key: cord-0977909-7dkqwaiu authors: Portela‐Sánchez, Sofía; Sánchez‐Soblechero, Antonio; Melgarejo Otalora, Pedro José; Rodríguez López, Ángela; Velilla Alonso, Gabriel; Palacios‐Mendoza, Michael Armando; Cátedra Caramé, Carlos; Amaya Pascasio, Laura; Mas Serrano, Miguel; Massot‐Tarrús, Andreu; De La Casa‐Fages, Beatriz; Díaz‐Otero, Fernando; Catalina, Irene; García Domínguez, Jose Manuel; Pérez‐Sánchez, Javier Ricardo; Muñoz‐Blanco, José Luis; Grandas, Francisco title: Neurological complications of COVID‐19 in hospitalized patients: The registry of a neurology department in the first wave of the pandemic date: 2021-02-03 journal: Eur J Neurol DOI: 10.1111/ene.14748 sha: 41dfd09ed70d0b63145822ab656abad813600d2f doc_id: 977909 cord_uid: 7dkqwaiu OBJECTIVE: To describe the spectrum of neurological complications observed in a hospital‐based cohort of COVID‐19 patients who required a neurological assessment. METHODS: We conducted an observational, monocentric, prospective study of patients with a COVID‐19 diagnosis hospitalized during the 3‐month period of the first wave of the COVID‐19 pandemic in a tertiary hospital in Madrid (Spain). We describe the neurological diagnoses that arose after the onset of COVID‐19 symptoms. These diagnoses could be divided into different groups. RESULTS: Only 71 (2.6%) of 2750 hospitalized patients suffered at least one neurological complication (77 different neurological diagnoses in total) during the timeframe of the study. The most common diagnoses were neuromuscular disorders (33.7%), cerebrovascular diseases (CVDs) (27.3%), acute encephalopathy (19.4%), seizures (7.8%), and miscellanea (11.6%) comprising hiccups, myoclonic tremor, Horner syndrome and transverse myelitis. CVDs and encephalopathy were common in the early phase of the COVID‐19 pandemic compared to neuromuscular disorders, which usually appeared later on (p = 0.005). Cerebrospinal fluid severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) polymerase chain reaction was negative in 15/15 samples. The mortality was higher in the CVD group (38.1% vs. 8.9%; p = 0.05). CONCLUSIONS: The prevalence of neurological complications is low in patients hospitalized for COVID‐19. Different mechanisms appear to be involved in these complications, and there was no evidence of direct invasion of the nervous system in our cohort. Some of the neurological complications can be classified into early and late neurological complications of COVID‐19, as they occurred at different times following the onset of COVID‐19 symptoms. [ [4] [5] [6] [7] Similarly to its SARS-CoV and MERS infection predecessors, SARS-CoV-2 infection has been associated with possible pathogenic processes in the nervous system. [8] The first reports of neurological manifestations associated with COVID-19 in hospitalized patients included non-specific symptoms such as myalgia, dizziness, and headache as the most common neurological features. [9, 10] In other series of patients, severe SARS-CoV-2 infection has been shown to be associated with encephalopathy and corticospinal tract signs. [11] Cerebrovascular disease (CVD) has also been reported with severe COVID-19. [12] As the pandemic progressed, other neurological complications have been described such as acute necrotizing encephalopathy, [13] acute necrotizing myelitis, [14] Guillain-Barré syndrome (GBS), [15] and other para-/ post-infectious complications such as encephalitis. [16] Anosmia and dysgeusia are common in the early phase of the disease. [17] The pathogenesis of these neurological manifestations and complications has not yet been elucidated. Limited access to proper neurological assessments and diagnostic procedures could have led to the possible neurological complications being overlooked or misjudged during the peak of the COVID-19 pandemic. In order to obtain a better understanding of the neurological symptoms associated with SARS-CoV-2 infection, we here describe the spectrum of neurological complications observed in a hospitalbased cohort of COVID-19 patients who required a formal neurological assessment. To evaluate the possible neurological complications of SARS-CoV-2 infection we generated a prospective registry of patients admitted to the COVID-19 wards and the intensive care unit (ICU) at the Hospital General Universitario Gregorio Marañón (Madrid, Spain) and who had been referred to the neurology department. In this survey, we considered consecutive patients registered from 7 March to 7 June 2020. Patients were recruited at the time that they were referred to the neurology department. The inclusion criteria comprised being an adult; a confirmed or probable COVID-19 diagnosis, and new onset of neurological symptoms. Patients with a previous neurological disease or condition that could either in part or fully explain the new neurological symptoms were excluded. We extracted the personal history, demographic data, COVID-19 non-neurological symptoms, and the first ancillary tests results of every patient from the electronic medical records. The COVID-19 treatments were also documented for every patient. The severity of the disease was established according to clinical (severe hypoxemia: partial pressure arterial oxygen and fraction of inspired oxygen [PaO2:FiO2] ratio < 300 mmHg), laboratory (D-dimer, Creactive protein, ferritin, interleukin-6 levels), or radiological (bilateral pneumonia) prognostic factors on admission to the COVID-19 ward. The time from the onset of COVID-19 symptoms to the manifestation of neurological symptoms was recorded. We also evaluated the complementary test results after neurological assessments comprising cerebrospinal fluid (CSF) analysis, neurologic radiological examinations (brain computed tomography The statistical analysis was performed using the SPSS ® (Statistical Package for the Social Sciences) software, version 26. The categorical variables are reported as the number of cases and percentages. The continuous variables are expressed as medians and ranges. The ratios were compared using Chi-squared or Fisher's exact tests. The quantitative variables were compared using non-parametric tests (Mann−Whitney U, Kruskal−Wallis, or Wilcoxon test). A p value <0.05 was considered statistically significant. Multiple comparisons were applied in cases of more than two quantitative variables and a p value <0.05. During the 3-month period of the first wave of the pandemic in Spain 2750 COVID-19 patients were admitted to the Hospital General Universitario Gregorio Marañón (Madrid, Spain). Seventy-one patients (2.6%) met the study requirements and were included in the survey. Six of them received two different neurological diagnoses. Their demographic and clinical characteristics are shown in Table 1 . Thirteen of these patients (18.3%) were admitted to the ICU, and Table 2 . Table S3 . Six patients (7.8%) suffered persistent hiccups (lasting longer than 48 h). All of these patients were male, and they exhibited bilateral Conversely, the hyperimmune response and cytokine storm, which are more prominent in the later stages of the disease, may play a major role in some of the neuromuscular complications. [25] Thus, in patients with acute inflammatory polyneuropathy, the onset of symptoms during the convalescent period of the disease, together with the detection of ganglioside antibodies in one of the cases, suggest a post-infectious mechanism mediated by molecular mimicry associated with COVID-19. [26] Nevertheless, the broad range of the various complications de- The peripheral nerve damage of the afferent or efferent motor fibers of the phrenic or accessory nerve caused by multiple pulmonary infiltrates is the most probable cause of persistent hiccups. [34] Similarly, Horner syndrome, which is a rare complication of pneumonia that affects the adjacent pleura, was noted in one patient due to focal pneumonia in the ipsilateral lung apex and pleura. [35] An immune-mediated origin related to SARS-CoV-2 infection was suspected in a patient with a self-limited myoclonic tremor that had a late onset of symptoms after COVID-19. [36] Finally, the etiologies of the other complications, such as four cases of unexplained acute encephalopathy, one case of generalized tonic−clonic seizure, two focal seizures with impaired awareness, a trochlear palsy, and a para-infectious dorsal myelitis remain unknown. Therefore, a clear relationship with COVID-19 cannot be established. The presence of concomitant hyposmia or dysgeusia was low in our cohort (4.2%). This could be explained by a lower prevalence of these symptoms in hospitalized patients compared to non-hospitalized patients. [37] Moreover, the greater severity of patients with neurological complications could mask these symptoms. The mortality in our cohort was low (16.9%). The death rate was higher in the CVD group, while the encephalopathy cases had a better outcome, probably due to the presence of a reversible etiology in most of them. This study has limitations associated with the study design, while the pandemic context resulted in difficulties with performing a complete workup. Additionally, limiting the inclusion to patients who required a neurological assessment could have led to underestimation of some of the neurological complications. Further studies with longer follow-ups will be invaluable for elucidation of the complete spectrum of neurological complications associated with SARS-CoV-2. Our findings indicate that neurological complications associated with SARS-CoV-2 infection are uncommon in hospitalized patients and that they appear to be due to a variety of causes. However, no evidence of a potential direct invasion of the nervous system was observed in our cohort. The various causal mechanisms could explain the broad clinical spectrum and the different times at which the neurological symptoms appeared during the infection. This allowed them to be classified into early and late neurological complications of COVID-19. We also report, for the first time, cases of persistent hiccups and Horner syndrome related to COVID-19. The authors have stated explicitly that there are no conflicts of interest in connection with this article. The data that support the findings of this study are available from the corresponding author upon reasonable request. 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