key: cord-0879738-o6v56tin
authors: Oliveira, Vanessa; Seabra, Mafalda; Rodrigues, Rita; Carvalho, Vanessa; Mendes, Michel; Pereira, Diogo; Caldeiras, Catarina; Martins, Bárbara; Silva, Renata; Azevedo, Ana; Lima, Maria João; Monteiro, Catarina; Varela, Ricardo; Malheiro, Sofia; Abreu, Miguel; Azevedo, Elsa; Leal Loureiro, José; Tedim Cruz, Vítor; Silva, Mário Rui; Magalhães, Rui; Silva, Carolina; Maia, Luís F.; Correia, Manuel
title: Neuro‐COVID frequency and short‐term outcome in the Northern Portuguese population
date: 2021-05-24
journal: Eur J Neurol
DOI: 10.1111/ene.14874
sha: 8e8467e1acba26218a1a203a5f99a1c5ed144ac4
doc_id: 879738
cord_uid: o6v56tin

BACKGROUND AND PURPOSE: COVID‐19‐related acute neurological phenotypes are being increasingly recognised, with neurological complications reported in more than 30% of hospitalised patients. However, multicentric studies providing a population‐based perspective are lacking. METHODS: We conducted a retrospective multicentric study at five hospitals in Northern Portugal, representing 45.1% of all hospitalised patients in this region, between 1 March and 30 June 2020. RESULTS: Among 1261 hospitalised COVID‐19 patients, 457 (36.2%) presented neurological manifestations, corresponding to a rate of 357 per 1000 in the North Region. Patients with neurologic manifestations were younger (68.0 vs. 71.2 years, p = 0.002), and the most frequent neurological symptoms were headache (13.4%), delirium (10.1%), and impairment of consciousness (9.7%). Acute well‐defined central nervous system (CNS) involvement was found in 19.1% of patients, corresponding to a rate of 217 per 1000 hospitalised patients in the whole region. Assuming that all patients with severe neurological events were hospitalised, we extrapolated our results to all COVID‐19 patients in the region, estimating that 116 will have a severe neurological event, corresponding to a rate of nine per 1000 (95% CI = 7–11). Overall case fatality in patients presenting neurological manifestations was 19.8%, increasing to 32.6% among those with acute well‐defined CNS involvement. CONCLUSIONS: We characterised the population of hospitalised COVID‐19 patients in Northern Portugal and found that neurological symptoms are common and associated with a high degree of disability at discharge. CNS involvement with criteria for in‐hospital admission was observed in a significant proportion of patients. This knowledge provides the tools for adequate health planning and for improving COVID‐19 multidisciplinary patient care.

A novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in December 2019 and is responsible for the coronavirus disease 2019 (COVID-19) pandemic, with more than 100 million diagnosed patients and more than 2.3 million deaths [1] .

SARS-CoV-2 has been shown to attach to cell membranes by binding to angiotensin-converting enzyme 2 (ACE2) [2] . Human tissue studies revealed that this receptor can be found in epithelia of the lung and small intestine and in endothelial cells from arteries and veins across different organs, including the brain [3] . Furthermore, studies using animal models demonstrated that ACE2 is expressed at the neuronal level, in the cytoplasm of cell bodies [4, 5] . Recent neuropathology studies of tissue samples have detected SARS-CoV-2 viral load in some of the evaluated brain sections, but without clear evidence of direct virus damage [6, 7] . These studies also showed ischaemic lesions in the brain, as well as inflammation characterised by T lymphocyte infiltration (particularly in the brain stem and cerebellum) [7] .

Consistently, over the course of the pandemic, neurological involvement in COVID-19 patients (NeuroCovid) has been increasingly recognised. In the acute phase of the disease, multiple neurological presentations have been described, such as anosmia, ageusia, encephalopathy, stroke, necrohaemorrhagic encephalitis, Guillain-Barré syndrome, polyneuritis cranialis, and posterior reversible encephalopathy syndrome [8] [9] [10] [11] [12] [13] [14] [15] [16] . Retrospective studies of hospitalised patients with COVID-19 have reported a rate of neurological complications ranging from 36.4% to 57.4% [13, 14, 17] . These manifestations can be considered as directly related to the effect of the virus, as para-or postinfectious immune-mediated, or as complications of the systemic manifestations of COVID-19 [18] .

Despite the growing number of reports of acute neurological phenotypes and retrospective studies of hospitalised patients, studies providing a populational perspective are still lacking. Therefore, we performed a multicentric retrospective study, involving the hospitals of Northern Portugal, to characterise the neurological manifestations of a hospitalised population of patients with COVID-19.

The 23 public hospitals in the North Region of Portugal are organised into 14 National Health System trusts, and one hospital per trust received COVID-19 patients ( Figure 1 ). All of these hospitals made available the distribution by age and sex of hospitalised patients between 1 March and 30 June 2020, diagnosed by realtime reverse transcriptase polymerase chain reaction detection of In the presence of neurological manifestations, further data were collected, including accompanying symptoms, previous comorbidities (diabetes, hypertension, pulmonary chronic obstructive disease, chronic kidney disease, cardiac disease, cerebrovascular disease, active cancer, and immunosuppression), laboratory parameters, treatments, and outcome. Functional outcome was determined using the modified Rankin Scale (mRS) at hospital discharge. Acute welldefined central nervous system (CNS) involvement was defined as the presence of acute cerebrovascular disorder, seizure, delirium, consciousness impairment, and myelopathy. Severe neurological events directly or indirectly associated with COVID-19 included acute cerebrovascular disease, seizure, posterior reversible encephalopathy syndrome, Guillain-Barré syndrome, myelopathy, cranial multineuritis, and multiple sclerosis or myasthenia gravis exacerbations. Patients with severe neurological involvement met criteria for hospitalisation due to the neurological phenotype.

The goodness of fit chi-squared was used to test representativeness of sample according to population characteristics. Rates of neurological manifestations are described, and rate ratios by sex, age, and type of hospital (tertiary vs. others) were calculated using Poisson regression models. Patients with and without acute well-defined CNS involvement were compared using the qui-squared test. Statistical significance was set at p < 0.05. at the other hospitals (599 of 1899; see Figure S1 ), but the distribution by sex and age of the sample was not significantly different from that of the target population (p = 0.2; Figure 2 and Figure S2 ).

In 457 (36.2%) patients, at least one neurological manifestation was registered, with no evidence of gender differences. However, patients with neurologic manifestations were younger than patients without (68.0 ± 18.2 vs. 71.2 ± 16.6 years, p = 0.002).

There were also no differences in registered neurological manifestations according to type of hospital (Table S1 ). The most frequently reported neurological symptoms were headache (13.4%), delirium (10.1%), and consciousness impairment (9.7%; Figure 3 ).

Headache was more frequently reported in women (16.4% vs. 10 .5%) and delirium in men (12.4% vs. 7.7%), with no other differences regarding gender ( Table 1 ). The frequency of delirium, consciousness impairment, and acute cerebrovascular disease increased with age, whereas other symptoms (headache, myalgia, myopathy, hyposmia, dysgeusia, and sleep disorders) were more frequent in the younger population (Table 1) . Male patients with neurological manifestations had more comorbidities (pulmonary chronic obstructive disease and cardiac disease), and more severe respiratory and systemic disease, with increased need for oxygen therapy, mechanical ventilation, intensive care admission, and higher lethality (Table S2) .

Acute well-defined CNS involvement was reported in 19.1% of patients, more frequently in men (21.6% vs. 16 .4%) and in older patients (24.0% vs. 9.3%). Acute cerebrovascular disorder was the final diagnosis in 23 (1.8%) patients: 15 ischaemic strokes, four haemorrhagic strokes, three transient ischaemic attacks, and one cerebral vein thrombosis.

Seizures occurred in 19 (1.5%) patients: 16 acute symptomatic seizures (three cases evolving into nonconvulsive status epilepticus) and three patients with a previous epilepsy with a seizure triggered by the infection. One patient presented with a myelopathy. No encephalitis, meningitis, or vasculitis attributed to SARS-CoV-2 infection was reported (according to the attending clinician criteria).

Peripheral nerve symptoms were described in 11 patients, including one patient with a Guillain-Barré syndrome and one with a sensorimotor polyneuropathy. Less common diagnoses were reported in eight patients, including two cases of posterior reversible encephalopathy syndrome, one nonarteritic anterior ischaemic optic neuropathy, and one cranial multineuritis.

Among patients with neurological manifestations, acute well-defined CNS involvement was present in 52.7% (Table 2) .

These patients were older and predominantly men and presented more comorbidities compared to patients with other neurological manifestations. Typical COVID-19 symptoms such as cough, odynophagia, nausea/vomiting, and diarrhoea were less frequent in those with acute well-defined CNS involvement, whereas hypoxia and subsequent treatment (oxygen therapy and mechanical F I G U R E 3 Spectrum of neurological symptoms in hospitalised patients. "Others" includes visual symptoms, myelopathy, myasthenia gravis, and multiple sclerosis exacerbation. CNS, central nervous system ventilation) were more frequent in this group. At hospital discharge, 42.3% of these patients had an mRS ranging between 0 and 3 (ambulating unassisted), whereas 32.6% died during hospitalisation, compared to 89.4% and 5.6% in patients with other neurological manifestations, respectively. Regarding the cause of death, the majority of patients (61%) died due to respiratory complications of COVID-19. aOthers include two posterior reversible encephalopathy syndrome, one myasthenia gravis exacerbation, one multiple sclerosis exacerbation, one autoimmune encephalitis, one nonarteritic anterior ischaemic optic neuropathy, one cranial multineuritis, and one dysphagia of undetermined cause.

In this study, we characterised the full spectrum of neurological [17] . Since then, higher rates have been described in the United States (42.2%) and Spain (57.4%) [13, 14] . The diverse definitions used for neurological manifestation may partially explain those differences. In some cohorts, as an example, the presence of an elevated creatine kinase or syncope alone was considered to be a neurological manifestation [13, 14] .

Consistently with previous studies, the most frequent neurological symptoms in our cohort were headache, delirium, consciousness impairment, and myalgias [13, 14] . previous descriptions [13, 14, 20] . Myelopathy is a rare diagnosis in the acute phase of the infection; one case was recognised in our cohort, and only three other cases were previously described in the literature [18, 20] . Muscle complains including myopathy were frequent, with critical illness myopathy being the final diagnosis made by the assisting clinician in all patients. Nonetheless, it is difficult to exclude a direct role of the virus in the pathogenesis of these myopathies. In our series, we had one patient with Guillain-Barré syndrome. Although both the North American and Spanish cohorts also reported a low frequency of acute polyneuropathies [13, 14] a higher rate of Guillain-Barré syndrome has been described at an Italian hospital, with 17 cases in a cohort of 1760 COVID-19 patients [20] .

Hence, further data are still needed to clarify the true rate of acute polyneuropathies associated with COVID-19.

In Northern Portugal, hospitalised patients who presented any neurological symptoms were slightly younger than patients without neurological symptoms. This has been previously described by Liotta et al. [14] in a cohort of 509 hospitalised patients. The authors speculated that it could be explained by the clinical emphasis being focused on potential respiratory failure in older patients rather than on minor accompanying neurological manifestations. Furthermore, in our study, patients with milder symptoms such as headache, myalgias, hyposmia, and dysgeusia were more frequently younger, whereas delirium and consciousness disturbances were more frequent in older patients. It is also important to note that rates of milder symptoms particularly rely on the patient's recognition. Thus, besides a probable underreporting of those symptoms in older patients by the clinician, there may also be an interference of the consciousness level on the elderly's ability to recognise and report them.

In our cohort, few differences were found between genders.

Headache was more frequently reported in women, which may partially be explained by common headache disorders being up to two times more prevalent in women [21] . In contrast, acute CNS involvement was found to be more frequent in men, mainly due to an increased rate of delirium. As male patients with neurological manifestations had more comorbidities and severe disease, they may be more susceptible to consciousness impairment.

The fatality in our hospitalised cohort was 19.8%, and 15.6% of patients were highly disabled at discharge, demonstrating the large functional impact of the infection.

The main limitation of our study was the retrospective nature of the data collection, which relied mainly on clinical records, and only reflects the neurological manifestations of hospitalised patients, who were not observed by neurologists in most of the cases.

Ongoing initiatives such as the ENERGY registry will probably complement such limitation, as only patients observed by a neurologist are included [22] . We tried to overcome this by using a systematic and harmonised analysis of patient e-records. 

None. 

This study was registered at all centres where the study was conducted, and it received approval from the institutional ethical standards committee. A waiver of written informed consent was obtained, after assessment of the public relevance of the study according to the Portuguese legislation that regulates data protection and clinical research. The authors confirm that they have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

The data that support the findings of this study are available from the corresponding author upon reasonable request. 

Coronavirus disease (COVID-2019) situation reports

Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system

Does SARS-Cov-2 invade the brain? Translational lessons from animal models

Neuropathological Features of Covid-19

Neuropathology of patients with COVID-19 in Germany: a post-mortem case series

COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features

Large-vessel stroke as a presenting feature of Covid-19 in the young

Miller Fisher Syndrome and polyneuritis cranialis in COVID-19

Guillain-Barré Syndrome associated with SARS-CoV-2

Hemorrhagic posterior reversible Encephalopathy Syndrome as a manifestation of COVID-19 infection

Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry

Frequent neurologic manifestations and encephalopathy-associated morbidity in Covid-19 patients

Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence?

Acute ischemic stroke and COVID-19

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

Neurological associations of COVID-19

The international European Academy of Neurology survey on neurological symptoms in patients with COVID-19 infection

Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital

Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study

The European Academy of Neurology COVID-19 registry (ENERGY): an international instrument for surveillance of neurological complications in patients with COVID-19

Neurologic Manifestations in a Prospective Unselected Series of Hospitalized Patients With COVID-19

Neuro-COVID frequency and short-term outcome in the Northern Portuguese population