Mariotto S, Savoldi A, Donadello K, Zanzoni S, Bozzetti S, Carta S, Zivelonghi C, Alberti D, Piraino F, Minuz P, Girelli D, Crisafulli E, Romano S, Marcon D, Marchi G, Gottin L, Polati E, Zanatta P, Monaco S, Tacconelli E and Ferrari S.
J Neurol Neurosurg Psychiatry. 2020 Jun 23
Neurofilament light chain (NfL) is the most abundant and soluble protein of the neuronal cytoskeleton and is released during axonal injury. An increase of cerebrospinal fluid (CSF) and serum levels of NfL has been demonstrated in patients with several inflammatory and degenerative neurological disorders of the nervous system, in correlation with clinical and radiological activity. Several clinical reports showed that patients with COVID-19 suffer from neurological symptoms including non-specific manifestations as headache, hyposmia, dysgeusia and altered consciousness. To date, the pathogenesis of the aforementioned symptoms and the role of inflammatory factors in the context of this severe systemic condition have not been elucidated. Different possible mechanisms of neuronal damage have been hypothesised, including direct viral nervous system invasion through hematogenous dissemination or neuronal retrograde dissemination and indirect injury mediated by inflammatory processes due to the cytokine storm. The aim of this study was to explore the nervous system involvement in patients with COVID-19 by evaluating the presence of neurological symptoms and measuring serum NfL levels as biomarker of axonal damage.
Patients and methods
We performed a 1-week point prevalence survey and evaluated all patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection admitted at the COVID-19 medical and intensive care unit (ICU) areas of the University Hospital of Verona, Italy. Exclusion criteria were neurological comorbidities, which could be independently associated with neuroaxonal damage.
Clinical data and testing
The diagnosis of COVID-19 was based on the presence of SARS-CoV-2 confirmed by positive assay of nasopharyngeal samples on reverse transcriptase PCR. Demographic, anamnestic and clinical data, including presence of comorbidities, symptom onset, antecedent/current treatments, symptoms of respiratory/intestinal involvement, symptoms possibly suggesting nervous system involvement (ie, presence of altered consciousness, myalgia, fatigue, headache, vertigo, hypogeusia and hyposmia), were prospectively analysed in each included case and collected in a standardised form.
Investigators blinded to clinical data measured serum NfL concentration in duplicate in patients and in a group of healthy controls (n=54) for comparison using SIMOA Nf-light kit in SR-X immunoassay analyser, Simoa (Quanterix Corporation, Billerica, Massachusetts, USA), which runs ultrasensitive paramagnetic bead-based enzyme-linked immunosorbent assays.
Continuous and categorical variables were reported as mean (SD) and percentages, respectively. χ2 test and t-test were used for comparison between the subgroup of patients with NfL concentration within the normal range and those with increased levels. Reference threshold for normal range of serum NfL levels among age groups has been extracted from a 10-year local group of healthy controls and, for age-intervals not available in our cohort (>70 years), from literature. A second comparison was performed between the subgroup of patients with neurological symptoms and subjects not presenting those manifestations. Analyses were performed using STATA V.15, and statistical significance was set at <0.05.
Characteristics of the analysed cohort
Among the initial cohort (n=131 cases), 24 patients were excluded because of antecedent neurological comorbidities (history of cognitive impairment, n=19; recent history of ischaemic stroke, n=4; and haemorrhagic stroke, n=1) which could independently alter NfL values.
Overall, 107 patients were included in the point prevalence survey; 25 patients were women (23.4%), and the mean age was 66 years (SD 1.9). The severity of the respiratory failure required admission to ICU in 46 cases (43%). Comorbidities were observed in 91 patients (85%), mainly hypertension (69.2%), diabetes (25.2%) and cardiovascular diseases (23.6%). Respiratory failure and fever were common (91.6% and 96% of cases, respectively), while diarrhoea was more rarely observed (23.4% of cases). Neurological symptoms were recorded in 59 patients (85.5%), most frequently fatigue (68.1%), hypogeusia (31.9%), myalgia (23.2%), hyposmia (21.7%), altered consciousness (18.8%), headache (17.4%), vertigo (8.7%) and syncope (8.7%). None of the included cases presented focal symptoms, visual, language or speech dysfunctions.