Tuesday, May 19, 2020

Neurological symptoms occur in more than 90% of patients with SARS-CoV2 infection; women more frequently present subjective neurological symptoms than men

Subjective neurological symptoms frequently occur in patients with SARS-CoV2 infection. Claudio Liguori et al. Brain, Behavior, and Immunity, May 19 2020. https://doi.org/10.1016/j.bbi.2020.05.037

• COVID-19 is a novel pathology due to SARS-CoV2 infection.
• Nervous system manifestations of SARS-CoV2 infection has been reported.
• Neurological symptoms occur in more than 90% of patients with SARS-CoV2 infection.
• Women more frequently present subjective neurological symptoms than men.

Objective: Coronavirus disease 2019 (COVID-19) represents a novel pneumonia leading to severe acute respiratory syndrome (SARS). Recent studies documented that SARS-Coronavirus2 (SARS-CoV2), responsible for COVID-19, can affect the nervous system. The aim of the present observational study was to prospectively assess subjective neurological symptoms (sNS) in patients with SARS-CoV2 infection.

Methods: We included patients hospitalized at the University Hospital of Rome Tor Vergata, medical center dedicated to the treatment of patients with COVID-19 diagnosis, who underwent an anamnestic interview about sNS consisting of 13 items, each related to a specific symptom, requiring a dichotomized answer.

Results: We included 103 patients with SARS-CoV2 infection. Ninety-four patients (91.3%) reported at least one sNS. Sleep impairment was the most frequent symptom, followed by dysgeusia, headache, hyposmia, and depression. Women more frequently complained hyposmia, dysgeusia, dizziness, numbeness/paresthesias, daytime sleepiness, and muscle ache. Moreover, muscle ache and daytime sleepiness were more frequent in the first 2 days after admission. Conversely, sleep impairment was more frequent in patients with more than 7 days of hospitalization. In these patients we also documented higher white blood cells and lower C-reactive protein levels. These laboratory findings correlated with the occurrence of hyposmia, dysgeusia, headache, daytime sleepiness, and depression.

Conclusions: Patients with SARS-CoV2 infection frequently present with sNS. These symptoms were present from the early phases of the disease. The possibly intrinsic neurotropic properties of SARS-CoV2 may justify the very high frequency of sNS. Further studies targeted at investigating the consequences of SARS-CoV2 infection on the CNS should be planned.

Keywords: SARS-CoV2 infectionCOVID-19neurological symptomscentral nervous systemsex

7. Discussion

This observational study, carried out in 103 patients affected by SARS-CoV2 infection, documented the high prevalence of sNS during the course of the disease, even immediately after admission to the Hospital.
Although the involvement of nervous system during SARS-CoV2 infection has been extensively proposed, [10][11][12] few studies focused the investigation on neurological symptoms in patients with COVID-19. [4][7] The largest study examining the neurological manifestations of hospitalized patients with COVID-19 was a retrospective analysis achieved by reviewing patients’ clinical charts.4 The authors documented a neurological manifestation in 36.4% of cases, reporting that patients with severe COVID-19 showed more nervous system symptoms than patients with the non-severe form of the infection. [4] Moreover, other reports, not centered on the neurological manifestations of COVID-19, reported the presence of few neurological symptoms in patients with SARS-CoV2 infection. [5][6][13][14] However, since all these studies have a retrospective design and data were achieved by the extraction from electronic medical records, detection of slight neurological manifestations, such as sleep and wake impairment, headache, dysgeusia, hyposmia, and dizziness, could be limited HYPERLINK "SPS:refid::bib15" [15]
In the present study, we performed a prospective observation in patients with non-severe respiratory form of SARS-CoV2 by using an anamnestic interview designed to better determinate the occurrence and type of sNS over the course of the disease. Based on the prospective design of this examination, we documented a very high number of patients complaining sNS. Consistently, only 9 out of 103 patients (less than 10%) did not report sNS and more than 65% of the whole sample described three or more sNS at the interview. Namely, in the total group of patients, sleep impairment, dysgeusia, headache and hyposmia were the most frequent complained sNS. Notably, the frequency of sNS was elevated from the early phases of the disease, immediately after the admission to the hospital, remaining high also after a prolonged hospitalization. Considering the different timing of administration of the anamnestic interview in the patients included, we documented that muscle ache and daytime sleepiness were more frequent in the first two days after admission, whereas sleep impairment appeared more frequently after the 7th day of hospitalization.
Taking all the findings of this study into account, it appeared evident that patients with SARS-CoV2 frequently experienced sNS. Accordingly, during the infection, sNS seem to be present from the very early stages of the disease and in some cases prior to the hospitalization, as previously reported. [7][16] We documented that patients may complain more than one sNS during the prolonged hospitalization and sleep impairment was the main complain in patients interviewed after the 7th day from admission. It has been already explained that hospitalization may significantly disrupt sleep, thus clinically producing insomnia symptoms[17] HYPERLINK "SPS:refid::bib17"
The mechanisms at the basis of the high frequency of neurologic complaints in patients with SARS-CoV2 infection are not completely understood and thus they are still hypothetical. [8][18][19] The autoptic studies performed in patients with COVID-19 documented hyperemia, oedema, and neuronal degeneration reflecting nervous system damage. [3] Therefore, the intrinsic properties of this novel coronavirus may represent possible mechanisms for affecting the nervous system. SARS-CoV2 may enter the nervous system through hematogenous or non-hematogenous routes. No study demonstrated the ability of the novel coronavirus to pass the BBB, but only singular case reports documented encephalitis due to SARS-CoV2 possibly passing the BBB by increasing its permeability through the production of cytokines or by the action of concomitant bacteria destroying it. Therefore, the non-hematogenous route of infection has been mostly hypothesized. [8][20][21][22] Considering this latter route of infection, neuronal pathway represents the most suitable mechanism of infection, since it is considered an important vehicle for neurotropic viruses to enter the CNS. In the hypothetical model of CNS invasion, virus can migrate by infecting nerve endings and achieving retrograde or anterograde neuronal transport through the motor proteins, dynein and kinesins. [23] The main gate of CNS infection by neurotropic viruses is the olfactory pathway. [24] As a consequence, SARS-CoV2, as the other coronaviruses affecting the nasal mucosa, can enter the brain through the olfactory tract from the early stages of infection. [8][25][26] Moreover, coronaviruses can migrate from the olfactory bulb to cortex, basal ganglia, and midbrain, which are affected during their spreading. [27] This hypothesis has been confirmed in animal models by the removal of the olfactory bulb, which resulted in a restricted invasion of coronaviruses into CNS. [28] Taken together, the potential neuroinvasive propensity of SARS-CoV2 may justify the sNS complained by patients. Further possible mechanism explaining the involvement of nervous system during COVID-19 is related to ACE2 that represents the functional receptor of SARS-CoV2 and is widely expressed in multiple tissues, including the nervous system. [29][30] Finally, the nervous system can by indirectly affected by SARS-CoV2 due to the mediated effects generated by the immune system. [31] Accordingly, this neurotropic virus can trigger the development of a systemic inflammatory response syndrome (SIRS). SIRS can be localized also in the nervous system and is mediated by activated glial cells inducing a pro-inflammatory state during the SARS-CoV2 infection. [32] As a consequence, activated glial cells release several inflammatory factors, such as interleukin (IL)-6, which is an important member of the cytokine storm. [28][33] This inflammatory response may be responsible for sNS in patients with COVID-19. Consistently, IL-6, IL-1, and tumor necrosis factor (TNF)-α have been reported to induce symptoms such as impaired mood, anxiety, cognitive disturbances, fatigue, hyperalgesia. [34][35][36] We also included in the analysis the main laboratory findings used for quantifying the immune and inflammatory response, such as WBC and CRP, in order to investigate the relationship between these immune parameters and the occurrence of sNS. Significantly, the increment of CRP was evident in the first days after admission, while WBC count was higher in patients evaluated after a prolonged hospitalization. This finding may reflect the initial inflammatory response and possibly subsequent bacterial co-infection in patients with SARS-CoV2 infection. [37] In patients with more than 3 sNS the CRP tended to be higher, but the distribution of patients in the three groups cannot allow achieving the statistical significance. This point needs to be further analyzed in studies focused on the relationship between the inflammatory response and the occurrence of sNS in patients with SARS-CoV2 infection. [15]
The sex-based distribution of patients demonstrated that female patients [17] reported more frequently sNS than men. In particular, hyposmia, dysgeusia, headache, dizziness, numbness/paresthesia, daytime sleepiness, and muscle ache were more frequent in women than men. This sex-based difference can be attributed to the humoral and innate immune responses to viral infections more marked in women than men. [38][39][40] However, we documented higher CRP, WBC, and neutrophil cell count in men than women, which can reflect an higher immune response in men possibly driven by the occurrence of a concomitant bacterial infection leading to a more severe infection[37][37][41]
In this study we documented the high frequency of neurological symptoms in patients with SARS-CoV2 infection. In particular, sNS were present in patients not admitted to intensive care units and without severe pneumonia. Hence, it is conceivable that the infection per se, more than the severity of pneumonia, prolonged hospitalization, or adverse effects of the anti-COVID treatments, may affect the CNS and thus cause the neurological symptoms in patients with COVID-19. [42] To check this hypothesis, we documented the relationship between the occurrence of sNS and the alteration of the main laboratory findings reflecting the immune and inflammatory responses (CRP and WBC); however, this very [41]preliminary impression needs to be further investigated in larger studies evaluating different infection-related biomarkers, inflammatory cytokines, and WBC subsets.

8. Limitations

We are aware that this study presents some limitations. We included patients admitted to a single hospital recognized by the Government for treating patients with SARS-CoV2 infection; more information about patients confined to home isolation can be useful to mitigate the possibly negative effects of hospitalization. We performed an observational, but cross-sectional analysis, in patients at different time points during their hospitalization and a longitudinal evaluation of patients during the course of the disease can give more information about the progression of the sNS. However, the strength of this study is the homogeneous sample of patients prospectively evaluated by using an anamnestic interview centered on sNS, which were categorized for better analyzing their prevalence.

Even for severe cases of childhood maltreatment identified through court records, risk of psychopathology linked to objective measures was minimal in the absence of subjective reports

Objective and subjective experiences of child maltreatment and their relationships with psychopathology. Andrea Danese & Cathy Spatz Widom. Nature Human Behaviour, May 18 2020. https://www.nature.com/articles/s41562-020-0880-3

Abstract: Does psychopathology develop as a function of the objective or subjective experience of childhood maltreatment? To address this question, we studied a unique cohort of 1,196 children with both objective, court-documented evidence of maltreatment and subjective reports of their childhood maltreatment histories made once they reached adulthood, along with extensive psychiatric assessment. We found that, even for severe cases of childhood maltreatment identified through court records, risk of psychopathology linked to objective measures was minimal in the absence of subjective reports. In contrast, risk of psychopathology linked to subjective reports of childhood maltreatment was high, whether or not the reports were consistent with objective measures. These findings have important implications for how we study the mechanisms through which child maltreatment affects mental health and how we prevent or treat maltreatment-related psychopathology. Interventions for psychopathology associated with childhood maltreatment can benefit from deeper understanding of the subjective experience.