Neurologic manifestations associated with COVID-19: a multicentre registry.

OBJECTIVES: To provide an overview of the spectrum, characteristics and outcomes of neurologic manifestations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We conducted a single-centre retrospective study during the French coronavirus disease 2019 (COVID-19) epidemic in March-April 2020. All COVID-19 patients with de novo neurologic manifestations were eligible. RESULTS: We included 222 COVID-19 patients with neurologic manifestations from 46 centres in France. Median (interquartile range, IQR) age was 65 (53-72) years and 136 patients (61.3%) were male. COVID-19 was severe or critical in 102 patients (45.2%). The most common neurologic diseases were COVID-19-associated encephalopathy (67/222, 30.2%), acute ischaemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%) and Guillain-Barré syndrome (15/222, 6.8%). Neurologic manifestations appeared after the first COVID-19 symptoms with a median (IQR) delay of 6 (3-8) days in COVID-19-associated encephalopathy, 7 (5-10) days in encephalitis, 12 (7-18) days in acute ischaemic cerebrovascular syndrome and 18 (15-28) days in Guillain-Barré syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 magnetic resonance imaging (70.7%). Among patients with acute ischaemic cerebrovascular syndrome, 13 (22.8%) of 57 had multiterritory ischaemic strokes, with large vessel thrombosis in 16 (28.1%) of 57. Brain magnetic resonance imaging of encephalitis patients showed heterogeneous acute nonvascular lesions in 14 (66.7%) of 21. Cerebrospinal fluid of 97 patients (43.7%) was analysed, with pleocytosis found in 18 patients (18.6%) and a positive SARS-CoV-2 PCR result in two patients with encephalitis. The median (IQR) follow-up was 24 (17-34) days with a high short-term mortality rate (28/222, 12.6%). CONCLUSIONS: Clinical spectrum and outcomes of neurologic manifestations associated with SARS-CoV-2 infection were broad and heterogeneous, suggesting different underlying pathogenic processes.

Neurobiological Correlates of Psilocybin Response in Depression.

Objective: To synthesize the neurobiological basis of brain-resetting effects of psilocybin and identify neuroimaging correlates of psilocybin response in depressed patients.Data Sources: MEDLINE(R), Embase, APA PsycINFO, Cochrane, and CINAHL were systematically searched on June 3, 2022, with no date restrictions using the following string: (psilocybin) AND (psychedelics) AND (MRI) OR (fMRI)) OR (PET)) OR (SPECT)) OR (imaging)) OR (neuroimaging)).Study Selection: After duplicates were removed from 946 studies, 391 studies remained, of which 8 qualified for full-text analysis, but only 5 fulfilled the eligibility criteria of randomized, double-blind, or open-label neuroimaging study with psilocybin treatment in depressed patients.Data Extraction: The Covidence platform was used for deduplication and bias assessment. The a priori data points included concomitant psychological intervention, modality of neuroimaging technique, changes in depression scores, brain functional changes, and association between functional and psilocybin response. Assessment bias was assessed with the standard risk of bias tool for randomized controlled trials and the tool for risk of bias in nonrandomized studies of interventions.Results: Four studies were open-label, and one was a combined open-label and randomized controlled trial using functional magnetic resonance imaging. Psilocybin-assisted psychotherapy was administered in 3 studies, 1 in refractory and 2 in nonrefractory patients. The remaining 2 studies were in refractory patients. The transient increase in psilocybin-induced global connectivity in major neural tracts and specific areas of brain activation was associated with antidepressant response.Conclusions: Transient functional brain changes with psilocybin therapy resemble the "brain reset" phenomenon and may serve as the putative predictors of psilocybin antidepressant response.

Brain hypoxia, neurocognitive impairment, and quality of life in people post-COVID-19.

OBJECTIVE: Systemic hypoxia occurs in COVID-19 infection; however, it is unknown if cerebral hypoxia occurs in convalescent individuals. We have evidence from other conditions associated with central nervous system inflammation that hypoxia may occur in the brain. If so, hypoxia could reduce the quality of life and brain function. This study was undertaken to assess if brain hypoxia occurs in individuals after recovery from acute COVID-19 infection and if this hypoxia is associated with neurocognitive impairment and reduced quality of life. METHODS: Using frequency-domain near-infrared spectroscopy (fdNIRS), we measured cerebral tissue oxygen saturation (StO2) (a measure of hypoxia) in participants who had contracted COVID-19 at least 8 weeks prior to the study visit and healthy controls. We also conducted neuropsychological assessments and health-related quality of life assessments, fatigue, and depression. RESULTS: Fifty-six percent of the post-COVID-19 participants self-reported having persistent symptoms (from a list of 18), with the most reported symptom being fatigue and brain fog. There was a gradation in the decrease of oxyhemoglobin between controls, and normoxic and hypoxic post-COVID-19 groups (31.7 ± 8.3 µM, 27.8 ± 7.0 µM and 21.1 ± 7.2 µM, respectively, p = 0.028, p = 0.005, and p = 0.081). We detected that 24% of convalescent individuals' post-COVID-19 infection had reduced StO2 in the brain and that this relates to reduced neurological function and quality of life. INTERPRETATION: We believe that the hypoxia reported here will have health consequences for these individuals, and this is reflected in the correlation of hypoxia with greater symptomology. With the fdNIRS technology, combined with neuropsychological assessment, we may be able to identify individuals at risk of hypoxia-related symptomology and target individuals that are likely to respond to treatments aimed at improving cerebral oxygenation.

Olfactory Loss and Brain Connectivity after COVID-19: Structural Follow-Up at One Year.

The structural connectivity from the primary olfactory cortex to the main secondary olfactory areas was previously reported as relatively increased in the medial orbitofrontal cortex in a cohort of 27 recently SARS-CoV-2-infected (COV+) subjects, of which 23/27 had clinically confirmed olfactory loss, compared to 18 control (COV-) normosmic subjects, who were not previously infected. To complement this finding, here we report the outcome of an identical high angular resolution diffusion MRI analysis on follow-up data sets collected in 18/27 COV+ subjects (10 males, mean age ± SD: 38.7 ± 8.1 years) and 10/18 COV- subjects (5 males, mean age ± SD: 33.1 ± 3.6 years) from the previous samples who repeated both the olfactory functional assessment and the MRI examination after ~1 year. By comparing the newly derived subgroups, we observed that the increase in the structural connectivity index of the medial orbitofrontal cortex was not significant at follow-up, despite 10/18 COV+ subjects were still found hyposmic after ~1 year from SARS-CoV-2 infection. We concluded that the relative hyperconnectivity of the olfactory cortex to the medial orbitofrontal cortex could be, at least in some cases, an acute or reversible phenomenon linked to the recent SARS-CoV-2 infection with associated olfactory loss.

Changes in Brain Activation Patterns During Working Memory Tasks in People With Post-COVID Condition and Persistent Neuropsychiatric Symptoms.

BACKGROUND AND OBJECTIVES: Post-COVID condition (PCC) is common and often involves neuropsychiatric symptoms. This study aimed to use blood oxygenation level-dependent fMRI (BOLD-fMRI) to assess whether participants with PCC had abnormal brain activation during working memory (WM) and whether the abnormal brain activation could predict cognitive performance, motor function, or psychiatric symptoms. METHODS: The participants with PCC had documented coronavirus disease 2019 (COVID-19) at least 6 weeks before enrollment. Healthy control participants had no prior history of COVID-19 and negative tests for severe acute respiratory syndrome coronavirus 2. Participants were assessed using 3 NIH Toolbox (NIHTB) batteries for Cognition (NIHTB-CB), Emotion (NIHTB-EB), and Motor function (NIHTB-MB) and selected tests from the Patient-Reported Outcomes Measurement Information System (PROMIS). Each had BOLD-fMRI at 3T, during WM (N-back) tasks with increasing attentional/WM load. RESULTS: One hundred sixty-nine participants were screened; 50 fulfilled the study criteria and had complete and usable data sets for this cross-sectional cohort study. Twenty-nine participants with PCC were diagnosed with COVID-19 242 ± 156 days earlier; they had similar ages (42 ± 12 vs 41 ± 12 years), gender proportion (65% vs 57%), racial/ethnic distribution, handedness, education, and socioeconomic status, as the 21 uninfected healthy controls. Despite the high prevalence of memory (79%) and concentration (93%) complaints, the PCC group had similar performance on the NIHTB-CB as the controls. However, participants with PCC had greater brain activation than the controls across the network (false discovery rate-corrected p = 0.003, Tmax = 4.17), with greater activation in the right superior frontal gyrus (p = 0.009, Cohen d = 0.81, 95% CI 0.15-1.46) but lesser deactivation in the default mode regions (p = 0.001, d = 1.03, 95% CI 0.61-1.99). Compared with controls, participants with PCC also had poorer dexterity and endurance on the NIHTB-MB, higher T scores for negative affect and perceived stress, but lower T scores for psychological well-being on the NIHTB-EB, as well as more pain symptoms and poorer mental and physical health on measures from the PROMIS. Greater brain activation predicted poorer scores on measures that were abnormal on the NIHTB-EB. DISCUSSION: Participants with PCC and neuropsychiatric symptoms demonstrated compensatory neural processes with greater usage of alternate brain regions, and reorganized networks, to maintain normal performance during WM tasks. BOLD-fMRI was sensitive for detecting brain abnormalities that correlated with various quantitative neuropsychiatric symptoms.

Feasibility of diffusion-tensor and correlated diffusion imaging for studying white-matter microstructural abnormalities: Application in COVID-19.

There has been growing attention on the effect of COVID-19 on white-matter microstructure, especially among those that self-isolated after being infected. There is also immense scientific interest and potential clinical utility to evaluate the sensitivity of single-shell diffusion magnetic resonance imaging (MRI) methods for detecting such effects. In this work, the performances of three single-shell-compatible diffusion MRI modeling methods are compared for detecting the effect of COVID-19, including diffusion-tensor imaging, diffusion-tensor decomposition of orthogonal moments and correlated diffusion imaging. Imaging was performed on self-isolated patients at the study initiation and 3-month follow-up, along with age- and sex-matched controls. We demonstrate through simulations and experimental data that correlated diffusion imaging is associated with far greater sensitivity, being the only one of the three single-shell methods to demonstrate COVID-19-related brain effects. Results suggest less restricted diffusion in the frontal lobe in COVID-19 patients, but also more restricted diffusion in the cerebellar white matter, in agreement with several existing studies highlighting the vulnerability of the cerebellum to COVID-19 infection. These results, taken together with the simulation results, suggest that a significant proportion of COVID-19 related white-matter microstructural pathology manifests as a change in tissue diffusivity. Interestingly, different b-values also confer different sensitivities to the effects. No significant difference was observed in patients at the 3-month follow-up, likely due to the limited size of the follow-up cohort. To summarize, correlated diffusion imaging is shown to be a viable single-shell diffusion analysis approach that allows us to uncover opposing patterns of diffusion changes in the frontal and cerebellar regions of COVID-19 patients, suggesting the two regions react differently to viral infection.

Cerebral hypoperfusion in post-COVID-19 cognitively impaired subjects revealed by arterial spin labeling MRI.

Cognitive impairment is one of the most prevalent symptoms of post Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV-2) state, which is known as Long COVID. Advanced neuroimaging techniques may contribute to a better understanding of the pathophysiological brain changes and the underlying mechanisms in post-COVID-19 subjects. We aimed at investigating regional cerebral perfusion alterations in post-COVID-19 subjects who reported a subjective cognitive impairment after a mild SARS-CoV-2 infection, using a non-invasive Arterial Spin Labeling (ASL) MRI technique and analysis. Using MRI-ASL image processing, we investigated the brain perfusion alterations in 24 patients (53.0 ± 14.5 years, 15F/9M) with persistent cognitive complaints in the post COVID-19 period. Voxelwise and region-of-interest analyses were performed to identify statistically significant differences in cerebral blood flow (CBF) maps between post-COVID-19 patients, and age and sex matched healthy controls (54.8 ± 9.1 years, 13F/9M). The results showed a significant hypoperfusion in a widespread cerebral network in the post-COVID-19 group, predominantly affecting the frontal cortex, as well as the parietal and temporal cortex, as identified by a non-parametric permutation testing (p < 0.05, FWE-corrected with TFCE). The hypoperfusion areas identified in the right hemisphere regions were more extensive. These findings support the hypothesis of a large network dysfunction in post-COVID subjects with cognitive complaints. The non-invasive nature of the ASL-MRI method may play an important role in the monitoring and prognosis of post-COVID-19 subjects.

Associations between brain gene expression perturbations implicated by COVID-19 and psychiatric disorders.

BACKGROUND: Currently, there is increasing evidence from clinic, epidemiology, as well as neuroimaging, demonstrating neuropsychiatric abnormalities in COVID-19, however, whether there were associations between brain changes caused by COVID-19 and genetic susceptibility of psychiatric disorders was still unknown. METHODS: In this study, we performed a meta-analysis to investigate these associations by combing single-cell RNA sequencing datasets of brain tissues of COVID-19 and genome-wide association study summary statistics of psychiatric disorders. RESULTS: The analysis demonstrated that among ten psychiatric disorders, gene expression perturbations implicated by COVID-19 in excitatory neurons of choroid plexus were significantly associated with schizophrenia. CONCLUSIONS: Our analysis might provide insights for the underlying mechanism of the psychiatric consequence of COVID-19.

Post-COVID-19 Brain [18F] FDG-PET Findings: A Retrospective Single-Center Study in the United States.

BACKGROUND AND PURPOSE: The pathophysiology of neurologic manifestations of postacute sequelae of Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection is not clearly understood. Our aim was to investigate brain metabolic activity on [18F] FDG-PET/CT scans in patients with a history of coronavirus disease 2019 (COVID-19) infection before imaging. MATERIALS AND METHODS: This retrospective study included 45 patients who underwent [18F] FDG-PET/CT imaging for any reason and had, at least once, tested positive for COVID-19 at any time before imaging. Fifteen patients had available [18F] FDG-PET scans obtained under identical conditions before the infection. A group of 52 patients with melanoma or multiple myeloma who underwent [18F] FDG-PET/CT were used as controls. Whole-brain 2-sample t test analysis was performed using SPM software to identify clusters of hypo- and hypermetabolism and compare brain metabolic activity between patients with COVID-19 and controls. Paired sample t test comparison was also performed for 15 patients, and correlations between metabolic values of clusters and clinical data were measured. RESULTS: Compared with the control group, patients with a history of COVID-19 infection exhibited focal areas of hypometabolism in the bilateral frontal, parietal, occipital, and posterior temporal lobes and cerebellum (P = .05 uncorrected at the voxel level, family-wise error-corrected at the cluster level) that peaked during the first 2 months, improved to near-complete recovery around 6 months, and disappeared at 12 months. Hypermetabolism involving the brainstem, cerebellum, limbic structures, frontal cortex, and periventricular white matter was observed only at 2-6 months after infection. Older age, neurologic symptoms, and worse disease severity scores positively correlated with the metabolic changes. CONCLUSIONS: This study demonstrates a profile of time-dependent brain PET hypo- and hypermetabolism in patients with confirmed SARS-CoV-2 infection.

Use of disease assessment tools to increase the value of case reports on Susac syndrome: two case reports.

BACKGROUND: Susac syndrome is an immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy that threatens the brain, retina, and inner ear. There is a need for disease assessment tools that can help clinicians and patients to more easily, accurately, and uniformly track the clinical course and outcome of Susac syndrome. Ideally, such tools should simultaneously facilitate the clinical care and study of Susac syndrome and improve the value of future case reports. To meet this need, two novel clinical assessment tools were developed: the Susac Symptoms Form and the Susac Disease Damage Score. The former is a comprehensive self-report form that is completed by patients/families to serially document the clinical status of a patient. The latter documents the extent of damage perceived by individual patients/families and their physicians. Both forms were initially trialed with two particularly representative and instructive patients. The results of this trial are shared in this report. CASE PRESENTATION: Patient 1 is a 21-year-old Caucasian female who presented with an acute onset of headache, paresthesias, cognitive dysfunction, and emotional lability. Patient 2 is a 14-year-old Caucasian female who presented with an acute onset of headache, cognitive dysfunction, urinary incontinence, ataxia, and personality change. Both patients fulfilled criteria for a definite diagnosis of Susac syndrome: both eventually developed brain, retinal, and inner ear involvement, and both had typical "snowball lesions" on magnetic resonance imaging. The Susac Symptoms Form documented initial improvement in both patients, was sufficiently sensitive in detecting a subsequent relapse in the second patient, and succinctly documented the long-term clinical course in both patients. The Disease Damage Score documented minimal disease damage in the first patient and more significant damage in the second. CONCLUSIONS: The Susac Symptoms Form and the Disease Damage Score are useful disease assessment tools, both for clinical care and research purposes. Their use could enhance the value of future case reports on Susac syndrome and could improve opportunities to learn from a series of such reports.

Long COVID: Does SARS-CoV-2 induce lingering brain lesions?

Hundreds of millions of COVID cases have been reported so far and long-term lingering clinical symptoms are frequent and are called long COVID. Neurological signs including cognitive complaints are often described in long Covid. In COVID patients, the Sars-Cov-2 virus can reach the brain and could be responsible for cerebral anomalies observed in long COVID. Long-term careful clinical follow-up of these patients is necessary to detect early signs of neurodegeneration.

Effects of COVID-19 on brain and cerebellum: a voxel based morphometrical analysis.

OBJECTIVE: COVID-19 is caused by SARS-CoV-2 virus and turned into a pandemic in a short time, affects many organs and systems, especially the nervous system. In the present study, it was aimed to determine the morphological and volumetric changes in cortical and subcortical structures in recovered COVID-19 patients. BACKGROUND: We think that COVID-19 has a long-term effect on cortical and subcortical structures. METHODS: In our study, 50 post-COVID-19 patients and 50 healthy volunteers participated. In both groups, brain parcellations were made with Voxel-Based Morphometry (VBM) and regions showing density changes in the brain and cerebellum were determined. Gray matter (GM), white matter, cerebrospinal fluid and total intracranial volume were calculated. RESULTS: Neurological symptoms developed in 80% of COVID-19 patients. In post-COVID-19 patients, a decrease in GM density was detected in pons, gyrus frontalis inferior, gyri orbitales, gyrus rectus, gyrus cinguli, lobus parietalis, gyrus supramarginalis, gyrus angularis, hippocampus, lobulus semilunaris superior of cerebellum, declive, and Brodmann area 7-11-39-40. There was a significant decrease in GM density in these regions and an increase in GM density in amygdala (p<0.001). The GM volume of post-COVID-19 group was found to be less than in the healthy group. CONCLUSIONS: As a result, it was seen that COVID-19 negatively affected many structures related to the nervous system. This study is a pioneering study to determine the consequences of COVID-19, especially in the nervous system, and to determine the etiology of these possible problems (Tab. 4, Fig. 5, Ref. 25). Text in PDF www.elis.sk Keywords: COVID-19, pandemic, Voxel-based morphometry (VBM), brain, magnetic resonance imaging (MRI).

Causal association of the brain structure with the susceptibility, hospitalization, and severity of COVID-19: A large-scale genetic correlation study.

Brain structure is related to its ability to resist external pathogens. Furthermore, there are several abnormal anatomical brain events and central system symptoms associated with COVID-19. This study, which was conducted based on genetic variables, aimed to identify the causal association between brain structure and COVID-19 phenotypes. We performed a two-sample bidirectional Mendelian randomization analysis using genetic variables obtained from large genome-wide association studies as instruments to identify the potential causal effects of various brain imaging-derived phenotypes (BIDPs) traits on susceptibility, hospitalisation, and severity of COVID-19. We explored the genetic correlations of 1325 BIDPs with the susceptibility, hospitalisation, and severity of COVID-19 using Linkage Disequilibrium Score Regression. We observed a causal relationship between increased cortical thickness of the left inferior temporal area and an increased risk of increased COVID-19 infection (p = 4.29 × 10-4) and hospitalisation (p = 3.67 × 10-3). Moreover, the larger total surface area of the whole brain was negatively correlated with the risk of hospitalisation for COVID-19. Furthermore, there was a significant causal association between increased cerebrospinal fluid volume and decreased severity of COVID-19 (p = 3.74 × 10-3). In a conclusion, we provide new insights into the causal association between BIDPs and COVID-19 phenotypes, which may help elucidate the aetiology of COVID-19.

Post-Vaccination/Post-COVID Immune-Mediated Demyelination of the Brain and Spinal Cord: A Novel Neuroimaging Finding.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which not only produces respiratory symptoms but is known to involve almost every system, and its neuroinvasive properties have been well demonstrated throughout the pandemic. Also, to combat the pandemic, there was rapid development and induction of various vaccination drives, following which many adverse events following immunization (AEFIs) have been reported, which include neurological complications as well. Method: We present a series of three cases, post vaccination, with and without a history of COVID illness that showed remarkably similar findings on magnetic resonance imaging (MRI). Result: A 38-year-old male presented with complaints of weakness of the bilateral lower limbs with sensory loss and bladder disturbance a day after receiving his first dose of ChadOx1 nCoV-19 (COVISHIELD) vaccine. A 50-year-old male with hypothyroidism characterized by autoimmune thyroiditis and impaired glucose tolerance experienced difficulty in walking 11.5 weeks after being administered with COVID vaccine (COVAXIN). A 38-year-old male presented with subacute onset progressive symmetric quadriparesis 2 months after their first dose of a COVID vaccine. The patient also had sensory ataxia, and his vibration sensation was impaired below C7. All three patients had typical pattern of involvement of the brain and spine on MRI with signal changes in bilateral corticospinal tracts, trigeminal tracts in the brain, and both lateral and posterior columns in the spine. Conclusion: This pattern of brain and spine involvement on MRI is a novel finding and is likely a result of post-vaccination/post-COVID immune-mediated demyelination.

Structural brain changes in post-acute COVID-19 patients with persistent olfactory dysfunction.

OBJECTIVE: This research aims to study structural brain changes in patients with persistent olfactory dysfunctions after coronavirus disease 2019 (COVID-19). METHODS: COVID-19 patients were evaluated using T1-weighted and diffusion tensor imaging (DTI) on a 3T MRI scanner, 9.94 ± 3.83 months after COVID-19 diagnosis. Gray matter (GM) voxel-based morphometry was performed using FSL-VBM. Voxelwise statistical analysis of the fractional anisotropy, mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity was carried out with the tract-based spatial statistics in the olfactory system. The smell identification test (UPSIT) was used to classify patients as normal olfaction or olfactory dysfunction groups. Intergroup comparisons between GM and DTI measures were computed, as well as correlations with the UPSIT scores. RESULTS: Forty-eight COVID-19 patients were included in the study. Twenty-three were classified as olfactory dysfunction, and 25 as normal olfaction. The olfactory dysfunction group had lower GM volume in a cluster involving the left amygdala, insular cortex, parahippocampal gyrus, frontal superior and inferior orbital gyri, gyrus rectus, olfactory cortex, caudate, and putamen. This group also showed higher MD values in the genu of the corpus callosum, the orbitofrontal area, the anterior thalamic radiation, and the forceps minor; and higher RD values in the anterior corona radiata, the genu of the corpus callosum, and uncinate fasciculus compared with the normal olfaction group. The UPSIT scores for the whole sample were negatively associated with both MD and RD values (p-value ≤0.05 FWE-corrected). INTERPRETATION: There is decreased GM volume and increased MD in olfactory-related regions explaining prolonged olfactory deficits in post-acute COVID-19 patients.

Impact of perinatal COVID on fetal and neonatal brain and neurodevelopmental outcomes.

After three years of the COVID-19 pandemic, we have learned many aspects of the disease and the virus: its molecular structure, how it infects human cells, the clinical picture at different ages, potential therapies, and the effectiveness of prophylaxis. Research is currently focused on the short- and long-term consequences of COVID-19. We review the available information on the neurodevelopmental outcome of infants born during the pandemic from infected and non-infected mothers, as well as the neurological impact of neonatal SARS-CoV-2 infection. We also discuss the mechanisms that could potentially affect the fetal or neonatal brain including direct impact after vertical transmission, maternal immune activation with a proinflammatory cytokine storm, and finally the consequences of complications of pregnancy secondary to maternal infection that could affect the fetus. Several follow-up studies have noted a variety of neurodevelopmental sequelae among infants born during the pandemic. There is controversy as to the exact etiopathogenesis of these neurodevelopmental effects: from the infection itself or as a result of parental emotional stress during that period. We summarize case reports of acute neonatal SARS-CoV-2 infections associated with neurological signs and neuroimaging changes. Many infants born during previous pandemics caused by other respiratory viruses demonstrated serious neurodevelopmental and psychological sequelae that were only recognized after several years of follow-up. It is essential to warn health authorities about the need for very long-term continuous follow up of infants born during the SARS-CoV-2 pandemic for early detection and treatment that could help mitigate the neurodevelopmental consequences of perinatal COVID-19.

Time-dependent recovery of brain hypometabolism in neuro-COVID-19 patients.

PURPOSE: We evaluated brain metabolic dysfunctions and associations with neurological and biological parameters in acute, subacute and chronic COVID-19 phases to provide deeper insights into the pathophysiology of the disease. METHODS: Twenty-six patients with neurological symptoms (neuro-COVID-19) and [¹⁸F]FDG-PET were included. Seven patients were acute (< 1 month (m) after onset), 12 subacute (4 ≥ 1-m, 4 ≥ 2-m and 4 ≥ 3-m) and 7 with neuro-post-COVID-19 (3 ≥ 5-m and 4 ≥ 7-9-m). One patient was evaluated longitudinally (acute and 5-m). Brain hypo- and hypermetabolism were analysed at single-subject and group levels. Correlations between severity/extent of brain hypo- and hypermetabolism and biological (oxygen saturation and C-reactive protein) and clinical variables (global cognition and Body Mass Index) were assessed. RESULTS: The "fronto-insular cortex" emerged as the hypometabolic hallmark of neuro-COVID-19. Acute patients showed the most severe hypometabolism affecting several cortical regions. Three-m and 5-m patients showed a progressive reduction of hypometabolism, with limited frontal clusters. After 7-9 months, no brain hypometabolism was detected. The patient evaluated longitudinally showed a diffuse brain hypometabolism in the acute phase, almost recovered after 5 months. Brain hypometabolism correlated with cognitive dysfunction, low blood saturation and high inflammatory status. Hypermetabolism in the brainstem, cerebellum, hippocampus and amygdala persisted over time and correlated with inflammation status. CONCLUSION: Synergistic effects of systemic virus-mediated inflammation and transient hypoxia yield a dysfunction of the fronto-insular cortex, a signature of CNS involvement in neuro-COVID-19. This brain dysfunction is likely to be transient and almost reversible. The long-lasting brain hypermetabolism seems to reflect persistent inflammation processes.