Aim The aim of this paper is to describe the clinical features of COVID‐19‐related encephalopathy and their metabolic correlates using brain 2‐desoxy‐2‐fluoro‐D‐glucose (FDG)‐positron‐emission tomography (PET)/computed tomography (CT) imaging. Background and purpose A variety of neurological manifestations have been reported in association with COVID‐19. COVID‐19‐related encephalopathy has seldom been reported and studied. Methods We report four cases of COVID‐19‐related encephalopathy. The diagnosis was made in patients with confirmed COVID‐19 who presented with new‐onset cognitive disturbances, central focal neurological signs, or seizures. All patients underwent cognitive screening, brain magnetic resonance imaging (MRI), lumbar puncture, and brain 2‐desoxy‐2‐fluoro‐D‐glucose (FDG)‐positron‐emission tomography (PET)/computed tomography (CT) (FDG‐PET/CT). Results The four patients were aged 60 years or older, and presented with various degrees of cognitive impairment, with predominant frontal lobe impairment. Two patients presented with cerebellar syndrome, one patient had myoclonus, one had psychiatric manifestations, and one had status epilepticus. The delay between first COVID‐19 symptoms and onset of neurological symptoms was between 0 and 12 days. None of the patients had MRI features of encephalitis nor significant cerebrospinal fluid (CSF) abnormalities. SARS‐CoV‐2 RT‐PCR in the CSF was negative for all patients. All patients presented with a consistent brain FDG‐PET/CT pattern of abnormalities, namely frontal hypometabolism and cerebellar hypermetabolism. All patients improved after immunotherapy. Conclusions Despite varied clinical presentations, all patients presented with a consistent FDG‐PET pattern, which may reflect an immune mechanism.

Purpose Little is known about the neuronal substrates of neuropsychiatric symptoms associated with COVID-19 and their evolution during the course of the disease. We aimed at describing the longitudinal brain metabolic pattern in COVID-19related encephalopathy using 18F-FDG-PET/CT. Methods Seven patients with variable clinical presentations of COVID-19-related encephalopathy were explored thrice with brain 18F-FDG-PET/CT, once in the acute phase, 1 month later and 6 months after COVID-19 onset. PET images were analysed with voxel-wise and regions-of-interest approaches in comparison with 32 healthy controls. Results Patients' neurological manifestations during acute encephalopathy were heterogeneous. However, all of them presented with predominant cognitive and behavioural frontal disorders. SARS-CoV-2 RT-PCR in the CSF was negative for all patients. MRI revealed no specific abnormalities for most of the subjects. All patients had a consistent pattern of hypometabolism in a widespread cerebral network including the frontal cortex, anterior cingulate, insula and caudate nucleus. Six months after COVID-19 onset, the majority of patients clinically had improved but cognitive and emotional disorders of varying severity remained with attention/executive disabilities and anxio-depressive symptoms, and lasting prefrontal, insular and subcortical 18F-FDG-PET/CT abnormalities. Conclusion The implication of this widespread network could be the neural substrate of clinical features observed in patients with COVID-19, such as frontal lobe syndrome, emotional disturbances and deregulation of respiratory failure perception. This study suggests that this network remains mildly to severely impaired 6 months after disease onset.

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A variety of neuropsychiatric complications has been described in association with Covid-19 infection. Large scale studies presenting a wider picture of these complications and their relative frequency are lacking. The objective of our study was to describe the spectrum of neurological and psychiatric complications in patients with Covid-19 seen in a multidisciplinary hospital center over six months. We conducted a retrospective, observational study on all patients showing neurological or psychiatric symptoms in the context of Covid-19 seen in the medical and university neuroscience department of Assistance Publique Hopitaux de Paris -Sorbonne University. We collected demographic data, comorbidities, symptoms and severity of Covid-19 infection, neurological and psychiatric symptoms, neurological and psychiatric examination data and, when available, results from CSF analysis, MRI, EEG and EMG. A total of 249 Covid-19 patients with a de novo neurological or psychiatric manifestation were included in the database and 245 were included in the final analyses. One-hundred fourteen patients (47%) were admitted to the intensive care unit and 10 (4%) died. The most frequent neuropsychiatric complications diagnosed were encephalopathy (43%), critical illness polyneuropathy and myopathy (26%), isolated psychiatric disturbance (18%), and cerebrovascular disorders (16%). No patients showed CSF evidence of SARS-CoV-2. Encephalopathy was associated with older age and higher risk of death. Critical illness neuromyopathy was associated with an extended stay in the intensive care unit. The majority of these neuropsychiatric complications could be imputed to critical illness, intensive care and systemic inflammation, which contrasts with the paucity of more direct SARS-CoV-2-related complications or post-infection disorders.

Background: Although a growing number of very elderly patients with atrial fibrillation (AF), multiple conditions and polypharmacy, receive direct oral anticoagulants (DOAC), few studies specifically investigated both apixaban/rivaroxaban pharmacokinetics and pharmacodynamics in such patients. Aims: To investigate: i/DOAC concentration-time profiles; ii/thrombin generation (TG); and iii/clinical outcomes 6-months after inclusion in very elderly AF in-patients receiving rivaroxaban or apixaban. Methods: ADAGE-NCT02464488 was an academic prospective exploratory multicenter study, enrolling AF in-patients aged 80-years, receiving DOAC for at least 4 days. Each patient had 1-5 blood samples at different time-points over 20-days. DOAC concentrations were determined using chromogenic assays. TG was investigated using ST-Genesia (STG-ThromboScreen, STG-DrugScreen). Results: We included 215 patients (women 71.1%, mean age 87±4-years), 104-rivaroxaban and 111-apixaban, 79.5% receiving reduced-dose regimen. We observed important inter-individual variabilities (CV) whatever the regimen, at Cmax [49-46%] and Cmin [75-61%] in 15mg-rivaroxaban and 2.5mg-apixaban patients, respectively. Dose regimen was associated with Cmax and Cmin plasma concentrations in apixaban (p=0.0058 and p=0.0222, respectively), but not in rivaroxaban samples (multivariate analysis). Moreover, substantial variability of thrombin peak-height (STG-Thromboscreen) was noticed at a given plasma concentration for both xabans, suggesting an impact of the underlying coagulation status on TG in elderly in-patients. After 6-month follow-up, major bleeding/thrombo-embolic event/death rates were 6.7%/1.0%/17.3% in rivaroxaban and 5.4%/3.6%/18.9% in apixaban patients, respectively. Conclusion: Our study provides original data in very elderly patients receiving DOAC in real-life setting, showing great inter-individual variability in plasma concentrations and TG parameters. Further research is needed to understand the potential clinical impact of these findings.