CandeSpartan Study: Candesartan Spanish Response-prediction and Tolerability study in migraine.

INTRODUCTION: Effectiveness of candesartan in migraine prevention is supported by two randomized controlled trials. We aimed to assess the effectiveness, tolerability, and response predictors of candesartan in the preventive treatment of migraine. METHODS: Observational, multicenter, prospective cohort study. The 50%, 75% and 30% responder rates, between weeks 8-12 and 20-24, were compared with the baseline. Treatment emergent adverse effects were systematically evaluated. Response predictors were estimated by multivariate regression models. RESULTS: Eighty-six patients were included, 79.1% females, aged 39.5 (inter-quartile range [IQR] 26.3-50.3), with chronic migraine (43.0%), medication overuse headache (55.8%) and a median of two (inter-quartile range: 0.75-3) prior preventive treatments. At baseline patients had 14 (10-24) headache and 8 (5-11) migraine days per month. The 30%, 50% and 75% responder rates were 40%, 34.9% and 15.1% between weeks 8-12, and 48.8%, 36%, and 18.6% between weeks 20-24. Adverse effects were reported by 30 (34.9%) and 13 (15.1%) patients between weeks 0-12 and 12-24, leading to discontinuation in 15 (17.4%) patients. Chronic migraine, depression, headache days per month, medication overuse headache, and daily headache at baseline predicted the response between weeks 20-24. CONCLUSION: Candesartan effectiveness and tolerability in migraine prevention was in line with the clinical trials' efficacy.Trial registration: The study protocol is registered in ClinicalTrials.gov (NCT04138316).

Clinical predictors of therapeutic failure of occipital nerve stimulation in refractory chronic cluster headache.

BACKGROUND: Occipital nerve stimulation (ONS) is a treatment with evidence in refractory chronic cluster headache (CCH). However, the variable response rate and cost make it necessary to investigate predictors of response. METHODS: This is a cross-sectional study conducted through the review of medical records of CCH patients from six hospitals in Madrid. Epidemiological and clinical variables were compared between patients with ONS failure and the rest. ONS failure was defined as the need for device withdrawal or switch off because of lack of response or adverse events. RESULTS: From a series of 88 CCH, 26 (29.6%) underwent ONS surgery, of whom 13/26 (50.0%) failed because lack of response. ONS failure group had an earlier headache onset (mean ± SD) of 27.7 ± 6.9 vs. 36.7 ± 11.8 years, p = 0.026) and a higher smoking rate (100% vs. 42.9%, p = 0.006). Stational fluctuations (58.3% vs. 7.7%, p = 0.007) and nocturnal exacerbations (91.7% vs. 53.9%, p = 0.035) were more frequent in the ONS failure group as well. There was no difference between groups in diagnostic delay, years of evolution prior to surgery, mental illness, comorbidity with other headache disorders or chronic pain conditions or prior response to occipital nerves anesthetic blocks. CONCLUSIONS: Some clinical features such as an early debut, smoking and seasonal or circadian fluctuations could be related to failure of ONS in refractory CCH.

Evaluation of the concomitant use of prophylactic treatments in patients with migraine under anti-calcitonin gene-related peptide therapies: The PREVENAC study.

BACKGROUND AND PURPOSE: Anti-calcitonin gene-related peptide (CGRP) therapies are recent preventive therapies approved for both episodic and chronic migraine. One of the measures of effectiveness is the withdrawal of other preventive treatments. The objective of this study is to quantify the impact of anti-CGRP drugs in concomitant preventive treatment in patients with migraine. METHODS: This was an observational, retrospective, multicenter cohort study with patients from nine national headache units. Patients with migraine undergoing treatment for at least 6 months with anti-CGRP antibodies, who were initially associated with some preventive treatment (oral and/or onabotulinumtoxinA) were included. Demographic and clinical variables were collected, as well as variables related to headache. Differences according to withdrawal or nonwithdrawal were evaluated. RESULTS: A total of 408 patients were included, 86.52% women, 48.79 (SD = 1.46) years old. Preventive treatment was withdrawn in 43.87% (179/408), 20.83% partially and 23.04% totally. In 27.45% (112/408), it was maintained exclusively due to comorbidity and in 28.6% (117/408) due to partial efficacy. The most frequent time of withdrawal was between 3 and 5 months after the start of treatment. The baseline characteristics associated with nonwithdrawal were comorbidities: insomnia, hypertension and obesity, chronic migraine, and medication overuse. In the multivariate analysis, the absence of high blood pressure, a greater number of preventive treatments at the start, and a lower number of migraine days/month after anti-CGRP treatment were independently associated with withdrawal of the treatment (p < 0.05). CONCLUSIONS: Anti-CGRP antibodies allow the withdrawal of associated preventive treatment in a significant percentage of patients, which supports its effectiveness in real-life conditions.

Effectiveness, tolerability, and response predictors of preventive anti-CGRP mAbs for migraine in patients over 65 years old: a multicenter real-world case-control study.

OBJECTIVE: To evaluate clinical characteristics, effectiveness, and tolerability of preventive anti- calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) in the elderly. Anti-CGRP mAbs have demonstrated efficacy and safety in patients with migraine although there is limited information regarding the elderly. DESIGN: We performed a multicenter case-control study of cases (patients over 65 years old) and controls (sex-matched patients under 55 years old) with migraine receiving anti-CGRP mAbs. METHODS: We included the demographic characteristics, effectiveness-reduction in the number of monthly headache days (MHD) and monthly migraine days (MMD), 30%, 50%, and 75% responder rates-and treatment emergent adverse events (TEAEs). The primary endpoint was the 50% response rate regarding MHD at weeks 20-24; exploratory 50% response predictors in the elderly were evaluated. RESULTS: In total, 228 patients were included: 114 cases , 114 controls-. Among cases 84.2% (96/114) were women, 79.8% (91/114) CM; mean age of cases 70.1 years old (range: 66-86); mean age of controls was 42.9 years old(range: 38-49). Cases had a higher percentage of vascular risk factors (P < .05),older age of onset (P < .001) and more reported prior preventive treatments (P < .001). Regarding effectiveness in cases, 50% response rate was achieved by 57.5% (42/73) at 20-24 weeks, with lower reduction in the MHD at 8-12 weeks (5 [7.2], 8 [9.1]; P = .001) and a higher reduction in MMD at 20-24 weeks (10.7 [9.1], 9.2 [7.7]; P = .04) compared to the control group. The percentage of TEAEs was similar in the 2 groups. Diagnosis of episodic migraine (EM) (P = .03) and lower number of MHD at baseline (P = .001) were associated with a 50% response in the elderly in univariate analysis. CONCLUSIONS: Our study provides real world evidence of effectiveness and safety of anti-CGRP mAbs for migraine in patients without upper age-limit and possible predictors of anti-CGRP response in the elderly.

Neurotological emergencies: a narrative review.

INTRODUCTION: Vestibular symptoms, including vertigo, dizziness, and gait unsteadiness, are a frequent reason of urgent medical assistance. Their causes are numerous and diverse, including neurological, otorhinolaryngological, and systemic diseases. Therefore, following a systematic approach is essential to differentiate striking but benign conditions from others that can compromise the patient's life. This study is intended to review vestibular disorders from a practical perspective and provide guidance to physicians involved in the emergency care of patients with vestibular symptoms. MATERIALS AND METHODS: A narrative review was performed, revisiting the main causes of vestibular disorders. RESULTS: Based on the speed of onset, duration, and history of similar episodes in the past, vestibular disorders can be categorized into three syndromic entities (acute, recurrent, and chronic vestibular syndromes). The most representative conditions pertaining to each group were reviewed (including their diagnosis and treatment) and a practical algorithm was proposed for their correct management in the acute care setting. CONCLUSIONS: Carrying out a correct categorization of the vestibular disorders is essential to avoid diagnostic pitfalls. This review provides useful tools for clinicians to approach their patients with vestibular symptoms at the emergency room.

Incidence, clinical, risk factors and outcomes of Guillain-Barré in Covid-19.

We diagnosed 11 Guillain-Barré syndrome (GBS) cases among 71,904 COVID patients attended at 61 Spanish emergency departments (EDs) during the 2-month pandemic peak. The relative frequency of GBS among ED patients was higher in COVID (0.15‰) than non-COVID (0.02‰) patients (odds ratio [OR] = 6.30, 95% confidence interval [CI] = 3.18-12.5), as was the standardized incidence (9.44 and 0.69 cases/100,000 inhabitant-years, respectively, OR = 13.5, 95% CI = 9.87-18.4). Regarding clinical characteristics, olfactory-gustatory disorders were more frequent in COVID-GBS than non-COVID-GBS (OR = 27.59, 95% CI = 1.296-587) and COVID-non-GBS (OR = 7.875, 95% CI = 1.587-39.09) patients. Although COVID-GBS patients were more frequently admitted to intensive care, mortality was not increased versus control groups. Our results suggest SARS-CoV-2 could be another viral infection causing GBS. ANN NEUROL 2021;89:598-603.

Sensitivity of the SNNOOP10 list in the high-risk secondary headache detection.

AIM: To evaluate the diagnostic accuracy of the SNNOOP10 list in the detection of high-risk headaches. METHODS: Patients that visited the Hospital Clínico San Carlos (Madrid) emergency department due to headache that were allocated to a Manchester Triage System level between critical and urgent were prospectively included but retrospectively analysed. A researcher blind to the patients' diagnosis administered a standardised questionnaire and afterwards a neurologist blind to the questionnaire results diagnosed the patient according to the International Classification of Headache Disorders. The primary endpoint was to assess the sensitivity of the SNNOOP10 list in the detection of high-risk headaches. Secondary endpoints included the evaluation of the sensitivity, specificity, positive predictive value, negative predictive value and area under the curve of each SNNOOP10 item. RESULTS: Between April 2015 and October 2021, 100 patients were included. Patients were 44 years old (inter-quartile range: 33.6-64.7) and 57% were female. We identified 37 different diagnoses. Final diagnosis was a primary headache in 33%, secondary headache in 65% and cranial neuralgia in 2%. There were 46 patients that were considered as having high-risk headache. Patients from the primary headache group were younger and more frequently female. Sensitivity of SNNOOP10 list was 100% (95% confidence interval: 90.2%-100%). The items with higher sensitivity were neurologic deficit or disfunction (75.5%), pattern change or recent onset of the headache (64.4%), onset after 50 years (64.4%). The most specific items were posttraumatic onset of headache (94.5%), neoplasm in history (89.1%) and systemic symptoms (89%). The area under the curve of the SNNOOP10 list was 0.66 (95% CI: 0.55-0.76). CONCLUSION: The red flags from the SNNOOP10 list showed a 100% sensitivity in the detection of high-risk headache disorders.

Post-COVID-19 persistent headache: A multicentric 9-months follow-up study of 905 patients.

BACKGROUND: Headache is a frequent symptoms of coronavirus disease 2019 (COVID-19). Its long-term evolution remains unknown. We aim to evaluate the long-term duration of headache in patients that presented headache during the acute phase of COVID-19. METHODS: This is a post-hoc multicenter ambisective study including patients from six different third-level hospitals between 1 March and 27 April 2020. Patients completed 9 months of neurological follow-up. RESULTS: We included 905 patients. Their median age was 51 (IQR 45-65), 66.5% were female, and 52.7% had a prior history of primary headache. The median duration of headache was 14 (6-39) days; however, the headache persisted after 3 months in 19.0% (95% CI: 16.5-21.8%) and after 9 months in 16.0% (95% confidence interval: 13.7-18.7%). Headache intensity during the acute phase was associated with a more prolonged duration of headache (Hazard ratio 0.655; 95% confidence interval: 0.582-0.737). CONCLUSION: The median duration of headache was 2 weeks, but in approximately a fifth of patients it became persistent and followed a chronic daily pattern.

Clinical exacerbation of SARS-CoV2 infection after fingolimod withdrawal.

The role of disease-modifying therapies in patients with autoimmune disorders during severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is controversial. Immunocompromised patients could have a more severe coronavirus disease-2019 (COVID-19) due to the absence of an adequate immune response against the SARS-CoV-2. However, therapies that act on immune response could play a protective role by dampening the cytokine-release syndrome. Fingolimod is a drug used for immune therapy in patients with multiple sclerosis (MS) through the sequestration of activated lymphocytes in the lymph nodes. We report the case of a 57-year-old man with relapsing-remitting MS treated with fingolimod that showed a reactivation of COVID-19 with signs of hyperinflammation syndrome after fingolimod withdrawal. Our case suggests that discontinuation of fingolimod during COVID-19 could imply a worsening of SARS-CoV2 infection.

ACE2, TMPRSS2, and Furin variants and SARS-CoV-2 infection in Madrid, Spain.

It has been suggested that some individuals may present genetic susceptibility to SARS-CoV-2 infection, with particular research interest in variants of the ACE2 and TMPRSS2 genes, involved in viral penetration into cells, in different populations and geographic regions, although insufficient information is currently available. This study addresses the apparently reasonable hypothesis that variants of these genes may modulate viral infectivity, making some individuals more vulnerable than others. Through whole-exome sequencing, the frequency of exonic variants of the ACE2, TMPRSS2, and Furin genes was analyzed in relation to presence or absence of SARS-CoV-2 infection in a familial multiple sclerosis cohort including 120 individuals from Madrid. The ACE2 gene showed a low level of polymorphism, and none variant was significantly associated with SARS-CoV-2 infection. These variants have previously been detected in Italy. While TMPRSS2 is highly polymorphic, the variants found do not coincide with those described in other studies, with the exception of rs75603675, which may be associated with SARS-CoV-2 infection. The synonymous variants rs61735792 and rs61735794 showed a significant association with infection. Despite the limited number of patients with SARS-CoV-2 infection, some variants, especially in TMPRSS2, may be associated with COVID-19.

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

INTRODUCTION: The evaluation of red flags is crucial for the accurate the diagnosis of headache disorders, especially for thunderclap headache. We analysed if secondary headache disorders were adequately ruled out in patients that presented to the emergency room with thunderclap headache. METHODS: In this retrospective cohort study, we screened all patients that visited the emergency room for headache, including those that described thunderclap headache. We measured the frequency with which secondary causes were not adequately ruled out. We analysed the order of the exams, the final diagnosis, and the time elapsed between arrival, initial request for imaging, and the completion of the imaging. RESULTS: We screened 2132 patients, and 42 (1.9%) fulfilled eligibility criteria. Mean age was 43.1 ± 17.1 years, and 57% of patients were female. For 22 (52.4%) patients, the work-up was incomplete. Vascular study was missing in 16 (38.1%) patients, cerebrospinal fluid evaluation in nine (21.4%), and magnetic resonance imaging in seven (16.7%), with multiple assessments missing in six (14.3%). There were ten different combinations in which the exams were performed, with the most frequent being the second exam's cerebral spinal fluid evaluation in 18 (52.9%) and the computed tomography angiogram in 10 (29.4%). A secondary cause of thunderclap headache was found in 16 (38.1%) patients, and four (9.5%) had a primary headache diagnosis after an adequate and complete study. CONCLUSIONS: Thunderclap onset was described in one of every 50 patients that visited the emergency room for headache. More than half of these patients were not adequately managed. More than a third of thunderclap headache patients had a secondary cause.

Incidence, clinical characteristics, risk factors and outcomes of meningoencephalitis in patients with COVID-19.

We investigated the incidence, clinical characteristics, risk factors, and outcome of meningoencephalitis (ME) in patients with COVID-19 attending emergency departments (ED), before hospitalization. We retrospectively reviewed all COVID patients diagnosed with ME in 61 Spanish EDs (20% of Spanish EDs, COVID-ME) during the COVID pandemic. We formed two control groups: non-COVID patients with ME (non-COVID-ME) and COVID patients without ME (COVID-non-ME). Unadjusted comparisons between cases and controls were performed regarding 57 baseline and clinical characteristics and 4 outcomes. Cerebrospinal fluid (CSF) biochemical and serologic findings of COVID-ME and non-COVID-ME were also investigated. We identified 29 ME in 71,904 patients with COVID-19 attending EDs (0.40‰, 95%CI=0.27-0.58). This incidence was higher than that observed in non-COVID patients (150/1,358,134, 0.11‰, 95%CI=0.09-0.13; OR=3.65, 95%CI=2.45-5.44). With respect to non-COVID-ME, COVID-ME more frequently had dyspnea and chest X-ray abnormalities, and neck stiffness was less frequent (OR=0.3, 95%CI=0.1-0.9). In 69.0% of COVID-ME, CSF cells were predominantly lymphocytes, and SARS-CoV-2 antigen was detected by RT-PCR in 1 patient. The clinical characteristics associated with a higher risk of presenting ME in COVID patients were vomiting (OR=3.7, 95%CI=1.4-10.2), headache (OR=24.7, 95%CI=10.2-60.1), and altered mental status (OR=12.9, 95%CI=6.6-25.0). COVID-ME patients had a higher in-hospital mortality than non-COVID-ME patients (OR=2.26; 95%CI=1.04-4.48), and a higher need for hospitalization (OR=8.02; 95%CI=1.19-66.7) and intensive care admission (OR=5.89; 95%CI=3.12-11.14) than COVID-non-ME patients. ME is an unusual form of COVID presentation (<0.5‰ cases), but is more than 4-fold more frequent than in non-COVID patients attending the ED. As the majority of these MEs had lymphocytic predominance and in one patient SARS-CoV-2 antigen was detected in CSF, SARS-CoV-2 could be the cause of most of the cases observed. COVID-ME patients had a higher unadjusted in-hospital mortality than non-COVID-ME patients.

COVID-19 anosmia and gustatory symptoms as a prognosis factor: a subanalysis of the HOPE COVID-19 (Health Outcome Predictive Evaluation for COVID-19) registry.

Olfactory and gustatory dysfunctions (OGD) are a frequent symptom of coronavirus disease 2019 (COVID-19). It has been proposed that the neuroinvasive potential of the novel SARS-CoV-2 could be due to olfactory bulb invasion, conversely studies suggest it could be a good prognostic factor. The aim of the current study was to investigate the prognosis value of OGD in COVID-19. These symptoms were recorded on admission from a cohort study of 5868 patients with confirmed or highly suspected COVID-19 infection included in the multicenter international HOPE Registry (NCT04334291). There was statistical relation in multivariate analysis for OGD in gender, more frequent in female 12.41% vs 8.67% in male, related to age, more frequent under 65 years, presence of hypertension, dyslipidemia, diabetes, smoke, renal insufficiency, lung, heart, cancer and neurological disease. We did not find statistical differences in pregnant (p = 0.505), patient suffering cognitive (p = 0.484), liver (p = 0.1) or immune disease (p = 0.32). There was inverse relation (protective) between OGD and prone positioning (0.005) and death (< 0.0001), but no with ICU (0.165) or mechanical ventilation (0.292). On univariable logistic regression, OGD was found to be inversely related to death in COVID-19 patients. The odds ratio was 0.26 (0.15-0.44) (p < 0.001) and Z was - 5.05. The presence of anosmia is fundamental in the diagnosis of SARS.CoV-2 infection, but also could be important in classifying patients and in therapeutic decisions. Even more knowing that it is an early symptom of the disease. Knowing that other situations as being Afro-American or Latino-American, hypertension, renal insufficiency, or increase of C-reactive protein (CRP) imply a worse prognosis we can make a clinical score to estimate the vital prognosis of the patient. The exact pathogenesis of SARS-CoV-2 that causes olfactory and gustative disorders remains unknown but seems related to the prognosis. This point is fundamental, insomuch as could be a plausible way to find a treatment.

Frequency and Type of Red Flags in Patients With Covid-19 and Headache: A Series of 104 Hospitalized Patients.

OBJECTIVE: In this study, we aimed to evaluate the frequency of the main red flags in patients with headache who do have Covid-19. BACKGROUND: Headache is one of the most frequent neurologic symptoms of Coronavirus disease 2019 (Covid-19). Diagnosis of secondary headache disorders is still based on the presence of red flags. DESIGN AND METHODS: Cross-sectional study of hospitalized patients with confirmed Covid-19 disease. We interrogated every patient about the presence of headache and if so, a headache expert conducted a structured interview assessing the presence and type of the main red flags. We evaluated the presence of laboratory abnormalities on admission. RESULTS: We screened 576 consecutive patients, 130/576 (22.6%) described headache, and 104 were included in the study. Mean age of patients was 56.7 (standard deviation: 11.2) and 66/104 (63.4%) were female. Red flags concerning prior medical history were present in 79/104 (76.0%) cases, and those related to the headache itself were observed in 99/104 (95.2%) patients. All patients 104/104 (100%) described systemic symptoms and 86/104 (82.7%) some neurologic symptoms. Laboratory results were abnormal in 98/104 (94.2%) cases. The most frequent red flags were fever, in 93/104 (89.4%) patients, cough, in 89/104 (85.6% cases), and increased C-reactive protein in 84/100 (84.0%) cases. CONCLUSION: In patients with Covid-19 that described the headache red flags were present in most cases. There was not any universal red flag, being necessary the comprehensive evaluation of all of them.

Spectrum of Headaches Associated With SARS-CoV-2 Infection: Study of Healthcare Professionals.

BACKGROUND: Series of patients with SARS-CoV-2 infection report headache in 6%-15% of cases, although some data suggest that the actual frequency is higher, and that headache is not associated with fever. No study published to date has analyzed the characteristics of headache in these patients. OBJECTIVE: To analyze the characteristics of COVID-19 related headaches. METHODS: We conducted a survey of Spaniard healthcare professionals who have been infected by SARS-CoV-2 and presented headache during the course of the disease. The survey addressed respondents' medical history and headache characteristics, and we analyzed the association between both. RESULTS: We analyzed the responses of a sample of 112 healthcare professionals. History of migraine was reported by 20/112 (17.9%) of respondents, history of tension-type headache by 8/112 (7.1%), and history of cluster headache was reported by a single respondent; 82/112(73.2%) of respondents had no history of headache. Headache presented independently of fever, around the third day after symptom onset. The previous history of migraine was associated with a higher frequency of pulsating headache (20% in patients with previous migraine vs 4.3% in those with no history of migraine, P = .013). CONCLUSION: Headache is often holocranial, hemicranial, or occipital, pressing, and worsens with physical activity or head movements. Because the characteristics of the headache and the associated symptoms are heterogeneous in our survey, we suggest that several patterns with specific pathophysiological mechanisms may underlie the headache associated with COVID-19.

Quality assurance in specialized headache units in Spain: an observational prospective study.

OBJECTIVE: To assess the quality of the therapeutic approach in Specialized Headache Units in Spain. METHODS: An observational (prospective) study was conducted. Anonymized data of 313 consecutive patients during a defined period of time were analyzed and a comparison of performance in 13 consensual quality indicators between Specialized Headache Units and neurology consultations was calculated. Specialized Units and neurology consultations represented the type of provision that Spaniards receive in hospitals. RESULTS: The consensus benchmark standard was reached for 8/13 (61%) indicators. Specialized Headache Units performed better in the indicators, specifically in relation to accessibility, equity, safety, and patient satisfaction. Patients attended in Specialized Headache Units had more complex conditions. CONCLUSION: Although there is variability among Specialized Headache Units, the overall quality was generally better than in traditional neurology consultations in Spain.

Facial epicrania fugax: A prospective series of eight new cases.

Introduction Epicrania fugax (EF) is a primary headache whose main feature is the dynamic character of the pain. EF pain typically moves across different dermatomes in a linear or zigzag trajectory. Recently, a facial variant of EF has been described, with the pain starting in the lower face and radiating upwards. Aim We report eight patients with an EF-type of pain of facial location and either upward or downward radiation. Methods For each patient, we recorded relevant demographic and clinical data. Magnetic resonance imaging (MRI) with fast imaging employing steady state acquisition (FIESTA) was obtained in all cases for the assessment of neurovascular compression of the trigeminal nerve. Results There were seven women and one man, and the mean age was 76.1 years (standard deviation, 11.3). Six patients had a paroxysmal pain starting at the lower face and moving upwards, while two patients had downward radiation. The pain always followed a fixed linear trajectory across different dermatomes. All cases had triggers, and pain intensity was consistently severe. Half of the patients had accompanying autonomic features. Neurovascular compression with imprinting over the trigeminal root on the symptomatic side was identified in three patients. All cases responded to antiepileptic drugs, and three had spontaneous remissions. Conclusions This series reinforces the facial variant of EF and extends the phenotype with cases of downward radiation. It also contributes to enriching the differential diagnosis of facial pain. Neurovascular compression of the trigeminal nerve may be found in some cases, although a possible pathogenic link needs further research.