key: cord-0885590-yevdupvi
authors: Luigetti, Marco; Iorio, Raffaele; Bentivoglio, Anna Rita; Tricoli, Luca; Riso, Vittorio; Marotta, Jessica; Piano, Carla; Primiano, Guido; Zileri Del Verme, Lorenzo; Lo Monaco, Maria Rita; Calabresi, Paolo
title: Assessment of neurological manifestations in hospitalized patients with COVID‐19
date: 2020-07-18
journal: Eur J Neurol
DOI: 10.1111/ene.14444
sha: 4a4da75ec82187c301914b14ca4577892465f611
doc_id: 885590
cord_uid: yevdupvi

BACKGROUND: The objective of this study is to assess the neurological manifestations in a series of consecutive SARS‐CoV‐2 positive patients, comparing their frequency with a population hospitalized in the same period for flu/respiratory symptoms, finally not related to SARS‐CoV‐2. METHODS: We retrospectively enrolled patients with flu‐respiratory symptoms admitted to Fondazione Policlinico Gemelli hospital from March, 14th 2020 to April, 20th 2020. Frequency of neurological manifestation of patients with SARS‐CoV‐2 infection were compared with control group. RESULTS: 213 patients resulted positive for SARS‐CoV‐2, after real‐time PCR on nasal or throat swabs, while 218 patients resulted negative, and were used as control group. Regarding central nervous system manifestations, we observed in SARS‐CoV‐2 positive patients a higher frequency of headache, hyposmia, and encephalopathy always related to systemic conditions (fever or hypoxia). Furthermore, muscular involvement was more frequent in SARS‐CoV‐2 infection. CONCLUSIONS: Patients with COVID‐19 commonly have neurologic manifestations but only hyposmia and muscle involvement seem more frequent if compared with other flu diseases.

In December 2019, the current outbreak of the novel Coronavirus 19 (CoV) started in Wuhan, China and then rapidly spread over the world. Italy was the first country involved in Europe since February 2020. 1 Patients with the novel CoV were reported to have symptoms resembling those of severe acute respiratory syndrome CoV (SARSCoV) in 2002-2004, sharing both viruses the same receptor, angiotensin-converting enzyme 2 (ACE2). 2, 3 Therefore, the new virus was named SARS-CoV-2, and in February 2020 the World Health Organization (WHO) named the disease coronavirus disease 2019 . 4, 5 Infection in humans often leads to severe clinical symptoms and high mortality. 4, 5 Several studies have described the typical clinical manifestations including fever, cough, diarrhea, and fatigue and also characteristic laboratory findings (increase of IL-6 and Ddimer values), and lung computed tomography abnormalities (bilateral lung involvement with subpleural ground-grass opacities). [4] [5] [6] [7] Neurological manifestations of COVID-19 are not infrequent, being reported in about one third of patients: symptoms and signs may involve nervous system at all levels from brain to muscles. 5 Here we assess the neurological manifestations in a series of consecutive patients with COVID-19 admitted to a referral center in Rome, Italy, comparing their frequency with a population hospitalized in the same period for flu/respiratory symptoms, finally not related to COVID-19.

This is a retrospective, observational study done at Fondazione Policlinico Gemelli hospital, a centre designated to treat patients with COVID-19. The study was approved by the Ethical Committee of the Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore. All participants provided informed consent.

We retrospectively enrolled consecutive patients hospitalized in non-intensive COVID-19 units, from March, 14th 2020 to April, 20th 2020. A confirmed case of COVID-19 was defined as a

This article is protected by copyright. All rights reserved positive result of real-time PCR on nasal or throat swabs. We used as control group the population hospitalized in the same period for flu/respiratory symptoms, tested negative for SARS-CoV-2. To consider a patient negative for SARS-CoV-2 nasal or throat swabs had to be repeated and resulted negative twice. Patients with severe flu/respiratory symptoms compatible with COVID-19 were not included in the study, even if multiple nasal or throat swabs tested negative.

We reviewed electronic medical and nursing records, laboratory findings, and radiologic tests of all patients with laboratory-confirmed SARS-CoV-2 infection and of controls. We collected data on age, sex, comorbidities (hypertension, diabetes, cardiac disease, malignancy, and chronic kidney disease), typical respiratory symptoms from onset to hospital admission (dyspnea, fever, cough), neurological symptoms, and laboratory findings. Clinical severity of respiratory symptoms was assessed with P/F ratio (arterial pO2 divided by the FIO2): patients with P/F <200 were considered with moderate/severe respiratory failure.

Subjective symptoms were collected by clinicians from conscious, cognitively and mentally preserved patients, at the admission or during the hospitalization. Uncomplete electronic records were not included.

Neurologic manifestations were categorized into 2 categories: central nervous system (CNS) manifestations (headache, dizziness, balance impairment, encephalopathy related to fever or hypoxia, encephalopathy not related to fever or hypoxia, taste or smell impairment, seizures, stroke, encephalitis, myelitis) and muscular manifestations (generalized weakness, myalgia, skeletal muscle injury).

Encephalopathy, that is any disorder or disease of the brain leading to an overall brain dysfunction, characterized by altered mental state, ore delirium 8 , was considered as a consequence of fever if temperature > 39.5° C or, as a consequence of hypoxia, if O2 saturation was < 85%, and if it was reversible once resolved respiratory or metabolic dysfunctions. Acute cerebrovascular disease included ischemic stroke and cerebral hemorrhage diagnosed by clinical symptoms and head CT. Seizure was based on the clinical symptoms at the time of presentation. Skeletal muscle injury was defined as when a patient had myalgia and elevated serum creatine kinase (CK) level greater than 200 U/L. 5

The two-tailed Fisher's exact test was performed to compare categorical variables and the Mann-Whitney test was used to compare continuous variables. P value < 0.05 was considered significant.

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A total of 452 patients were hospitalized for flu/respiratory symptoms in the period examined. 213 patients resulted positive for SARS-CoV-2, after real-time PCR on nasal or throat swabs; 21 patients were excluded because although multiple nasal or throat swabs resulted negative for SARS-CoV-2, a therapy with anti-retroviral, anti-IL6 or hydroxychloroquine was started, considering radiological findings and clinical manifestations suspicious for COVID-19; 23 patients were excluded for uncomplete electronic records; 218 patients resulted negative for SARS-CoV-2 after real-time PCR on nasal or throat swabs, and were used as control group. In the control group a microbiological agent was found in 63/214 patients (28%).

Patients' demographic, laboratory, clinical characteristics regarding flu/respiratory symptoms, and administered therapies are summarized in Table 1 . Neurological manifestations are summarized in Table 2 . Regarding neurological signs/symptoms, CNS manifestations were similarly reported between the two groups. We observed in COVID-19 patients a higher frequency of headache and encephalopathy but only related to fever or hypoxia. Olfactory dysfunction was a common clinical finding in SARS-CoV-2 positive patients, more frequent when compared with controls.

This article is protected by copyright. All rights reserved Moreover, muscular involvement, was more frequent in SARS-CoV-2 infection.

Interestingly, one patient presented symptoms suggestive of encephalitis: cerebrospinal fluid (CSF) analysis revealed no pleocytosis and increased protein (115 mg/dL), but RT-PCR for SARS-CoV-2 resulted negative. Brain CT scan was normal. The patient improved after treatment with hydroxychloroquine and tocilizumab and was discharged. No patients presented myelitis.

Neurological manifestations have been reported within clinical spectrum of COVID- 19. 5 However, the full-blown syndrome of this virus is not still clear. To assess the frequency of neurological manifestations of hospitalized patients with COVID-19 we compared the neurological disturbances of SARS-CoV-2 positive patients with those experienced by a group of patients hospitalized in the same period for similar symptoms, but resulted negative after real-time PCR on nasal or throat swabs.

We know that our study has several limitations: (1) it is a retrospective study with a nonsystematic neurologic phenotype assessment; (2) the control group is heterogeneous and include patients with respiratory syndrome due to undefined etiology; (3) false-negative COVID-19 patients in the control group or in the excluded patients may represent a bias; (4) in some patients compliance might have been decreased by concurrent encephalopathy.

Neurological manifestations were observed in 64/213 patients (30%), confirming previous data on Chinese population. 5 Generally, CNS manifestations showed a low frequency if compared with previous published data 5 , and were not different with respect to control population.

Encephalopathy was the most frequent CNS manifestation reported, but only due to a possible secondary effect related to respiratory symptom. Indeed, we analysed its frequency in patients without predisposing systemic/respiratory conditions, and we did not find any difference between two groups. Furthermore, a direct invasion of virus on CNS seems extremely rare, being reported only in few cases. [9] [10] [11] In our cohort just one patient was diagnosed as affected by encephalitis. In this case CSF examination confirmed signs of inflammation, but virus was not detected. Although the definitive diagnosis of viral encephalitis largely depends on virus isolation, this is difficult to obtain for

This article is protected by copyright. All rights reserved COVID-19 because SARS-CoV-2 dissemination is transient and its CSF titer may be extremely low. 9 The other CNS manifestation more frequent in SARS-CoV-2 positive patients when compared with controls was headache; however, its frequency was lower if matched with previous published paper. 5 Hyposmia and hypogeusia are considered typical manifestation of COVID-19 infection. 12 In our cohort, though their frequency was similar to previously reported studies 5 , only hyposmia was more frequent if compared with controls. Probably hypogeusia could have been underestimated during clinical interview, or its presence is more frequent in mild or not hospitalized COVID-19 patients. 12 The frequency of seizures and stroke was higher and lower, respectively, if compared with published data. 5 Considering ischemic stroke, the lower frequency respect to the literature may depend on the considered population (old patients hospitalized in non-intensive units), since this complication occurs more often in patients with severe disease 5, 13 , or in young cases. 14 Furthermore, in our experience ischemic stroke was more frequent in control group. The inhomogeneity of the two populations with regard to mean age and other possible stroke risk factors (as cancer or chronic renal failure) may explain the results of our study. Despite stroke may be a consequent of SARS-CoV-2 infection, older patients have also higher cardiovascular comorbidities and higher rates of stroke. 5, [13] [14] On the other hand, PNS involvement seems more frequent in SARS-CoV-2 infection. Until now several cases of Guillain Barrè syndrome have been reported suggesting that the virus may have a role. 15, 16 Muscle could be one target of the virus too 17 : muscular symptoms were more common among SARS-CoV-2 positive patients and CK level was higher when compared with controls.

Unfortunately, to avoid contamination, muscle MRI and electromyography have not been performed in these cases, so we have not enough data to speculate about pathogenesis of muscular involvement.

In conclusion three main pathogenic mechanisms could be hypothesized in COVID-19: a direct invasion of the nervous system by the virus, a possible immune-mediated damage, or abnormal production of pro-inflammatory cytokines. 3, [18] [19] [20] Considering inflammatory markers, in our cohort only PCR was more elevated in SARS-CoV2 positive patients when compared with control.

Unfortunately, we had not samples for D-dimer and IL-6 for the entire cohort and these data could explain the lack of difference in these dosages. It is not clear which mechanism is responsible for Accepted Article 

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