Headache Disorders, 3rd version, 2018 (right). 34 Table 5 . Major groups and/or subgroups of the ICHD-3 classification that include high-risk headache disorders. Part One: The Primary Headaches Group 1 1.2.2 Migraine with brainstem aura 1.2.3 Hemiplegic migraine 1.2.4 Retinal migraine 1.4.2 Persistent aura without infarction 1.4.4 Migraine aura-triggered seizure Group 2 None Group 3 None* Group 4 4.1 Primary cough headache 4.2 Primary exercise headache 4.3 Primary headache associated with sexual activity 4.4 Primary thunderclap headache 4.9 Hypnic headache 4.10 New daily persistent headache (NDPH) Part Two: The Secondary Headaches Group 5 5.1.1 Acute headache attributed to moderate or severe traumatic injury to the head Group 6 6.1 Headache attributed to cerebral ischemic event 6.2 Headache attributed to non-traumatic intracranial haemorrhage 6.3 Headache attributed to unruptured vascular malformation 6.4 Headache attributed to arteritis 6.5 Headache attributed to cervical carotid or vertebral artery disorder 6.6 Headache attributed to cranial venous disorder 6.7 Headache attributed to other acute intracranial arterial disorder 6.8 Headache and/or migraine-like aura attributed to chronic intracranial vasculopathy 6.9 Headache attributed to pituitary apoplexy Group 7 7.1 Headache attributed to increased cerebrospinal fluid (CSF) pressure 35 7.2 Headache attributed to low CSF pressure 7.3 Headache attributed to non-infectious inflammatory intracranial disease 7.4 Headache attributed to intracranial neoplasia Group 8 8.1.3 Carbon monoxide (CO)-induced headache 8.1.5 Cocaine-induced headache Group 9 9.1 Headache attributed to intracranial infection 9.2 Headache attributed to systemic infection Group 10 10.1 Headache attributed to hypoxia and/or hypercapnia 10.3 Headache attributed to arterial hypertension 10.6 Cardiac cephalalgia Group 11 11.3.1 Headache attributed to acute angle-closure glaucoma 11.3.3 Headache attributed to ocular inflammatory disorder 11.5.1 Headache attributed to acute or recurring rhinosinusitis Group 12 12.1 Headache attributed to somatization disorder 12.2 Headache attributed to psychotic disorder Part Three: Painful Cranial Neuropathies, Other Facial Pain and Other Headaches Group 13 13.1.1.2 Secondary trigeminal neuralgia 13.1.2 Painful trigeminal neuropathy 13.2.1.2 Secondary glossopharyngeal neuropathy 13.2.2 Painful glossopharyngeal neuropathy 13.3.1.2 Secondary nervus intermedius neuralgia 13.3.2.3 Painful nervus intermedius neuropathy attributed to other disease 13.6 Painful optic neuritis 13.7 Headache attributed to ischemic ocular motor nerve palsy 13.8 Tolosa-Hunt syndrome 13.9 Paratrigeminal oculosympathetic (Raeder’s) syndrome 13.10 Recurrent painful ophthalmoplegic neuropathy 13.13 Central neuropathic pain Group 14 14.2 Headache unspecified * A symptomatic cause must be ruled out in every patient with trigeminal autonomic cephalalgia. NDPH: new-daily persistent headache; CSF: cerebrospinal fluid; CO: carbon monoxide. 36 Presence and type of headache is the cornerstone in the diagnosis of many of those disorders. One of the causes that should not be missed is cancer (Goldlust et al, 2010). On the one hand, headache might be the presenting symptom in many cases of systemic and craniocervical cancer (Rushton et al, 1964; Vazquez-Baquero et al, 1994). On the other hand, it is one of the most frequent symptoms, if not the most frequent, during the course of the disease (Schankin et al, 2007). Table 6 depicts the frequency of headache in the well-known published series of cancer patients. Table 6 . Frequency of headache in the well-known series of cancer patients. First Author Year of publica -tion Study design & Period Country Sample size Frequency of headache Rushton 1964 Case series 1960 USA 221 59.7% (24.9% as first symptom) Forsyth 1993 Case series 1991-1992 USA 111 47.7% Suwanwela 1994 Cross-sect 1991-1992 Thailand 171 71.3% VazquezBarquero 1994 Prosp 1991-1993 Spain 183 At the moment of diagnosis: 37 33.0% in primary CNS cancer and 31.4% in metastases Counsell 1998 Syst review 1966-1995 Worldwide 55 72.1% Pfund 1999 Case series 1994-1995 Hungary 279 58.8% Christiaans 2002 Prosp 1997-2000 The Netherlands 68 cancer patients 32.4% cancer patients with new or changed headache had intracranial metastasis Wilne 2006 Retrosp 1998-2001 UK 200 children 41.0% (first symptom) Schankin 2007 Case series 2002 Germany 85 60.0% Valentinis 2010 Prosp 2007-2008 Italy 211 55.0% Rostami 2016 Syst Review Worldwide 14599 (Breast cancer) 35.0% Cross-sect: Cross-sectional design; Prosp: Prospective design; Retrosp: Retrospective design; Syst: Systematic; CNS: Central nervous system, USA: United States of America; UK: United Kingdom. 38 Inappropriate diagnosis of CNS cancer might have terrible consequences for the patient’s prognosis, and therefore, legal implications (Singh et al, 2007; Aaronson et al, 2019). Another feared group of disorders are CNS infections. In this case, prognosis is time dependent (Van de Beek et al, 2016). Headache is one of the most frequent symptoms (Table 7). Table 7 . Frequency of headache in the well-known series of central nervous system infections. First Author Year of public ation Study design Country Sample size Frequency of headache Mortality rate (%) Bacterial meningitis Durand 1993 Case series 1962-1988 USA 493 NS 25.0% Sigurdardóttir 1997 Case series 1975-1994 Iceland 132 NS 19.7% Hussein 2000 Case series 1985-1996 USA 103 66.0% 14.6% Van de Beck 2004 Case series 1998-2002 The Netherland s 696 86.9% 20.5% Thigpen 2011 Case series 1998-2007 USA 3155 NS 14.8% 39 Polkowska 2017 Case series 1995-2014 Finland 1361 NS 10.3% Meningitis and/or encephalitis Paradowska 2016 Case series 2014 Poland 3488 NS NS Viral meningitis Whitley 1982 HSV Case series USA 202 79.2% NS Robart 1998 Enterovirus Case series USA 39 100% 0% Brain abscess Chun 1986 Case series 1970-1983 USA 55 72.1% 40% Nicolosi 1991 Case series 1935-1981 USA 38 NS 38% Berlit 1996 Case series 1975-1993 Germany 67 19.4% (presenting symptom) 37.3% Grigoriadis 1997 Case series Streptococcu s pneumoniae Worldwide 24 81.0% 34.8% Fica 2006 Case series 1989-2005 Chile 30 58.6% 10.0% Carpenter 2007 Case series 2000-2004 UK 49 49.0% 10.2% HSV: Herpes simplex virus. USA: United States of America. UK: United Kingdom. NS: Not specified. 40 1.5. Aids in the diagnosis of headache disorders 1.5.1. Biomarkers in headache disorders In contrast with other painful syndromes (Azzopardi et al, 2016; Andruchow et al, 2018; Sendama et al, 2018), headache disorders lack specific biomarkers (Schytz et al, 2016). Biomarkers are elements that lead to the diagnosis of a certain condition, or that predict prognosis. Many medical and neurological diseases have specific biomarkers, including white matter lesions in multiple sclerosis, dopamine transporters scan (DaT scan) in Parkinson’s disease, electroencephalographic spikes and waves in epilepsy, hippocampal atrophy in Alzheimer’s disease, polysomnography in sleep disorders, and electromyographic and electroneurographic changes in neuromuscular diseases, among others (Pascual, 2009; Zarranz, 2018). Headache medicine may be the sub-specialty of neurology in which biomarkers are the least established. Before summarizing the existing biomarkers, it is important to consider the optimal characteristics of a biomarker (Chen et al, 2011). Table 8 lists some of the ideal features. The intended properties might vary depending on the purpose. When the main aim is diagnosis, sensitivity or specificity may be preferred depending on the frequency and severity of the condition. However, biomarkers are also used in the follow-up or to measure prognosis, the effect of the treatment, or the stage of the disease (Schuetz et al, 2015; Cardelli et al, 2018). 41 Table 8. Main characteristics of a biomarker. Characteristic Definition Precise Measures what it is intended to Sensitive Detects the condition whenever it is present Reproducible Further determinations yield the same result Rapidly measurable Provides the result quickly Affordable Has an acceptable cost Accessible Is available for most of the population Non-invasive Is neither painful nor invasive, easily obtainable Early Allows prompt and early diagnosis. Detects the condition early in the disease progression Clinically relevant Measures what is important to know Most of the biomarkers that have been used in headache medicine are related to the diagnosis of primary headache disorders, mainly migraine (Goadsby et al, 1990; Gallai et a,l 1995; Tuka et al, 2013) and cluster headache (Buture et al, 2019). Substantial efforts have been made in search of others, with several studies in the genetics field, imaging, electroencephalography, and laboratory studies (Schytz et al, 2016; Hadidchi et al, 2019). Despite this, there does not exist a single biomarker able to properly differentiate 48 Treatment resistant Strictly unilateral Precipitated by sneezing, coughing, or exercise Group C: Red flags related to the presence of associated symptoms Fever Weight loss Altered consciousness Abnormal behaviour Abnormal movements Unexplained vomiting Neurophthalmological symptoms (e.g., visual loss, diplopia) Focal neurological symptoms (e.g., weakness, hypoesthesia, gait disturbances) Group D: Red flags related to the presence of abnormal signs in the examination Papilledema Cranial autonomic symptoms Focal neurological signs (e.g., paresis, hypoesthesia, ataxia) 49 There are many studies addressing specific secondary headache disorders that describe the presence of red flags. They served as rationale for including them into the different lists of red flags. The most representative studies that describe each red flag in a group or subgroup of secondary headache disorders is listed in table 11. Table 11 . Main red flags of headache disorders and the groups or subgroups of the related secondary headache disorders. Group A: Red flags related to the prior history of patients Neoplasms in history 7.4.1 Headache attributed to intracranial neoplasm (Lassman et al, 2003, Rostami et al, 2016) 7.4.2 Headache attributed to carcinomatous meningitis (Nelson et al, 2014) 10.3.1 Headache attributed to phaeochromocytoma (Rojo et al, 2012) Immunosuppression 9.1 Headache attributed to intracranial infection (Durand et al, 1993) 9.2 Headache attributed to systemic infection (Martín-Davila et al, 2007) Cranial or cervical trauma 5.1.1 Acute headache attributed to moderate or severe traumatic injury to the head (Andersen et al, 2020) 6.2.3 Acute headache attributed to non-traumatic acute subdural haemorrhage (ASDH) (Yamada et al, 2018) 6.5.1 Headache or facial or neck pain attributed to cervical carotid or vertebral artery dissection (Schytz et al, 2014) 6.3.3 Headache attributed to dural arteriovenous fistula (DAVF) (Osbun et al, 2017) Drug use 50 6.1 Headache attributed to cerebral ischaemic event (Sordo et al, 2014) 8.1.5 Cocaine-induced headache (Fofi et al, 2014; Farooque et al, 2020) 8.1.11 Headache attributed to use of or exposure to other substances (Zhu et al, 2020). 8.2 Medication overuse headache (Bottiroli et al, 2019) 8.3 Headache attributed to substance withdrawal (Diener et al, 2010) Old age (Blum et al, 2017) 6.4.1 Headache attributed to giant cell arteritis (Ing et al, 2019) 7.4 Headache attributed to intracranial neoplasia (Schankin et al, 2007) 10.6 Cardiac cephalalgia (Wei et al, 2008) Increased risk of bleeding or thrombosis 6.6.1 Headache attributed to cerebral venous thrombosis (Komro et al, 2020) 6.2 Headache attributed to non-traumatic intracerebral haemorrhage (Tabibian et al, 2018) Pregnancy or puerperium 6.6.1 Headache attributed to cerebral venous thrombosis (Kashkoush et al, 2017) 6.9 Headache attributed to pituitary apoplexy (Piantanida et al, 2014; Galvao et al, 2017) 7.2.1 Post-dural puncture headache (Costa et al, 2019) 10.3.4 Headache attributed to pre-eclampsia or eclampsia (Fang et al, 2017) Group B: Red flags related to the phenotype of the headache Thunderclap onset (Blum et al, 2017) 6.1 Headache attributed to cerebral ischaemic event (Lebedeva et al, 2018) 6.2 Headache attributed to non-traumatic intracranial haemorrhage (Bo et al, 2008; Landtblom et al, 2012) 6.3.1 Headache attributed to unruptured saccular aneurysm (Day et al, 1986; Linn et al, 1994; Polmear et al, 2003, Lebedeva et al, 2020) 6.5.1 Headache or facial or neck pain attributed to cervical carotid or vertebral artery dissection (Hsu et al, 2014) 6.6.1 Headache attributed to cerebral venous thrombosis (Botta et al, 2017) 51 6.7.3.1 Acute headache attributed to reversible cerebral vasoconstriction syndrome (RCVS) (Caria et al, 2019) 6.9 Headache attributed to pituitary apoplexy (Suri et al, 2019) Positional headache 6.6 Headache attributed to cranial venous disorder (Timoteo et al, 2012) 7.1 Headache attributed to increased cerebrospinal fluid pressure (Wall et al, 2014; Yri et al, 2015) 7.2 Headache attributed to low cerebrospinal fluid intracranial hypotension (Mea et al, 2007) 7.4 Headache attributed to intracranial neoplasia (Suwanwela et al, 1994) 9.1.1.1 Acute headache attributed to bacterial meningitis or meningoencephalitis (Grände et al, 2002; Depreitere et al, 2016) 9.1.3.1 Acute headache attributed to intracranial fungal or other parasitic infection (Liu et al, 2019) Wake-up headache 6.1 Headache attributed to cerebral ischaemic event (Tentschert et al, 2004) 6.2 Headache attributed to non-traumatic intracranial haemorrhage (Schievink et al, 1989) 6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome (Calabrese et al, 2007) 7.1 Headache attributed to increased cerebrospinal fluid pressure (Markey et al, 2016) 7.4 Headache attributed to intracranial neoplasia (Pfund et al, 1999) Pattern change 6.2.4 Persistent headache attributed to past non-traumatic intracranial haemorrhage (Lai et al, 2018) 6.3 Headache attributed to unruptured vascular malformation (Kwon et al, 2015) 6.4 Headache attributed to arteritis (Pradeep et al, 2018) 6.5.1.2 Persistent headache or facial or neck pain attributed to past cervical carotid or vertebral artery dissection (Schytz et al, 2014) 52 6.6 Headache attributed to cranial venous disorder (Metha et al, 2019) 7.1 Headache attributed to increased cerebrospinal fluid pressure (Radojicic et al, 2019) 7.2 Headache attributed to low cerebrospinal fluid pressure (Friedman, 2018) 7.3 Headache attributed to non-infectious inflammatory intracranial disease (Hanly et al, 2013; Fritz et al, 2016) 7.4 Headache attributed to intracranial neoplasia (Rushton et al, 1964) 9.1 Headache attributed to intracranial infection (Thakur et al, 2018) Recent onset, worst headache ever 5.1 Acute headache attributed to traumatic injury to the head (Nordhaug et al, 2018) 6.1 Headache attributed to cerebral ischaemic event (Harriot et al, 2020) 6.2 Headache attributed to non-traumatic intracranial haemorrhage (Morgestern et al, 1998) 6.3 Headache attributed to unruptured vascular malformation (Linn et al, 1994) 6.4 Headache attributed to arteritis (Michiailidou et al, 2020) 6.5 Headache attributed to cervical carotid or vertebral artery disorder (Matsumoto et al, 2019) 6.6 Headache attributed to cranial venous disorder (Iurlaro et al, 2004) 6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome (Singhal et al, 2011) 7.1 Headache attributed to increased cerebrospinal fluid pressure (Liu et al, 2011) 7.2 Headache attributed to low cerebrospinal fluid pressure (Schievink, 2003) 7.3 Headache attributed to non-infectious inflammatory intracranial disease (Curone et al, 2013) 7.4 Headache attributed to intracranial neoplasia (Christiaans et al, 2002) 8.2 Medication overuse headache (Mose et al, 2018) 8.3 Headache attributed to substance withdrawal (Toom et al, 2020) 9.1 Headache attributed to intracranial infection (Robart et al, 1998; van de Beck et al, 2004; Logan et al, 2008) 9.2 Headache attributed to systemic infection (De Marinis et al, 1992; Eccles et al, 2005) 10.3 Headache attributed to arterial hypertension (Arca et al, 2019) 11.3 Headache attributed to disorder of the eyes (Friedman, 2015) 53 11.5 Headache attributed to disorder of the nose or paranasal sinuses (Kirsch, 2019) Progressive headache, treatment resistant 5.2 Persistent headache attributed to traumatic injury to the head (Larsen et al, 2019) 6.2.4 Persistent headache attributed to past non-traumatic intracranial haemorrhage (Lai et al, 2018) 6.3 Headache attributed to unruptured vascular malformation (Duvall et al, 2019) 6.4 Headache attributed to arteritis (Bustamante Maldonado et al, 2004) 6.5 Headache attributed to cervical carotid or vertebral artery disorder (Matsumoto et al, 2019) 6.6 Headache attributed to cranial venous disorder (Sparaco et al, 2015) 6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome (Singhal et al, 2011) 7.1 Headache attributed to increased cerebrospinal fluid pressure (Wakerley et al, 2015) 7.2 Headache attributed to low cerebrospinal fluid pressure (Capizzano et al, 2016) 7.3 Headache attributed to non-infectious inflammatory intracranial disease (Mekinian et al, 2018) 7.4 Headache attributed to intracranial neoplasia (Pfund et al, 1999) 8.2 Medication overuse headache (Munskgaard et al, 2012) 9.1 Headache attributed to intracranial infection (Robart et al, 1998) 9.2 Headache attributed to systemic infection (Kuchar et al, 2015) 10.3 Headache attributed to arterial hypertension (Courand et al, 2016) 11.3 Headache attributed to disorder of the eyes (Nesher et al, 2014) 11.5 Headache attributed to disorder of the nose or paranasal sinuses (Kaur et al, 2013) Strictly unilateral (Prakash et al, 2016) 6.1 Headache attributed to cerebral ischaemic event (Harriot et al, 2020) 6.2 Headache attributed to non-traumatic intracranial haemorrhage (Bazan et al, 2008) 6.3 Headache attributed to unruptured vascular malformation (Menal Muñoz et al, 2016) 6.4 Headache attributed to arteritis (Prakash et al, 2016) 54 6.5 Headache attributed to cervical carotid or vertebral artery disorder (Brilla et al, 2018) 6.6 Headache attributed to cranial venous disorder (Prakash et al, 2016) 7.3 Headache attributed to non-infectious inflammatory intracranial disease (Russo et al, 2018) 7.4 Headache attributed to intracranial neoplasia (Argyriou et al, 2002) 11.3 Headache attributed to disorder of the eyes (Ramón et al, 2013) 11.5 Headache attributed to disorder of the nose or paranasal sinuses (Prakash et al, 2016) Precipitated by sneezing, coughing, or exercise (Pascual et al, 1996) 6.3 Headache attributed to unruptured vascular malformation (Chen et al, 2009) 6.6 Headache attributed to cranial venous disorder (Timoteo et al, 2012) 6.8.3 Headache attributed to moyamoya angiopathy (Kraemer et al, 2017) 7.1 Headache attributed to increased cerebrospinal fluid pressure (Yri et al, 2015) 7.4 Headache attributed to intracranial neoplasia (Suwanwela et al, 1994) 7.7 Headache attributed to Chiari malformation type I (Mehta et al, 2015) Group C: Red flags related to the presence of associated symptoms Fever, weight loss 7.3 Headache attributed to non-infectious inflammatory intracranial disease (Limper et al; 2011) 7.4 Headache attributed to intracranial neoplasia (Marrodan et al, 2018) 9.1 Headache attributed to intracranial infection (Robart et al, 1998; Logan et al, 2008) 9.2 Headache attributed to systemic infection (Limper et al; 2011) Altered consciousness, abnormal behaviour, abnormal movements 6.1 Headache attributed to cerebral ischaemic event (Henon et al, 1999) 6.2 Headache attributed to non-traumatic intracranial haemorrhage (Wang et al, 2017) 6.4 Headache attributed to arteritis (Ioannides et al, 2009) 6.5 Headache attributed to cervical carotid or vertebral artery disorder (De Reuck et al, 2009) 55 6.6 Headache attributed to cranial venous disorder (Sha et al, 2018) 6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome (Singhal et al, 2011) 7.3 Headache attributed to non-infectious inflammatory intracranial disease (Amanat et al, 2019) 7.4 Headache attributed to intracranial neoplasia (Wilne et al, 2006) 8.3.2 Opioid-withdrawal headache (Jain et al, 2018) 9.1 Headache attributed to intracranial infection (Zoons et al, 2008) Unexplained vomiting 6.2 Headache attributed to non-traumatic intracranial haemorrhage (Shigematsu et al, 2013) 6.6 Headache attributed to cranial venous disorder (Terni et al, 2015) 7.1 Headache attributed to increased cerebrospinal fluid pressure (Roy et al, 2013) 7.3 Headache attributed to non-infectious inflammatory intracranial disease (Krief et al, 2010) 7.4 Headache attributed to intracranial neoplasia (Pfund et al, 1999; Christiaans et al, 2002) 9.1 Headache attributed to intracranial infection (Robart et al, 1998) Neurophthalmological symptoms (e.g., visual loss, diplopia) 6.4.1 Headache attributed to giant cell arteritis (Fein et al, 2019) 6.5 Headache attributed to cervical carotid or vertebral artery disorder (Song et al, 2019) 6.6.1 Headache attributed to cerebral venous thrombosis (Zhao et al, 2018) 7.1 Headache attributed to increased cerebrospinal fluid pressure (Hatem et al, 2018) 7.3 Headache attributed to non-infectious inflammatory intracranial disease (Campagna et al, 2019) 7.4 Headache attributed to intracranial neoplasia (Wilne et al, 2006) 9.1 Headache attributed to intracranial infection (Borges et al, 2018; Verma et al, 2019) 11.3 Headache attributed to disorder of the eyes (Lee et al, 2004) Focal neurological symptoms (e.g., weakness, hypoesthesia, gait disturbances) 56 6.1 Headache attributed to cerebral ischaemic event (Harriot et al, 2020) 6.2 Headache attributed to non-traumatic intracranial haemorrhage (Shinohara, 2009) 6.3 Headache attributed to unruptured vascular malformation (Tsai et al, 2004) 6.4 Headache attributed to arteritis (Salvarani et al, 2015) 6.5 Headache attributed to cervical carotid or vertebral artery disorder (Sturzenegger, 1994) 6.6 Headache attributed to cranial venous disorder (Diacinti et al, 2018) 6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome (Caria et al, 2019) 7.3 Headache attributed to non-infectious inflammatory intracranial disease (Nozaki et al, 2012) 7.4 Headache attributed to intracranial neoplasia (Argyriou et al, 2002) 9.1 Headache attributed to intracranial infection (Robart et al, 1998; Logan et al, 2008) 10.3.3 Headache attributed to hypertensive encephalopathy (Fugate et al, 2015) Group D: Red flags related to the presence of abnormal signs in the examination Papilledema 6.4.1 Headache attributed to giant cell arteritis (Balducci et al, 2017) 6.6.1 Headache attributed to cerebral venous thrombosis (Saadatnia et al, 2017) 7.1 Headache attributed to increased cerebrospinal fluid pressure (Radojicic et al, 2019) 7.4 Headache attributed to intracranial neoplasia (Suwanwela et al, 1994) 9.1 Headache attributed to intracranial infection (Verma et al, 2019) 11.3 Headache attributed to disorder of the eyes (Yip et al, 2019) Cranial autonomic symptoms 6.1 Headache attributed to cerebral ischaemic event (Jin et al, 2016; Lambru et al, 2017; Lei et al, 2020) 6.2 Headache attributed to non-traumatic intracranial haemorrhage (Bazan et al, 2008) 6.5 Headache attributed to cervical carotid or vertebral artery disorder (Lai et al, 2005; Caneloro et al, 2013; Elhfnawy et al, 2017) 6.6 Headache attributed to cranial venous disorder (Park et al, 2006; Rodriguez et al, 2008) 57 7.3 Headache attributed to non-infectious inflammatory intracranial disease (Edvardsson, 2014) 7.4 Headache attributed to intracranial neoplasia (Favier et al, 2007) Focal neurological signs (e.g., paresis, hypoesthesia, ataxia) (Blum et al, 2017) 6.1 Headache attributed to cerebral ischaemic event (Moulin et al, 2019) 6.2 Headache attributed to non-traumatic intracranial haemorrhage (Lawton et al, 2017) 6.3 Headache attributed to unruptured vascular malformation (Lv et al, 2018) 6.4 Headache attributed to arteritis (Salvarani et al, 2012) 6.5 Headache attributed to cervical carotid or vertebral artery disorder (Engelter et al, 2017) 6.6 Headache attributed to cranial venous disorder (de Brujin et al, 2001) 6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome (Ducros et al, 2012) 7.3 Headache attributed to non-infectious inflammatory intracranial disease (Kefella et al, 2017) 7.4 Headache attributed to intracranial neoplasia (Argyriou et al, 2002) 9.1 Headache attributed to intracranial infection (Logan et al, 2008) 10.3.3 Headache attributed to hypertensive encephalopathy (Fugate et al, 2015) When all the disorders included in a group may be related to the red flag, the entire group is listed. When only some of the disorders included in a group are related to the red flag, the specific ICHD-3 disorder is listed. 1.6. Pearls and pitfalls of red flags Red flags are widely accepted. They are used in other fields of neurology and medicine, and are part of daily practice (Ramanayake et al, 2018). The evidence supporting their use is mostly based on expert opinion, which is valuable but not fully precise (Edmeads, 1990; Evans et al, 2011; Friedman et al, 2011, Do et al, 2019). Most authors agree on the fact that the presence of any single red flag requires that a 64 If we analyse red flags from the biomarker perspective (Table 8), a strength includes apparently high sensitivity, even if they have never been formally tested. For obvious reasons, red flags as biomarkers are accessible, non-invasive and free, but despite that, they are not always used in practice (Dobb et al, 2013). Table 13 analyses the role of red flags as biomarkers. Table 13. Strengths and limitations of red flags as headache-related biomarkers. Characteristic Explanation Precise They may be present in many different secondary headache disorders and sometimes in primary headache disorders (i.e., low precision). Sensitive Their sensitivity is unclear for most of them and does not seem to be high. Reproducible There are few studies of validation. Rapidly measurable Most of them are rapidly measurable. Affordable They have excellent affordability. Accessible They can be evaluated by a physician or by using checklists. Non-invasive They are not invasive. Early They accelerate the diagnosis when used. Clinically relevant Their relevance could be improved. 65 66 II. RATIONALE 67 68 2. Rationale In order to evaluate the role of red flags in the diagnosis of headache disorders, three different disorders were selected and analysed in real-world conditions. Three different entities were chosen that represent the full spectrum of headache disorders. The study was titled “the good, the bad and the ugly” based on the potential consequences of each of those disorders. The good is tension-type headache (TTH), the most prevalent headache disorder and probably the most benign primary headache (Global Burden of Disease 2016 headache collaborators, 2018). As with every headache disorder, TTH can be disabling to patients, particularly those with chronic TTH, but in theory, it does not confer any harm or morbimortality risk for patients (Global Burden of Disease 2016 neurology collaborators, 2019). For these reasons, red flags should never be present in patients with a TTH diagnosis. The bad is cerebral venous sinus thrombosis (CVST). This is a life-threatening cause of headache (Canhao et al, 2005). Headache is the most frequent symptom of CVST (Bousser et al, 1985; Saposnik et al, 2011). Its prognosis relies on adequate and prompt diagnosis (Ferro et al, 2004; Dentali et al, 2012; Gameiro et al, 2012). Red flags may help identify patients with CVST; however, they have never been evaluated. The ugly is headache attributed to coronavirus disease 2019 (Covid-19). In this case, the disease is not invariably fatal (Huang et al, 2020), but inadequate diagnosis may confer risk of transmission for others and propagation of the disease (Henriquez 69 et al, 2020). Headache is within the most frequent neurological symptoms in hospitalized patients with Covid-19(Romero-Sánchez et al, 2020). In this case, we aimed to evaluate if the presence of Covid-19 can be suspected in patients who do have headache based on the presence of red flags. 70 III. HYPOTHESIS 71 72 3. Hypothesis The main hypothesis of the present work is that red flags can differentiate between patients with primary headache disorders and those with secondary headache disorders; thus, red flags would be useful in the diagnosis of headache disorders in clinical practice. Red flags are present in patients with secondary headache disorders. In patients with a suspected primary headache disorder, if red flags are present, diagnosis should be done only after excluding all possible secondary causes. 73 80 5. Methods To evaluate the frequencies and types of red flags in the above-mentioned three populations, three observational descriptive studies with cross-sectional designs were conducted. Two studies were retrospective and the other prospective. All three studies adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (Von Elm et al, 2007). Figure 4 summarizes the common elements of the study designs. Figure 4 . Common elements in the design of the three studies. Created with BioRender by David García-Azorín. 81 5.1. Study setting The studies that assessed CVST and TTH were done at the Hospital Clínico Universitario San Carlos, Madrid, Spain, a third level, academic, public hospital located in the metropolitan area of Madrid with a reference population of 700,000-1,000,000 people. The reference population varied in the TTH study (700,000) compared with the CVST study (1,000,000) since this centre covers a larger area in its role as a stroke centre. The study that assessed headache in Covid-19 patients was done at the Hospital Clínico Universitario de Valladolid, Valladolid, Spain, also a third level, academic, public hospital that receives patients from the eastern metropolitan area of Valladolid and 22 urban and rural primary care centres of the region. The reference population is 261,431 (Castilla y Leon Department of Health, 2020). 5.2. Ethical aspects Ethics Review Boards of both hospitals approved the studies (Supplementary appendix) (CP14/425, PI 20-1738). All studies were done in accordance with Good Clinical Practice guidelines and according to the principles of the Declaration of Helsinki (International Conference on Harmonization, 1996) and the convention for bioethical principles agreed to in Oviedo (Department of State, Official Document, 1997). In the case of Covid-19, the need for written consent was waived due to the risk of contagion; 82 however, patients were informed about the study aim and only those who agreed to participate were included. 5.3. Eligibility criteria The common elements of the inclusion criteria for the studies were the presence of headache, the fact that patients visited the ER, and the confirmed final diagnosis. In the case of CVST and Covid-19, determination of inclusion was done after an appropriate imaging evaluation in the case of CVST or after a positive polymerase chain reaction (PCR) or immunoglobulin M (IgM) in serum antibody test in the case of Covid-19. In the case of TTH, the certainty of the diagnosis came from the discharge report, where the final diagnosis was explicitly stated as TTH. Table 14 summarizes the eligibility criteria of all the studies. Table 14. Common elements of the inclusion and exclusion criteria of the studies (Extracted from the manuscripts). Inclusion criteria Criterion Tension-type headache CVST Covid-19 Emergency Room • Visited the ED • Presented at the ED • Were hospitalized 83 due to Covid19 Presence of headache • The reason for the ED visit was headache • Complained of headache at ED presentation • Headache occurred during the course of the disease Confirmed diagnosis • Were classified with a definite diagnosis of “tension-type headache” in the discharge report • Confirmed CVST • Fulfilled ICHD-3 criteria for headache attributed to cerebral venous thrombosis • Confirmed Covid-19 Exclusion criteria Other headache disorders • Another headache was diagnosed at the same time • Isolated cavernous sinus thrombosis • Infective thrombophlebitis • Not better accounted for by another IHD-3 diagnosis 84 • Isolated cortical venous thrombosis • Unable to be diagnosed • There was some degree of uncertainty in the diagnosis, such as “possible” or “probable” Unclear diagnosis after radiological reevaluation by an experienced neuroradiologist • Unstable medical condition Availability of information • Information was not available in the patient chart • Not applicable • Deceased • Psychiatric or cognitive impairment • Did not agree to participate Inclusion criteria Criterion CVST Covid-19 Tension-type headache 85 Emergency Room • Presented at the ED • Were hospitalized due to Covid19 • Visited the ED Presence of headache • Complained of headache at ED presentation • Headache occurred during the course of the disease • The reason for the ED visit was headache Diagnosis • Confirmed CVST • Fulfilled ICHD-3 criteria for headache attributed to cerebral venous thrombosis • Confirmed Covid-19 • Were classified with a definite diagnosis of “tension-type headache” in the discharge report Exclusion criteria Other headache disorders • Isolated cavernous sinus thrombosis • Not better accounted for by another • Another headache was 86 • Infective thrombophlebitis • Isolated cortical venous thrombosis IHD-3 diagnosis diagnosed at the same time Unable to be diagnosed • Unclear diagnosis after radiological re-evaluation by an experienced neuro-radiologist • Unstable medical condition • There was some degree of uncertainty in the diagnosis, such as “possible” or “probable” Availability of information • Not applicable • Deceased • Psychiatric or cognitive impairment • Did not agree to participate • Information was not available in the patient chart CVST: Cerebral Venous Sinus Thrombosis; Covid-19: coronavirus disease 2019; ED: emergency department; ICHD-3: the International Classification of Headache Disorders 3rd edition. 87 5.4. Study period and data sources For CVST, considering the rarity of the disorder, all patients who received a diagnosis of CVST in the centre between January 2009 and May 2015 were screened. All potential cases were systematically assessed across three different databases, including the Hospital General database, the Emergency Department database and the Department of Radiology database. In the case of TTH, the final diagnoses of all patients who visited the emergency department (ED) between January 2012 to July 2014 were systematically screened. The ED database was evaluated, and every single case was individually reviewed. In the case of Covid-19, all consecutive patients who were hospitalized due to Covid19 (i.e., from patient number 1 to patient number 576) between March 2020 and April 2020 were screened. In those patients, the presence of headache was screened for in primary care records, ED records and hospitalization records. Patients were contacted and interviewed about the presence of red flags. 5.5. Study procedures In each study, two neurologists with expertise on headache medicine screened for the presence of red flags in each patient who fulfilled the eligibility criteria. To do this, a pre-defined questionnaire that included the main red flags was used (supplementary 88 appendix). The International Headache Society’s Secondary Headache Special Interest Group proposal (Do et al, 2019) and the list of red flags present in the Headache Study Group of the Spanish Society of Neurology (Ezpeleta et al, 2015) were used to screen patients. Despite that the study periods were between 2009 and 2015 in two of the studies, data were re-analysed after the publication of those manuscripts. In the CVST and TTH studies, health records were retrospectively reviewed. In the Covid-19 study, patients were interviewed after the onset of symptoms. 5.6. Statistical aspects All three studies were mainly descriptive. Qualitative nominal variables and quantitative ordinal variables are presented as frequencies and percentages. Quantitative continuous variables are presented as mean and standard deviation if the distribution was normal, after evaluating normality with Kolmogorov-Smirnov tests or QQ plots; or by median and inter-quartile range if the distribution was not normal. For hypothesis testing, chi-squared tests or Fisher’s exact tests were used when variables were qualitative. When continuous variables were tested for differences, Student’s t-tests or Mann-Whitney U tests were used, depending on the type of distribution. To identify correlations between continuous variables, Pearson’s test was used. Multiple comparisons were adjusted for by using the Bonferroni method. The statistical significance threshold was set to P<0.05. The statistical analysis was done by using SPSS (IBM Corp. Armonk, NY). All the statistical analysis was done by David García Azorín. 89 96 Manuscript 1: Tension-type headache in the Emergency Department Diagnosis and misdiagnosis: The TEDDi study. García-Azorín D, Farid-Zahran M, Gutiérrez-Sánchez M, González-García MN, Guerrero AL, PortaEtessam J. Sci Rep 2020;10(1):2446. Published: February 12, 2020. 97 98 Tension-type headache in the Emergency Department Diagnosis and misdiagnosis: The TEDDi study David García-Azorín1, Mariam Fahrid-Zahram2, María Gutiérrez-Sánchez1, Nuria González-García3, Ángel L. Guerrero1, 4, 5, Jesus Porta-Etessam3. Author contribution statement: All authors participated in the design of the study. DGA and MF created the questionnaire, and ALG, JPE, MG and NGG reviewed the questionnaire. MF and DGA reviewed all cases, and NGG and MG solved disputes. DGA wrote the first draft, and all the authors reviewed and approved the final draft. Declarations: - Ethics approval and consent to participate: The Clinical Research Ethics Committee of Hospital Clínico San Carlos approved the study. Informed consent forms were obtained from the participants. - Consent for publication: All authors gave their consent for publication. -Availability of data and material: Study material and supplementary material are available upon request from the corresponding author. 99 -Competing interests: The authors declare no conflicts of interest. -Funding: All the authors declare that no specific Funding was received. -Authors contributions: All authors participated in the design of the study. DGA and MF created the questionnaire, and ALG, JPE, MG and NGG reviewed the questionnaire. MF and DGA reviewed all cases, and NGG and MG solved disputes. DGA wrote the first draft, and all the authors reviewed and approved the final draft. -Acknowledgements: We acknowledge our emergency department colleagues for all their support. -Authors’ information: We assure that this study represents original work. The present work was partially presented at the 2nd European Academy of Neurology Congress. 100 Tension-type headache in the Emergency Department Diagnosis and misdiagnosis: The TEDDi study ABSTRACT: Headache is a common reason to visit the emergency department (ED). Tension-type headache (TTH) is the commonest headache. The diagnosis of TTH implies a mild condition, with no need for special tests. We evaluated the use of the International Classification of Headache Disorders (ICHD) criteria for TTH in the ED. We performed a cross-sectional study including all ED patients with a definite TTH diagnosis in their discharge report for 2.5 years. We evaluated whether the ICHD criteria for TTH were referenced and met. We analysed discrepancies concerning anamnesis or prior history and reclassified patients. A total of 211 out of 2132 patients fulfilled the criteria (9.9%). Only five patients fulfilled TTH criteria. Criteria A-D were referenced in 60-84% of patients and met in 16-74% of these patients. Anamnesis was discrepant in 87.5% as was prior history in 20.8%. After re-reclassification, 21 patients fulfilled the criteria for TTH (five) or probable TTH (16). In 106 patients, another headache was diagnosed, with migraine in 40 (18.9%), secondary headache in 64 (30.3%), and a life-threatening disorder in 13 (6.1%). In our sample, TTH was overdiagnosed. Only a minority of patients fulfilled the ICHD criteria. Inconsistencies in prior medical history or anamnesis were frequent. Keywords: Headache disorders; Tension-type headache; Emergency department; diagnosis. 101 INTRODUCTION: Tension-type headache (TTH) is the most common primary headache disorder1, 2. The prevalence of TTH is estimated to be between 30 and 70% of the general population according to different studies2. The diagnostic criteria proposed by the International Classification of Headache Disorders (ICHD) have remained unaltered since the first edition in 19883-6. The criteria are based on bilateral, oppressive and mild pain, without typical migraine features and with no better explanation6. Given the mild nature of the disorder, few patients seek assistance, and in headache unit-based series, it is not a frequent diagnosis, accounting for 16% of all diagnoses7. On the other hand, it is not uncommon for migraine patients to be erroneously diagnosed with TTH8. Headache is one of the main reasons for consultation in the emergency department (ED). It seems remarkable that in some ED-based series, TTH diagnosis accounts for up to 2533% of all headache visits9, 10; particularly when other series are performed by neurologists or using ICHD criteria diagnosis, TTH represents only 1-6% of total headache patients11-15. In the ED setting, secondary headache detection represents the main priority. TTH is particularly threatening, as its typical phenotype is relatively unspecific, and many secondary headaches may mimic it. The use and knowledge of the ICHD criteria in the ED setting may be difficult. Most clinicians use red flag lists to rule out secondary headaches16. However, we hypothesize that TTH is probably overdiagnosed in the ED setting, which might represent a risk for 102 patients with nondetected secondary headaches. Establishing TTH diagnosis might be dangerous, as it implies that the patient has a harmless disorder. In this study, the first objective was to analyse the percentage of patients who fulfilled the ICHD6 criteria for tension-type headache and the percentage of patients presenting each of the different criteria. The second objective was to analyse the presence of data in the discharge reports that contradicted TTH diagnosis, such as relevant prior medical data, atypical symptoms or abnormal findings in the examination. The third objective was to analyse whether patients could be re-classified as having other headache disorders by using the ICHD-3 criteria. PATIENTS AND METHODS: This is an observational study with a cross-sectional design. Our study population included patients who visited the emergency department due to headache. The study was performed according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines17. The study took place at the ED of the Clínico San Carlos University Hospital, Madrid (Spain), a third-level hospital with a reference population of 700.000 people. The study period was between January 2012 and July 2014. Eligibility: The inclusion criteria were as follows: 1) patients visiting the ED because of headache and 2) patients with a definite diagnosis of “tension-type headache” in the ED discharge 103 report. We excluded patients with 1) some degree of uncertainty in the diagnosis, such as “possible” or “probable”; 2) another headache diagnosed at the same time; and 3) no available information in the patient chart. We screened all the patients who visited the ED during the study period because of headache by using the ED database, which codifies patients by initial reason for consultation. We reviewed the digitalized reports and gathered the information from the discharge reports. We did not review any additional sources, and we did not evaluate any patients. The rationale for this was that we aimed to see if with the information present in the ED reports, TTH diagnosis was appropriate or not. The included demographic variables were sex; age; and relevant prior medical history, including current or past cancer, pathology of the immune system, and prior headache history. Clinical variables included headache description, with special attention to the presence of any red flag, neurological examination and abnormal focal signs, vital signs and general examination. Study objectives: For the first objective, we reviewed the ICHD criteria for TTH4-6 (table 1). We analysed whether each criterion was referenced in the report and if it was fulfilled or not. Criterion A, alluding to the number of episodes, was considered to be met for an infrequent tension-type headache diagnosis if the patient had a minimum of 10 episodes. We did not differentiate the ICHD edition in the manuscript, given that there were no differences 104 between the TTH ICHD criteria in the second, third beta and third editions of the classification4-6 (Supplementary material). Table 1: The International Classification of Headache Disorders criteria for Tension-type headache. Criterion Feature Specific criterion A. Number of episodes At least 10 episodes of headache. B Episode duration Lasting from 30 minutes to seven days C Headache characteristics At least two of the following four characteristics: 1. Bilateral location 2. Pressing or tightening (non-pulsating) quality 3. Mild or moderate intensity 4. Not aggravated by routine physical activity, such as walking or climbing stairs D Associated symptoms Both of the following: 1. no nausea or vomiting 2. no more than one of photophobia or phonophobia E Exclusion Not better accounted for by another ICHD-3 diagnosis 105 For the second objective, we analysed discrepancies concerning both anamnesis and prior medical history. Anamnesis discrepancies were classified into five groups: 1: Presence of symptoms highly suggestive of another headache disorder, including pulsating quality, presence of both photophobia and phonophobia, worsening with exercise, cervical topography, neuralgiform pain, or highly localized pain. 2: Presence of abnormal neurological symptoms or signs, such as aphasia, dysarthria, sensory disturbances, paresis, visual symptoms, vertigo, instability, and papilledema. 3: Presence of red flags related to the headache description, such as thunderclap onset, severe intensity (>9/10), progressive worsening, recent onset, worsening with Valsalva manoeuvre, precipitation by exercise, and refractoriness to appropriate treatment. 4: Systemic symptoms, such as fever, chest pain, abdominal pain, arthralgia, diarrhoea, urethral syndrome, and localized ocular pain. 5: Close temporal relation with an event able to produce headache, including cranial trauma, high blood pressure, lumbar puncture, and cranial surgery. Discrepancies in prior medical history included prior headache disorders, cancer affecting encephalic structures, sinus disease, ophthalmological diseases able to produce ocular pain, sleep apnoea syndrome, and any other intraor extracranial conditions able to produce headache. For the third objective, two headache specialists (NGG, DGA) independently reviewed each case and analysed the information present in the discharge reports. With that information, when possible, patients were re-assessed according to ICHD-3 (77). In case of discrepancies, a third headache specialist (JPE) solved the disputes. 112 6.7.1 Headache attributed to an intracranial endarterial procedure (1) 6.4.1 Headache attributed to giant cell arteritis (1) 7. Headache attributed to nonvascular intracranial disorder 6 (2.8%) 7.2.1 Post-dural puncture headache (2) 7.2.3 Headache attributed to spontaneous intracranial hypotension (2) 7.4.1 Headache attributed to intracranial neoplasm (2) 8. Headache attributed to a substance or its withdrawal 2 (0.9%) 8.1.9 Headache attributed to occasional use of non-headache medication (2) 9. Headache attributed to infection 12 (5.7%) 9.2.2.1 Acute headache attributed to systemic viral infection (12) 10. Headache attributed to disorder of homeostasis 12 (5.7%) 10.3.2 Headache attributed to hypertensive crisis without 113 hypertensive encephalopathy (11) 10.1.4 Sleep apnoea headache (1) 11. Headache or facial pain attributed to disorder of the cranium, neck eyes, nose, sinuses, mouth or other facial or cervical structure 13 (6.2%) 11.3 Headache attributed to disorder of the eyes (2) 11.3.3 Headache attributed to ocular inflammatory disorder (2) 11.6 Headache attributed to disorder of the teeth 11.5.1 Headache attributed to acute rhinosinusitis (3) 11.5.2 Headache attributed to chronic or recurring rhinosinusitis (6) 12. Headache attributed to psychiatric disorder 0 0 13. Painful lesions of the cranial nerves and other facial pain 1 (0.5%) Occipital neuralgia (1) Appendix 1 (0.5%) A10.8.2 Headache attributed to other metabolic or systemic 114 disorder (polycythaemia vera, viscosity syndrome) (1) Not classifiable 84 (39.8%) Management of patients: The total duration of the ED visits, from admission to discharge, had a median length of 3.59 hours [IQR: 2.5-5.1], with a range between 0.35 and 19.10 hours. Neurological examination was described in the reports of 90.5% of patients and was abnormal in 6.8% of these patients. When the neurological exam was done, the duration of the ED visit was 4.0 hours vs. 3.9 hours when it was not done (Student’s t test, 22 df, p=0.87). Fundoscopy was performed in 10.9% of patients, and the results were normal in all cases. The diagnosis was more often appropriate in patients who underwent fundoscopy (chisquare test, 1 df, p=0.004). Regarding complementary exams, laboratory exams were performed in 32.6% of patients. Laboratory exams including erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) were performed in 48.6% of patients older than 65 years old. Cranial CT was performed in 11.3% of patients, and cervical or sinus X-ray was performed in 12.7% of patients. Only 2 CT exams were abnormal, one exhibiting a vascular malformation and the other with acute inflammation of the frontal sinuses. Figure 3 summarizes the percentage of patients who underwent each examination. 115 Figure 3: Percentage of patients that underwent each examination. CT scan (Cranial Tomography). When complementary exams were performed, the mean duration of the stay increased from 3.28 to 4.94 hours (Student’s t test, 217 df, p<0.001). Requests for complementary exams were not associated with a higher probability of proper diagnosis (chi-square, 1 df, p=0.71). At discharge, 21.3% of patients were referred for a neurological examination. In 90% of the discharge reports, some acute medications were prescribed. DISCUSSION: The present study was performed in the emergency department setting. We systematically analysed a series of patients with definite TTH diagnosis according to whether the diagnostic criteria were mentioned and fulfilled in the discharge report. We screened the reports for the presence of data that would contradict TTH diagnosis, and finally, we tried to reclassify patients based on the information provided in the reports. 116 The main findings of our study were that only a minority of patients, only 2.4% of the whole sample, fulfilled the ICHD criteria for TTH. In over 80% of patients, a discrepancy was found in the anamnesis, and in one-fifth of patients, prior medical history made TTH diagnosis unlikely. Finally, when we tried to reclassify patients, migraine diagnosis was two-times more frequent than TTH diagnosis. In almost 40% of patients, the information was not sufficient for a diagnosis, so in the best possible scenario, only half of patients with TTH diagnosis would have this condition, leading to a total percentage of 4.9% of the whole sample. Concerning the ICHD criteria6, the most frequently mentioned criterion was duration, followed by number of episodes and phenotype. The most surprising data were that criterion A, describing the number of episodes, was mentioned in 81% of cases, but it was only fulfilled in 16% of cases. This fact may reflect the idea that many patients visit the emergency department due to recent-onset headaches. New onset headache and progressive worsening are two of the main red flags18. In patients with primary headaches, a previous history of similar unchanged attacks might constitute a green flag. The ICHD Criteria for TTH, unchanged since the first edition3, attempt to differentiate TTH from the other main primary headache, migraine. The criteria include positive, negative and exclusion criteria. The positive criteria describe the typical characteristics of TTH: bilateral, pressing, and relatively mild. The negative criteria rule out the presence of typical migraine features, such as nausea, vomiting, photophobia and phonophobia or worsening as a result of activity. Finally, as in every ICHD diagnosis, the condition should 117 not be better described by any other diagnosis. In the literature, some series have diagnosed TTH in 53% of patients with nausea 19. Other series included patients who were diagnosed with TTH who had pulsating (23.8%) and hemicranial headaches (20.1%)20. The typical TTH phenotype is probably the most unspecific, and many conditions might have similar features, such as migraine, hemicrania continua, primary cough headache, primary exercise headache, primary headache associated with sexual activity, externalpressure headache, hypnic headache, new daily persistent headache and the vast majority of secondary headache disorders6, 8. Misdiagnosis might be related to the classification of patients based on pain phenotype; however, headache diagnosis should be performed by integrating prior medical history, headache anamnesis, presence of other symptoms and neurological examination, not solely by headache phenotype8, 21. The confusion surrounding TTH diagnosis might be partly influenced by the many names that have been used to describe this condition: tension headache, muscle contraction headache, psychomyogenic headache, stress headache, ordinary headache, essential headache, idiopathic headache, or psychogenic headache3-6. Some of these names may suggest a psychogenic cause. Currently, we consider stress and affective disorders a cause of worsening or a trigger rather than the cause of headache22, 23. Medical attention at the emergency department usually prioritizes the detection of lifethreatening conditions. The frequent saturation, rush and wide variety of conditions complicate the thorough and meticulous anamnesis that headache disorders require. In our sample, 30% of patients had a secondary headache, and 5% of patients had a 118 secondary headache with potential morbimortality. In a previous series, up to 10% of patients diagnosed with TTH had an abnormal examination18. One of the biggest needs in the headache field is the development of reliable biomarkers. Unlike other painful syndromes, such as chest or abdominal pain, we still base our diagnosis on anamnesis and neurological examination18. Some rules16 and lists of red flags have been proposed to detect secondary headaches24. CT and lumbar puncture, although frequently requested18, 25, 26, do not always rule out many entities, such as cerebral venous sinus thrombosis, intracranial space-occupying lesions, or cerebrospinal fluid pressure disorders. Headache is one of the leading reasons for consultation, accounting for 2.3% of all ED visits14, 15, 18; therefore, all ED physicians should be trained in headache medicine. In our sample, just a minority of patients underwent fundoscopy, and in many cases, even plain X-ray was requested. The use of lab tests was not properly selected for elderly patients, as less than half of the patients had an ESR or CRP exam. Sometimes an accurate diagnosis cannot be made; in our study, up to 38% of patients had an unspecific diagnosis, with this figure reaching 38-45% in the literature24, 27. In those cases, it is important to note that declaring a primary headache disorder without certainty might implicate the end of the diagnostic work-up and a higher risk of complications. In case of doubt, final diagnosis should be “possible” or “headache not otherwise specified”11, 13, 24. 119 The consequences of inaccurate diagnosis are the risk of morbimortality among patients, inappropriate use of diagnostic resources, and the potential cost of establishing the proper diagnosis. Treatment of different secondary headaches differs widely, and in many conditions, prognosis is correlated with a prompt and proper treatment, as in the case of temporal arteritis, cerebral venous sinus thrombosis, or central nervous system infections13. Although tension-type headache is supposed to be the most prevalent primary headache disorder28, 29, it is seldom treated in headache outpatient clinics30, and some authors even suggest that patients diagnosed with TTH suffer from improperly diagnosed migraines in at least one-third of the cases31, 32. Research on TTH and knowledge about its pathophysiology are also scarcer than those of other primary headaches, such as cluster headache or migraine2, 33. In many cases, TTH has been related to psychosocial factors22, and when patients complain of stress or mood disorders, TTH diagnosis is often made. It is well known that primary headache disorders are associated with significant personal, societal and familiar burdens30. The pre-test probability of having TTH is 60-70%1, 2 in the general population, but in the ED setting, it is important to clarify whether the headache that motivated the consult has changed, worsened progressively, resisted treatment or had new features. With regard to prior medical history, in our sample, one-fifth of the patients had conditions able to produce headaches, and 8% of the subjects were migraineurs. It is well known that chronic migraine exhibits a less typical phenotype, and some of the episodes might 120 resemble TTH episodes34. In the diagnosis of chronic migraine, only 8 out of the minimum 15 headaches per month are needed to fulfil the migraine without or with aura criteria6. The main limitations of the present study are the participation of a single centre, which might affect the generalizability of the results. Because of the design of the study, some data could have been asked and evaluated but not written; however, from a legal perspective, non-written data did not “occur”. The re-classification was performed without evaluating patients; therefore, there was potential for misclassification, and we used the current ICHD instead of the two editions valid during the study period (ICHD-2 and ICHD-3 beta). We did not follow up with patients to confirm the final diagnosis. The strengths of the study are the thorough review of every patient chart, the participation of headache experts and the three different analyses performed. CONCLUSION: In our sample, TTH was overdiagnosed in an emergency department, as only 2.4% of the patients fulfilled all ICHD criteria for TTH. Inconsistencies in prior medical history or anamnesis were present in the discharge reports in one-fifth and four-fifths of patients, respectively. Our analysis of medical records allowed us to reclassify these patients as having other primary or secondary headaches. Efforts to improve knowledge on headache disorders and ICHD are needed among ED physicians. List of abbreviations: Tension-type headache (TTH), the International Classification of Headache Disorders (ICHD), emergency department (ED), Strengthening the Reporting of Observational 121 Studies in Epidemiology (STROBE), cranial tomography (CT), degrees of freedom (df), blood pressure (BP), cerebrospinal fluid (CSF), erythrocyte sedimentation rate (ESR), Creactive protein (CRP), standard deviation (sd), inter-quartile range (IQR). Declarations: - Ethics approval and consent to participate: The Clinical Research Ethics Committee of Hospital Clínico San Carlos approved the study. - Consent for publication: All authors gave their consent for publication. -Availability of data and material: Study material and supplementary material are available upon request from the corresponding author. -Competing interests: The authors declare no conflicts of interest. -Funding: All the authors declare that no specific Funding was received. -Authors contributions: All authors participated in the design of the study. DGA and MF created the questionnaire, and ALGP, JPE, MG and NGG reviewed the questionnaire. MF and DGA reviewed all cases, and NGG and MG solved the disputes. DGA wrote the first draft, and all the authors reviewed and approved the final draft. -Acknowledgements: We acknowledge our emergency department colleagues for all their support. -Authors’ information: We assure that this study represents original work. The present was been partially presented at the 2nd European Academy of Neurology Congress. 128 Manuscript 2: Presence of red flags in patients with cerebral venous sinus thrombosis admitted to the emergency department because of headache: A STROBE compliant cohort-study. García-Azorín D, Monje MHG, González-García N, Guerrero AL, Porta-Etessam J. Medicine (Baltimore) 2020;99(29)e20900. Published: July 17, 2020. 129 130 Presence of red flags in patients with cerebral venous sinus thrombosis admitted to the Emergency Department because of headache. A STROBE compliant cohort-study. Authors: David García-Azorín, MD1, Mariana HG Monje MD2,3, Nuria González-García MD4, Ángel L Guerrero MD, PhD1, 5, Jesús Porta-Etessam MD, PhD4. Authors affiliation: 1 Headache Unit, Neurology Department. Hospital Universitario Clínico de Valladolid. Valladolid, Spain. 2 HM-CINAC, HM Puerta del Sur University Hospital, Móstoles, Madrid, Spain. 3 Anatomy, Histology and Neuroscience Department. Faculty of Medicine. Universidad Autónoma de Madrid, Madrid, Spain. 4 Headache Unit, Neurology Department. Hospital Universitario Clínico San Carlos, Madrid. 5 Institute for Biomedical Research of Salamanca, IBSAL, Salamanca, Spain. Corresponding author: David García-Azorín Headache Unit. Neurology Department. Hospital Clínico Universitario de Valladolid, Valladolid, Spain. Ramon y Cajal avenue, 5. Phone: +34 665872228 131 47003 Valladolid, Valladolid, Spain. Spain E-mail: [email protected] Conflict of interest: The Authors declare that there is no conflict of interest. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Keywords: Headache Disorders, secondary; sinus thrombosis, intracranial; venous thrombosis; diagnosis. Abbreviations: Cerebral venous Sinus Thrombosis (CVST), Secondary Headaches (SH), the International Classification of Headache Disorders, 3rd edition (ICHD-3), Emergency Department (ED), the Strengthening the Reporting of Observational in Epidemiology (STROBE) guidelines, Computed Tomography (CT), Standard deviation (SD), Inter-Quartile Range (IQR), Tension-type headache (TTH). 132 Abstract Introduction: Cerebral Venous Sinus Thrombosis (CVST) is a cause of secondary headache with substantial morbimortality. Headache dominates the clinical presentation, but no typical phenotype has been described. We aim to evaluate the presence of red flags in headache in patients with confirmed CVST at the moment of emergency department (ED) presentation. Patients and methods: Retrospective STROBE compliant cohort study including patients with confirmed CVST that consulted because of headache at the ED. We analyzed presence and type of red flags at the moment of consult. We evaluated if CVST was suspected at the moment of imaging request and analysed delay in the diagnosis. Results: Nineteen patients fulfilled inclusion and exclusion criteria. Mean age was 48.5 years, 47.4% were female. All the studied patients exhibited at least one red flag, being abnormal neurological examination the most frequent (79%), followed by the presence of other neurological symptoms (68%), alarm data related with headache phenotype (63%) or risk factors concerning prior medical history (47%). Temporal pattern of the headache was acute in 42.1%, thunderclap in 31.6% and subacute in 26.3%. In none patient CVST was the specific suspicion when imaging was requested. Median time since headache onset and ED presentation were 84 hours, being different in patients with associated symptoms (48 hours) when compared with isolated headache patients (168 hours). Time since ED presentation and the diagnosis also differed between the two groups, being more prolonged in patients with an isolated headache at presentation. 133 Conclusion: Headache attributed with CVST did not exhibit any distinctive phenotype, but all the patients presented some red flag, being abnormal neurological examination the most frequent. 134 Presence of red flags in patients with cerebral venous sinus thrombosis admitted to the Emergency Department because of headache. A STROBE compliant cohort-study. Introduction Cerebral venous Sinus Thrombosis (CVST) is a rare cause of stroke1. Its incidence is 1.32 cases per 100.000 patients/year but increases in middle-aged women, among which it might affect up to 2.78/100.000 patients/year2. The epidemiological picture of CVST is a middle-aged woman, being 73.7% of patients female aged 39.1 years in mean3, 4. Its prognosis with no adequate treatment is gloomy, with a mortality rate around 7.7%- 8.3%3, 4. Given the availability and efficacy of anticoagulation, diagnosis should be done as soon as possible4, 5. Diagnostic delay is common, around 3 days between hospital admission and diagnosis3, 4, probably related with the clinical heterogeneity, the lack of awareness and the need of specific radiological imaging sequences for its adequate diagnosis3, 4, 6, 7. Clinical presentation of CVST is variable, begin considered as one of the “great mimickers” of Neurology. Phenotype might influence by the topography of the affected sinus6, the existence of intracranial hypertension and the presence of complications such as subarachnoid hemorrhage of venous infarcts6, 7. Headache is, by far, the most frequent symptom at onset, present in 88.8% of patients613. It is usually accompanied by other neurological symptoms, but in 22.7-45.0% of the patients represents the sole symptom6, 8-10. Headache phenotype is polymorph, sometimes even mimicking “benign” headaches. Tension-Type Headache is a common misdiagnosis, as pain can be continuous in 88%, throbbing in 76% and progressive in 64%12, 13, nevertheless, the needed number prior episodes contradicts it. The 135 International Classification of Headache Disorders, 3rd edition (ICHD-3) does not require any specific headache phenotype for the diagnosis14. When headache is the only presenting symptom, the diagnostic delay might prolong up to 13.1 days12, 15-16. Secondary headaches (SH) are those produced by a cause able to originate headache17. The temporal relation with the onset, aggravation or improvement is required in the causation assumption14. Due to the lack of specific biomarkers for headache in the Emergency Department (ED), the detection of secondary headache is still based on the presence of red flags. Presence of red flags in headache attributed to CVST have been partially described9, 13, however presence of identifiable red flags at the ED admission has not been analyzed yet. In this study, we aim to evaluate if a secondary headache can be suspected due to the presence of any red flag at the moment of ED consultation in a series of CVST patients. Due to the needed index of suspicion and specific imaging modalities, we also pretend to evaluate if suspicion of CVST changes the study work-up and reduces the time to diagnosis. Material and methods We conducted an observational retrospective study. Our study population included patients with confirmed CVST that consulted at the ED because of headache. Our inclusion criteria were: 1) CVST confirmed by Magnetic Resonance Venography, Cranial Tomography Venography or Angiography; 2) Presenting at the Emergency Department; 3) Complaining because of headache at ED presentation; 4) Fulfilling ICHD-3 criteria for headache attributed to cerebral venous thrombosis18. Exclusion criteria were: 1) Isolated Cavernous Sinus Thrombosis; 2) infective thrombophlebitis; 3) Isolated Cortical venous 136 thrombosis; 4) Unclear diagnosis after radiological re-evaluation from an experienced Neuro-radiologist. The study took place in University Hospital Clinico San Carlos from Madrid, a third level public hospital with a reference population of 1 million inhabitants. The study period was between January 2009 and May 2015. We followed retrospectively all the patients since the ED presentation until the confirmation of the diagnosis. We screened all the available cases from the Hospital General Database, the Emergency Department specific database, and the Radiology Department database by ICD codes. Two different researchers reviewed the cases for eligibility and a third neurologist solved the disputes. We tried to avoid selection bias by doing a wide search and reviewing a high number of records. Data extraction: We carefully reviewed clinical information from the emergency department charts, evaluating demographical information such as age and gender. Information was obtained from computerized medical records. Two headache specialists evaluated the clinical data analyzing the presence of red flags at the moment of Emergency Department Visit. We classified the clinical data into four categories depending on the possible red flag. We adapted the classification of red flags to the CVST setting considering prior authors publications1, 6, 7, 13, 17. (Figure 1). The first category was related with prior medical history conditions that could be associated with CVST. The second category was the presence of red flags related to headache description 137 and phenotype. The third group included red flags due to the existence of other neurological or systemic symptoms other than headache. We described nausea and vomiting presence by separate because they can be present both in primary and secondary headache disorders. The last group was the presence of abnormal neurological signs detected in the neurological examination. In those red flags that could be either a symptom or a sign, for example neuro-ophthalmological red flags, we considered symptoms if they were referred by patients and signs if they were observed during the examination. The components of each category are detailed in Figure 1 --------- [insert Figure 1] Figure 1. Red flags in cerebral venous sinus thrombosis. Classification of red flags in patients with cerebral venous thrombosis adapted considering prior authors publications1,6,7,13,17,19 We classified patients based on the presence of only headache or existence of other symptoms. According previous studies6, 7, 9, 11, we defined isolated headache if at the moment of presentation, the patient did not complain about other neurological or 144 Figure 4. Graphical representation of the timing sequence since de clinical symptoms’ onset and the diagnosis of cerebral venous sinus thrombosis. Isolated headache clinical manifestation patients (yellow) has a more considerable time from symptoms onset to consultation (1) compared to a headache plus patients (red) (p<0.05). The time between consultation and first neuroimaging (2) and the time between first neuroimaging and diagnosis (3) was shorter in headache plus patients, although it did not reach significant statistical difference (p=0.1). Discussion In this study we analyzed if CVST can be suspected in the ED because of the presence of red flags. We also analyzed which red flag group is more frequently abnormal and the impact of red flags presence in the diagnostic work-up and delay. At the moment of ED presentation, all the patients presented at least one red flag and a secondary headache was suspected in all cases. Despite its potential consequences, CVST was not specifically mentioned in any patient. However, we found that diagnosis was delayed in many cases and specific imaging modalities were requested seldom. 145 During the study period, 31 patients were diagnosed of cerebral venous sinus thrombosis. After excluding those patients with infective thrombophlebitis or isolated cavernous sinus thrombosis, headache was the most frequent symptom of presentation in CVST patients in our sample, present at ED admission in 19/26 cases (73.0%). Many previous authors have highlighted the importance of headache as the key symptom in CVST diagnosis6-13. In our sample, all the patients had red flags at the moment of ED presentation. The most frequent red flags were encoded in the group of abnormal signs in the neurological examination, presents in 78.9% of patients. In 68.4% of patients, headache description contained some alarm characteristic and in 68.4% other alarm symptoms other than headache were present. Finally, some medical condition increasing the risk of a secondary headache was identified at ED presentation in 47.4% of patients. The clinical presentation may be related with CSVT extension. Venous sinus thrombosis is a dynamic process, so if venous drainage remains obstructed the intracranial hypertension is expected to rise. This may lead to a worsening of symptoms due to intracranial hypertension, venous infarcts and even hemorrhagic infarcts or subarachnoid haemorrhage8. The presence of hemorrhage has been also associated with seizures and the involvement of the deep venous system with decreased level of consciousness. Additionally, some authors described that the distension of the transverse sinus may be responsible of the lateralized pain11, 12. 146 History and examination can give some clues about the underlying pathophysiological process20, 21. Symptoms such as worsening with decubitus, morning predominance, vomiting without prior nausea or blurred vision; or signs such as papiledema or sixth nerve palsy can reflect intracranial hypertension. Seizures or focal signs might suggest venous infarcts or subarachnoid hemorrhage. The most useful manoeuvre in our sample was neurological examination, which should be always performed and might include fundus examination. Neither us nor other authors have found any specific pattern of headache22; the main “chameleon” is tension-type headache. Nevertheless, in our sample at least two thirds of patients described red flags about headache description, which would contradict TTH diagnosis. It is typical that there is not any distinctive phenotype, but in our sample, all patients exhibited some red flag, so primary headache disorders should be diagnosed only if no better explanation can be found8, 9, 12. Among the possible prior medical history, attention should be focused on conditions that may predispose to suffer a CVST. Classically it has been classified depending on which part of the Virchow triad was altered23, 24: hypercoagulability, hemodynamic changes or endothelial injury. The most frequent ones are changes in the composition of the blood, such as acquired hypercoagulability states, mainly secondary to oral contraceptives, pregnancy, puerperium, but also inherited ones, as prothrombin mutation G20210A, Factor V Leyden, Protein C and protein S deficiency. Second, the susceptibility to CVST can be related to endothelial damage: secondary to infections, inflammatory diseases, malignancies, mechanical causes, or trauma. Last but not least, hemodynamic changes 147 with stasis of the blood might contribute to the problem, as it frequently happens in dehydration and secondarily in intracranial hypertension23. Local causes of endothelial damage are less frequent in CVST than in other organ specific thrombosis (34% compared with 73-88% as it is found in portal, renal or pulmonary veins thrombosis), so systemic entities that may predispose to thrombosis should be considered23. Some of these conditions can be identified in history. Attention should be paid, not only because it may support the diagnosis, but also because some of these conditions could precise a specific and prompt treatment, as in the case of Behçet disease. In our sample, a secondary entity was suspected in all the patients when neuroimaging was ordered. Despite of that, diagnosis was deferred in many cases. It has previously described that diagnosis in patients with isolated headache may be delayed12. Theoretically, if secondary headache is suspected, even if basal CT is normal, a contrastenhanced CT or MRI should be done. If CSVT diagnosis is a possibility, venous sequences should be included in the study. In light with our findings, CVST should be considered also in the differential diagnosis of thunderclap headache. Venous specific imaging sequences should be included, because about a third of CVST patients in our sample and prior studies had a sudden onset of headache9. Potential limitations of our work are the: the small sample size; the retrospective nature of the study, which could underreport some symptoms that were not identified in the 148 medical records and with higher interobserver variability; the participation of a single center; the risk of biases. 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Neurology 2008;70(22 Pt 2):2109-15. 265 272 APPENDIX IV: Informed consent form HOJA DE INFORMACIÓN AL PACIENTE Estudio: “HERRAMIENTA CLÍNICA DE AYUDA DIAGNÓSTICA DE PATOLOGÍA DE ALTO RIESGO VITAL EN LOS PACIENTES ATENDIDOS POR CEFALEA EN UN SERVICIO DE URGENCIAS”. INTRODUCCION Nos dirigimos a usted para informarle sobre un estudio de investigación que estamos realizando en pacientes que son atendidos por episodio de dolor de cabeza en el Servicio de Urgencias y en el que se le invita a participar. El estudio ha sido aprobado por el Comité Ético de Investigación Clínica del Hospital Clínico San Carlos. Nuestra intención es tan solo que usted reciba la información correcta y suficiente para que pueda evaluar y juzgar si quiere o no participar en este estudio. Para ello lea esta hoja informativa con atención y nosotros le aclararemos las dudas que le puedan surgir después de la explicación. Además, puede consultar con las personas que considere oportuno. DESCRIPCIÓN GENERAL DEL ESTUDIO. El dolor de cabeza es un motivo de consulta frecuentes en los Servicios de Urgencias, y en ocasiones con consecuencias fatales. Por ello, estamos desarrollando un estudio con el objetivo de identificar una escala de datos clínicos que nos ayude a identificar si tiene o no una patología de riesgo vital en los pacientes atendidos por cefalea un Servicios de Urgencias Hospitalario. PROCEDIMIENTO El estudio consiste en una entrevista estructurada que consta de preguntas sobre sus datos demográficos, tratamientos farmacológicos, enfermedades previas y datos clínicos del episodio urgente. Se le practicará un fondo de ojo y una ecografía para medir el diámetro de la vaina del nervio óptico. Además, tras el alta, a los 30 días, un investigador contactará con usted mediante una llamada telefónica con el fin de conocer su situación de salud. No se va a realizar ningún procedimiento invasivo que no fuera a realizar en función de su problema de salud. BENEFICIOS Y RIESGOS DERIVADOS DE SU PARTICIPACIÓN EN EL ESTUDIO. Los participantes que intervengan en el estudio se les someterá a una valoración global integral pero es posible que no se obtenga ningún beneficio para su salud por participar en el mismo. No se espera a priori que los pacientes estén sometidos a ningún riesgo importante como consecuencia de la participación en el estudio. 273 PARTICIPACIÓN VOLUNTARIA. Debe saber que su participación en este estudio es voluntaria y que puede decidir no participar o cambiar su decisión y retirar el consentimiento en cualquier momento, sin que por ello se altere la relación con su médico ni se produzca perjuicio alguno en su tratamiento. CONFIDENCIALIDAD. El tratamiento, la comunicación y la cesión de los datos de carácter personal de todos los sujetos participantes se ajustará a lo dispuesto en la Ley Orgánica 15/1999, de 13 de diciembre de protección de datos de carácter personal. De acuerdo a lo que establece la legislación mencionada, usted puede ejercer los derechos de acceso, modificación, oposición y cancelación de datos, para lo cual deberá dirigirse a su médico del estudio. Los datos recogidos para el estudio estarán identificados mediante un código y solo su médico del estudio/colaboradores podrán relacionar dichos datos con usted y con su historia clínica. Por lo tanto, su identidad no será revelada a persona alguna salvo excepciones. El acceso a su información personal quedará restringido al médico del estudio/colaboradores, al Comité Ético de Investigación Clínica y personal autorizado por el grupo de estudio, cuando lo precisen para comprobar los datos y procedimientos del estudio, pero siempre manteniendo la confidencialidad de los mismos de acuerdo a la legislación vigente. COMPENSACIÓN ECONÓMICA. Su participación en el estudio no le supondrá ningún gasto. PREGUNTAS/INFORMACION Si usted o tiene cualquier pregunta sobre el estudio, contacte con el Investigador Principal de su Centro. Al firmar la hoja de consentimiento adjunta, se compromete a cumplir con los procedimientos del estudio que se le han expuesto. 274 Informed consent form FORMULARIO DE CONSENTIMIENTO INFORMADO Estudio: “HERRAMIENTA CLÍNICA DE AYUDA DIAGNÓSTICA DE PATOLOGÍA DE ALTO RIESGO VITAL EN LOS PACIENTES ATENDIDOS POR CEFALEA EN UN SERVICIO DE URGENCIAS”. Yo .................................................................................................................................. He leído la hoja de información que se me ha entregado. He podido hacer preguntas sobre el estudio. He recibido suficiente información sobre el estudio. He hablado con........................................................ Comprendo que mi participación es voluntaria. Comprendo que puedo retirarme del estudio: 1. Cuando quiera 2. Sin tener que dar explicaciones 3. Sin que esto repercuta en mis cuidados médicos Presto libremente mi conformidad para participar en el ensayo Fecha Firma del participante Fecha Firma del investigador 275 FORMULARIO DE CONSENTIMIENTO INFORMADO (DEL CUIDADOR) Estudio: “HERRAMIENTA CLÍNICA DE AYUDA DIAGNÓSTICA DE PATOLOGÍA DE ALTO RIESGO VITAL EN LOS PACIENTES ATENDIDOS POR CEFALEA EN UN SERVICIO DE URGENCIAS”. Yo .....................................................................................................................en calidad de .................................................. de ............................................................................................ He leído la hoja de información que se me ha entregado. He podido hacer preguntas sobre el estudio. He recibido suficiente información sobre el estudio. He hablado con........................................................ Comprendo que mi participación es voluntaria. Comprendo que puedo retirarme del estudio: 4. Cuando quiera 5. Sin tener que dar explicaciones 6. Sin que esto repercuta en mis cuidados médicos En mi presencia se ha dado a .............................................................................. toda la información pertinente adaptada a su nivel de entendimiento y esta de acuerdo en participar. Y Presto libremente mi conformidad para que ......................................... participe en el ensayo. Fecha Firma del participante Fecha Firma del investigador . 276 APPENDIX V: Suplementary table about severity of Covid-19 disease Severity of Covid-19 disease according to the American Thoracic Society guidelines for community-acquired pneumonia. Severity Description Mild illness Patients with uncomplicated upper respiratory tract viral infection symptoms and have non-specific symptoms such as fever, fatigue, cough (with or without sputum production), anorexia, malaise, muscle pain, sore throat, dyspnea, nasal congestion, diarrhea, nausea or vomiting or Pneumonia Presence of pneumonia but no signs of severe pneumonia and no need for supplemental oxygen. CURB scale≤1. Severe pneumonia Confirmed respiratory infection, plus one of the following: 4) Respiratory rate > 30 breaths/min. 5) Severe respiratory distress. 6) SpO2 ≤ 93% on room air. Acute respiratory distress syndrome (ARDS)16 Onset: within 1 week of a known clinical insult or new or worsening respiratory symptoms. Chest imaging (radiograph, CT scan, or lung ultrasound): bilateral opacities, not fully explained by volume overload, lobar or lung collapse, or nodules. Origin of pulmonary infiltrates : respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g. echocardiography) to exclude hydrostatic cause of infiltrates/oedema if no risk factor 277 present. Oxygenation impairment in adults : • Mild ARDS: 200 mmHg < PaO2/FiO2a ≤ 300 mmHg (with PEEP or CPAP ≥ 5 cmH2O, or non-ventilated) • Moderate ARDS: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg (with PEEP ≥ 5 cmH2O, or non-ventilated) • Severe ARDS: PaO2/FiO2 ≤ 100 mmHg (with PEEP ≥ 5 cmH2O, or non-ventilated) • When PaO2 is not available, SpO2/FiO2 ≤ 315 implies ARDS (including in non-ventilated patients). Sp: Saturation percentage. ADRS: Acute Distress Respiratory Syndrome. CT: Cranial Tomography. PaO2: Partial pressure of Oxygen. FiO2: Fraction of inspired Oxygen. PEEP: Positive end-expiratory pressure. CPAP: Continuous positive airway pressure. Adapted from: 33. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia: an official clinical practice guideline of the American Thoracic Society and Infectious Disease Society of America. Am J Respir Crit Care Med 2019;200(7):e45-e67. 278 Figures legends: Figure 1: The cover of the International Classification of Headache Disorders, 1st edition, 1988 (left), first page of the International Classification of Headache Disorders, 3rd version, 2018 (right). Figure 2 . Main groups of red flags. Figure 3 . Work-up of patients with red flags. Figure 4 . Common elements in the design of the three studies. Figure 5 . Frequency of red flags in CVST, Covid-19 and TTH groups separated by category of red flag. Figure 6. Number of publications per year related to migraine (blue) or tension-type headache (TTH) (orange) indexed in PubMed.gov from inception to November 11, 2020. Figure 7 . Graphical representation of ICHD-3 criteria for migraine and TTH. Figure 8 . Quality of evidence in studies assessing red flags. Figure 9 . Pathophysiology, symptoms and signs of cerebral venous sinus thrombosis. Figure 10 . Design of studies assessing frequency of headache in Covid-19 patients in Valladolid. Figure 11 . Interval (in days) between the first COVID-19 symptom and the headache onset (n=458). Figure 12 . Interpretation of PCR and serological tests to detect severe acute respiratory syndrome coronavirus 2. Adapted from Ezpeleta et al, 2020. 279 Tables legends: Table 1 . Studies analysing the main reasons for consulting the on-call neurologist in the emergency department setting. Table 2. Main groups of the International Classification of Headache Disorders. Table 3 : Core criteria for secondary headache disorders. Table 4 . ICHD-3 criteria for 9.2.2 Headache attributed to systemic viral infection. Table 5 . Major groups and/or subgroups of the ICHD-3 classification that include high-risk headache disorders. Table 6 . Frequency of headache in the well-known series of cancer patients. Table 7 . Frequency of headache in the well-known series of central nervous system infections. Table 8. Main characteristics of a biomarker. Table 9. Studies evaluating laboratory biomarkers for the diagnosis of headache. Table 10 . Main red flags of headache disorders. Table 11 . Main red flags of headache disorders and the groups or subgroups of the related secondary headache disorders. Table 12 . Studies in which red flags have been validated. Table 13. Strengths and limitations of red flags as headache-related biomarkers. Table 14. Common elements of the inclusion and exclusion criteria of the studies. Table 15. Evaluation of sensitivity and specificity of a test. Table 16. ICHD-3 criteria for 2. Tension type headache. Table 17. ICHD criteria for 2. Tension type headache: from the first edition to the third version. 280 Table 18. International Classification of Headache Disorders, 3rd version, criteria for 6.6.1 Headache attributed to cerebral venous thrombosis. Table 19. International Classification of Headache Disorders, 3rd version, criteria for 9.2.2: Headache attributed to systemic viral infection. Table 20. Demographic profile of patients included in the published series assessing headache in Covid-19: Table 21. Published cases of CVST in patients with Covid-19 to date. 281