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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.

Purpose: To investigate the peripapillary retinal nerve fiber layer thickness (RNFLT), macular RNFLT, ganglion cell layer (GCL), and inner plexiform layer (IPL) thickness in recovered COVID-19 patients compared to controls., Methods: Patients previously diagnosed with COVID-19 were included, while healthy patients formed the historic control group. All patients underwent an ophthalmological examination, including macular and optic nerve optical coherence tomography. In the case group, socio-demographic data, medical history, and neurological symptoms were collected., Results: One hundred sixty patients were included; 90 recovered COVID-19 patients and 70 controls. COVID-19 patients presented increases in global RNFLT (mean difference 4.3; CI95% 0.8 to 7.7), nasal superior (mean difference 6.9; CI95% 0.4 to 13.4), and nasal inferior (mean difference 10.2; CI95% 2.4 to 18.1) sectors of peripapillary RNFLT. Macular RNFL showed decreases in COVID-19 patients in volume (mean difference -0.05; CI95% -0.08 to -0.02), superior inner (mean difference -1.4; CI95% -2.5 to -0.4), nasal inner (mean difference -1.1; CI95% -1.8 to -0.3), and nasal outer (mean difference -4.7; CI95% -7.0 to -2.4) quadrants. COVID-19 patients presented increased GCL thickness in volume (mean difference 0.04; CI95% 0.01 to 0.07), superior outer (mean difference 2.1; CI95% 0.8 to 3.3), nasal outer (mean difference 2.5; CI95% 1.1 to 4.0), and inferior outer (mean difference1.2; CI95% 0.1 to 2.4) quadrants. COVID-19 patients with anosmia and ageusia presented an increase in peripapillary RNFLT and macular GCL compared to patients without these symptoms., Conclusions: SARS-CoV-2 may affect the optic nerve and cause changes in the retinal layers once the infection has resolved.

Objective: We investigated the incidence, predictor variables, clinical characteristics, and stroke outcomes in patients with COVID-19 seen in emergency departments (EDs) before hospitalization., Methods: We retrospectively reviewed all COVID-19 patients diagnosed with stroke during the COVID-19 outbreak in 62 Spanish EDs. We formed two control groups: COVID-19 patients without stroke (control A) and non-COVID-19 patients with stroke (control B). We compared disease characteristics and four outcomes between cases and controls., Results: We identified 147 strokes in 74,814 patients with COVID-19 seen in EDs (1.96‰, 95% confidence interval [CI] = 1.66‰ to 2.31‰), being lower than in non-COVID-19 patients (6,541/1,388,879, 4.71‰, 95% CI = 4.60‰ to 4.83‰; odds ratio [OR] = 0.42, 95% CI = 0.35 to 0.49). The estimated that standardized incidences of stroke per 100,000 individuals per year were 124 and 133 for COVID-19 and non-COVID-19 individuals, respectively (OR = 0.93 for COVID patients, 95% CI = 0.87 to 0.99). Baseline characteristics associated with a higher risk of stroke in COVID-19 patients were hypertension, diabetes mellitus, and previous cerebrovascular and coronary diseases. Clinically, these patients more frequently presented with confusion, decreased consciousness, and syncope and higher D-dimer concentrations and leukocyte count at ED arrival. After adjustment for age and sex, the case group had higher hospitalization and intensive care unit (ICU) admission rates (but not mortality) than COVID-19 controls without stroke (OR = 3.41, 95% CI = 1.27 to 9.16; and OR = 3.79, 95% CI = 1.69 to 8.50, respectively) and longer hospitalization and greater in-hospital mortality than stroke controls without COVID-19 (OR = 1.55, 95% CI = 1.24 to 1.94; and OR = 1.77, 95% CI = 1.37 to 2.30, respectively)., Conclusions: The incidence of stroke in COVID-19 patients presenting to EDs was lower than that in the non-COVID-19 reference sample. COVID-19 patients with stroke had greater need for hospitalization and ICU admission than those without stroke and longer hospitalization and greater in-hospital mortality than non-COVID-19 patients with stroke., (© 2021 Society for Academic Emergency Medicine.)

Background and Objective: CGRP, a neuropeptide involved in migraine pathophysiology, is also known to play a role in the respiratory system and in immunological conditions such as sepsis. We analyzed the impact of the use of CGRP antagonists in patients with migraine during the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus., Methods: This is a multicentre cross-sectional study. From May to November 2020, through a national survey distributed by the Spanish Society of Neurology, we collected data about the presence of COVID-19 symptoms including headache and their characteristics and severity in patients with migraine treated with anti-CGRP monoclonal antibodies (mAb), and compared them with patients with migraine not receiving this treatment. We also conducted a subanalysis of patients with COVID-19 symptoms., Results: We recruited 300 patients with migraine: 51.7% (155/300) were taking anti-CGRP mAbs; 87.3% were women (262/300). Mean age (standard deviation) was 47.1 years (11.6). Forty-one patients (13.7%) met diagnostic criteria for COVID-19, with no statistically significant difference between patients with and without anti-CGRP mAb treatment (16.1% vs 11.0%, respectively; P=.320). Of the patients with COVID-19, 48.8% (20/41) visited the emergency department and 12.2% (5/41) were hospitalised. Likewise, no clinical differences were found between the groups of patients with and without anti-CGRP mAb treatment., Conclusion: Anti-CGRP mAbs may be safe in clinical practice, presenting no association with increased risk of COVID-19., (Copyright © 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

A high proportion of people who have suffered from COVID-19 report, after recovery from the acute phase of the disease, clinical manifestations, both subjective and objective, that continue beyond 3 weeks or even 3 months after the original clinical disease. There is still no agreed nomenclature to refer to this condition, but perhaps the most commonly used is post-COVID syndrome. The Scientific Committee on COVID of the Madrid College of Physicians (ICOMEM) has discussed this problem with a multidisciplinary approach in which internists, infectious disease specialists, psychiatrists, pneumologists, surgeons, geriatricians, pediatricians, microbiologists, family physicians and other specialists have participated, trying to gather the existing information and discussing it in the group. The clinical manifestations are very variable and range from simple fatigue to persistent fibrosing lung lesions with objective alterations of pulmonary function. Post-COVID syndrome seems to be particularly frequent and severe in adults who have required admission to Intensive Care Units and has a peculiar behavior in a very small group of children. The post-COVID syndrome, which undoubtedly exists, is at first sight not clearly distinguishable from clinical manifestations that which occur after other acute viral diseases and after prolonged stays in ICUs due to other diseases. Therefore, it offers excellent research opportunities to clarify its pathogenesis and possibly that of other related entities. It is possible that progressively there will be an increased demand for care among the millions of people who have suffered and overcome acute COVID for which the health authorities should design mechanisms for the agile management of care that will possibly require well-coordinated multidisciplinary groups. This paper, structured in questions on different aspects of the post-COVID syndrome, attempts to stage the current state of this problem., (©The Author 2021. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

Purpose: To describe macular vessel density and perfusion in COVID-19 patients using coherence tomography angiography (OCTA) and to investigate whether there is a correlation between retinal vascular abnormalities and clinical and laboratory parameters., Methods: Cross-sectional analysis conducted at the Hospital Clinico San Carlos in Madrid, Spain. Patients with laboratory-confirmed COVID-19 that were attended in the Emergency Department (ED) from March 23 to March 29, 2020 were included. Fundus examination and OCTA were performed 4 weeks after being attended in ED. Macular OCTA parameters were analyzed and correlated with clinical (severity and hypoxemia- oxygen saturation<92%) and laboratory parameters during hospital stay (D-Dimer-DD, lactate dehydrogenase-LDH and C-reactive protein-CRP)., Results: 80 patients were included, mean age 55(SD9) years old; 46.3% male. We reported macular vessel density and perfusion measurements in COVID-19 patients. Those patients with D-Dimer≥500ng/ml during SARS-CoV-2 infection had a decrease of central vessel density (mean difference 2.2; 95%CI 0.4-3.9) and perfusion density (mean difference 4.9; 95%CI 0.9-8.9) after the acute phase of COVID-19. These variations of vessel density and perfusion density were not documented in patients with LDH≥500U/L, CRP≥10mg/L and hypoxemia., Conclusions: COVID-19 patients showed short-term retinal vasculature abnormalities which may be related to a prothrombotic state associated with SARS-CoV-2 infection. Since the retinal microvasculature shares many morphological and physiological properties with the vasculature of other vital organs, further research is needed to establish whether patients with increased D-Dimer levels require more careful assessment and follow-up after COVID-19., (Copyright © 2021 Elsevier España, S.L.U. All rights reserved.)

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., (© 2020 American Neurological Association.)

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., (© 2020 Wiley Periodicals LLC.)

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., (© 2020 Wiley Periodicals LLC.)

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., (© 2020 American Headache Society.)

Background and Purpose: Specific respiratory tract infections, including COVID-19, may cause smell and/or taste disorders (STDs) with increased frequency. The aim was to determine whether new-onset STDs are more frequent amongst COVID-19 patients than influenza patients., Method: This was a case-control study including hospitalized patients of two tertiary care centres. Consecutive patients positive for COVID-19 polymerase chain reaction (cases) and patients positive for influenza polymerase chain reaction (historical control sample) were assessed during specific periods, employing a self-reported STD questionnaire., Results: Seventy-nine cases and 40 controls were included. No significant differences were found in basal features between the two groups. New-onset STDs were significantly more frequent amongst cases (31, 39.2%) than in the control group (5, 12.5 %) [adjusted odds ratio 21.4 (2.77-165.4, P = 0.003)]. COVID-19 patients with new-onset STDs were significantly younger than COVID-19 patients without STDs (52.6 ± 17.2 vs. 67.4 ± 15.1, P < 0.001). Amongst COVID-19 patients who presented STDs, 22 (70.9%) recalled an acute onset and it was an initial manifestation in 11 (35.5%). Twenty-five (80.6%) presented smell disorders (mostly anosmia, 14, 45.2%) and 28 (90.3%) taste disorders (mostly ageusia, 14, 45.2%). Only four (12.9 %) reported concomitant nasal obstruction. The mean duration of STD was 7.5 ± 3.2 days and 12 patients (40%) manifested complete recovery after 7.4 ± 2.3 days of onset., Conclusion: New-onset STDs were significantly more frequent amongst COVID-19 patients than influenza patients; they usually had an acute onset and were commonly an initial manifestation. The use of STD assessment in anamnesis as a hint for COVID-19 and to support individuals' self-isolation in the current epidemic context is suggested., (© 2020 European Academy of Neurology.)

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., (© 2020 American Headache Society.)

Background: Management of disease-modifying therapies in Multiple Sclerosis (MS) during the COVID-19 pandemic is a controversial issue. Alemtuzumab is an immunosuppressive drug that induces lymphocytes depletion. In this study, we aimed to evaluate the frequency and severity of COVID-19 in a case series of patients treated with alemtuzumab in our center., Methods: Ten patients with a diagnosis of relapsing-remitting MS were phoned and asked about symptoms suggestive and COVID-19 using a semi-structured questionnaire., Results: The mean age was 43.7 ± 9.65 years old, and 8 (80%) were females. The mean time since disease diagnosis was 17.30 ± 8.59 years, and all were patients with relapsing-remitting MS. Mean time from the last dose of Alemtuzumab was 9.80 ± 6.64 months, and last lymphocyte count was 760 ± 231 / μL. Two patients (20%) developed symptoms highly suggestive of COVID-19. Disease duration was 2 and 7 days. None patient required hospital admission. Patients with COVID-19 symptoms had longer clinical course of MS. Conversely, we did not find statistically significant differences regarding age, EDSS, last lymphocyte count, and months since the last dose of alemtuzumab administered between patients having or not symptoms of COVID-19., Conclusions: Our data suggest that patients receiving alemtuzumab showed very mild symptoms of COVID-19. We speculate that immune reconstitution induced by treatment may induce positive changes in the immune system in the defense against SARS-CoV2. Further research about alemtuzumab and their role in COVID-infection is necessary to confirm these preliminary findings., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Since the beginning of the Covid-19 epidemic produced by SARS2-Cov virus, olfactory alterations have been observed at a greater frequency than in other coronavirus epidemics. While olfactory alterations may be observed in patients with rhinovirus, influenza virus, or parainfluenza virus infection, they are typically explained by nasal obstruction with mucus or direct epithelial damage; in the case of SARS-CoV-2, olfactory alterations may present without nasal congestion with mucus. We performed a study of patients presenting olfactory/gustatory alterations in the context of SARS-CoV-2 infection in order to contribute to the understanding of this phenomenon. Material and Methods: We performed a descriptive, cross-sectional, observational study of the clinical characteristics of olfactory/gustatory alterations using a self-administered, anonymous online questionnaire. Results: A total of 909 patients with SARS-CoV-2 infection and olfactory/gustatory alterations responded to the questionnaire in the 4-day data collection period; 824 cases (90.65%) reported simultaneous olfactory and gustatory involvement. Patients' responses to the questionnaire revealed ageusia (581, 64.1% of respondents), hypogeusia (256, 28.2%), dysgeusia (22, 2.4%), anosmia (752 82.8%), hyposmia (142, 15.6%), and dysosmia (8, 0.9%). Fifty-four percent (489) did not report concomitant nasal congestion or mucus. Conclusion: Olfactory alterations are frequent in patients with SARS-CoV-2 infection and is only associated with nasal congestion in half of the cases., (Copyright © 2020 Gómez-Iglesias, Porta-Etessam, Montalvo, Valls-Carbó, Gajate, Matías-Guiu, Parejo-Carbonell, González-García, Ezpeleta, Láinez and Matías-Guiu.)