[Pharmacological trials evaluating treatment options for neuropsychiatric symptoms in post-COVID. A narrative review]. / Essais pharmacologiques sur les traitements des symptômes neuropsychiatriques du post-Covid. Revue narrative de la littérature.

Post-COVID prevalence's is estimated at 10 % in the general population. The neuropsychiatric symptoms, which are frequent (up to 30 %), can severely affect the quality of life of patients affected by this condition, notably by significantly reducing their working ability. To date, no pharmacologic treatment is available for post-COVID, apart from symptomatic treatments. A large number of pharmacological clinical trials for post-COVID are underway since 2021. A number of these trials targets neuropsychiatric symptoms, based on the various underlying pathophysiological hypotheses. The objective of this narrative review is to provide an overview of these ongoing trials targeting neuropsychiatric symptoms in post-COVID.

La prévalence du syndrome post-Covid est évaluée à 10 % dans la population générale. Les symptômes neuropsychiatriques, fréquents (jusqu'à 30 %), peuvent sévèrement affecter la qualité de vie des patients qui en sont atteints et, notamment, en réduisant significativement leur capacité de travail. À ce jour, il n'existe pas de traitement médicamenteux pour le syndrome post-Covid, en dehors des traitements symptomatiques. C'est pourquoi, un grand nombre d'essais thérapeutiques concernant le post-Covid sont en cours depuis 2021. Un certain nombre d'entre eux ciblent les symptômes neuropsychiatriques en se basant sur les diverses hypothèses physiopathologiques élaborées sur le post-Covid. L'objectif de cette revue narrative est d'établir un état des lieux des essais thérapeutiques en cours ciblant les symptômes neuropsychiatriques du post-Covid.

The two-way route between delirium disorder and dementia: insights from Covid-19.

BACKGROUND: Delirium disorder is a frequent neurological complication of SARS-CoV-2 infection and associated with an increased disease severity and mortality. Cognitive impairment is a major risk factor for developing delirium disorder during Covid-19, which, in turn, increases the risk of subsequent neurological complications and cognitive decline. SUMMARY: The bidirectional connection between delirium disorder and dementia likely resides at multiple levels, and its pathophysiological mechanisms during Covid-19 include endothelial damage, blood-brain barrier dysfunction and local inflammation, with activation of microglia and astrocytes. Here, we describe the putative pathogenic pathways underlying delirium disorder during Covid-19 and highlight how they cross with the ones leading to neurodegenerative dementia. KEY MESSAGES: The analysis of the two-sided link can offer useful insights for confronting with long-term neurological consequences of Covid-19 and framing future prevention and early treatment strategies.

Brain functional connectivity alterations associated with neuropsychological performance 6-9 months following SARS-CoV-2 infection.

Neuropsychological deficits and brain damage following SARS-CoV-2 infection are not well understood. Then, 116 patients, with either severe, moderate, or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days postinfection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypofunctional and hyperfunctional connectivities in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention, subcortical, and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory, executive functions performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological performance 6-9 months following SARS-CoV-2 infection. SARS-CoV-2 infection causes long-term memory and executive dysfunctions, related to large-scale functional brain connectivity alterations.

The pandemic toll and post-acute sequelae of SARS-CoV-2 in healthcare workers at a Swiss University Hospital.

Healthcare workers have potentially been among the most exposed to SARS-CoV-2 infection as well as the deleterious toll of the pandemic. This study has the objective to differentiate the pandemic toll from post-acute sequelae of SARS-CoV-2 infection in healthcare workers compared to the general population. The study was conducted between April and July 2021 at the Geneva University Hospitals, Switzerland. Eligible participants were all tested staff, and outpatient individuals tested for SARS-CoV-2 at the same hospital. The primary outcome was the prevalence of symptoms in healthcare workers compared to the general population, with measures of COVID-related symptoms and functional impairment, using prevalence estimates and multivariable logistic regression models. Healthcare workers (n = 3083) suffered mostly from fatigue (25.5 %), headache (10.0 %), difficulty concentrating (7.9 %), exhaustion/burnout (7.1 %), insomnia (6.2 %), myalgia (6.7 %) and arthralgia (6.3 %). Regardless of SARS-CoV-2 infection, all symptoms were significantly higher in healthcare workers than the general population (n = 3556). SARS-CoV-2 infection in healthcare workers was associated with loss or change in smell, loss or change in taste, palpitations, dyspnea, difficulty concentrating, fatigue, and headache. Functional impairment was more significant in healthcare workers compared to the general population (aOR 2.28; 1.76-2.96), with a positive association with SARS-CoV-2 infection (aOR 3.81; 2.59-5.60). Symptoms and functional impairment in healthcare workers were increased compared to the general population, and potentially related to the pandemic toll as well as post-acute sequelae of SARS-CoV-2 infection. These findings are of concern, considering the essential role of healthcare workers in caring for all patients including and beyond COVID-19.

Functional connectivity underlying cognitive and psychiatric symptoms in post-COVID-19 syndrome: is anosognosia a key determinant?

Lack of awareness of cognitive impairment (i.e. anosognosia) could be a key factor for distinguishing between neuropsychological post-COVID-19 condition phenotypes. In this context, the 2-fold aim of the present study was to (i) establish the prevalence of anosognosia for memory impairment, according to the severity of the infection in the acute phase and (ii) determine whether anosognosic patients with post-COVID syndrome have a different cognitive and psychiatric profile from nosognosic patients, with associated differences in brain functional connectivity. A battery of neuropsychological, psychiatric, olfactory, dyspnoea, fatigue and quality-of-life tests was administered 227.07 ± 42.69 days post-SARS-CoV-2 infection to 102 patients (mean age: 56.35 years, 65 men, no history of neurological, psychiatric, neuro-oncological or neurodevelopmental disorder prior to infection) who had experienced either a mild (not hospitalized; n = 45), moderate (conventional hospitalization; n = 34) or severe (hospitalization with intensive care unit stay and mechanical ventilation; n = 23) presentation in the acute phase. Patients were first divided into two groups according to the presence or absence of anosognosia for memory deficits (26 anosognosic patients and 76 nosognosic patients). Of these, 49 patients underwent an MRI. Structural images were visually analysed, and statistical intergroup analyses were then performed on behavioural and functional connectivity measures. Only 15.6% of patients who presented mild disease displayed anosognosia for memory dysfunction, compared with 32.4% of patients with moderate presentation and 34.8% of patients with severe disease. Compared with nosognosic patients, those with anosognosia for memory dysfunction performed significantly more poorly on objective cognitive and olfactory measures. By contrast, they gave significantly more positive subjective assessments of their quality of life, psychiatric status and fatigue. Interestingly, the proportion of patients exhibiting a lack of consciousness of olfactory deficits was significantly higher in the anosognosic group. Functional connectivity analyses revealed a significant decrease in connectivity, in the anosognosic group as compared with the nosognosic group, within and between the following networks: the left default mode, the bilateral somatosensory motor, the right executive control, the right salient ventral attention and the bilateral dorsal attention networks, as well as the right Lobules IV and V of the cerebellum. Lack of awareness of cognitive disorders and, to a broader extent, impairment of the self-monitoring brain system, may be a key factor for distinguishing between the clinical phenotypes of post-COVID syndrome with neuropsychological deficits.

One-year persistent symptoms and functional impairment in SARS-CoV-2 positive and negative individuals.

BACKGROUND: Persistent symptoms of SARS-CoV-2 are prevalent weeks to months following the infection. To date, it is difficult to disentangle the direct from the indirect effects of SARS-CoV-2, including lockdown, social, and economic factors. OBJECTIVE: The study aims to characterize the prevalence of symptoms, functional capacity, and quality of life at 12 months in outpatient symptomatic individuals tested positive for SARS-CoV-2 compared to individuals tested negative. METHODS: From 23 April to 27 July 2021, outpatient symptomatic individuals tested for SARS-CoV-2 at the Geneva University Hospitals were followed up 12 months after their test date. RESULTS: At 12 months, out of the 1447 participants (mean age 45.2 years, 61.2% women), 33.4% reported residual mild to moderate symptoms following SARS-CoV-2 infection compared to 6.5% in the control group. Symptoms included fatigue (16% vs. 3.1%), dyspnea (8.9% vs. 1.1%), headache (9.8% vs. 1.7%), insomnia (8.9% vs. 2.7%), and difficulty concentrating (7.4% vs. 2.5%). When compared to the control group, 30.5% of SARS-CoV-2 positive individuals reported functional impairment at 12 months versus 6.6%. SARS-CoV-2 infection was associated with the persistence of symptoms (adjusted odds ratio [aOR] 4.1; 2.60-6.83) and functional impairment (aOR 3.54; 2.16-5.80) overall, and in subgroups of women, men, individuals younger than 40 years, those between 40-59 years, and in individuals with no past medical or psychiatric history. CONCLUSION: SARS-CoV-2 infection leads to persistent symptoms over several months, including in young healthy individuals, in addition to the pandemic effects, and potentially more than other common respiratory infections. Symptoms impact functional capacity up to 12 months post infection.

Long COVID Neuropsychological Deficits after Severe, Moderate, or Mild Infection

There is growing awareness that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, even in its mild or moderate respiratory forms, can include long-term neuropsychological deficits. Standardized neuropsychological, psychiatric, neurological, and olfactory tests were administered to 45 patients 236.51 ±22.54 days after hospital discharge following severe, moderate, or mild respiratory severity from SARS-CoV-2 infection (severe = intensive care unit hospitalization, moderate = conventional hospitalization, mild = no hospitalization). Deficits were found in all domains of cognition, and the prevalence of psychiatric symptoms was relatively high in the three groups. The severe infection group performed more poorly on long-term episodic memory tests and exhibited greater anosognosia than did the other two groups. Those with moderate infection had poorer emotion recognition, which was positively correlated with persistent olfactory dysfunction. Individuals with mild infection were more stressed, anxious, and depressed. The data support the hypothesis that the virus targets the central nervous system (notably the limbic system) and the notion that there are different neuropsychological phenotypes.

Atemnot und COVID-19: Ein Aufruf zu mehr Forschung

Atemnot, auch als Dyspnoe bezeichnet, ist ein häufiges und lähmendes Symptom. In mehreren Berichten wurde die Abwesenheit von Atemnot bei einer Untergruppe von Patienten mit COVID-19 hervorgehoben, die manchmal als «stille» oder «glückliche Hypoxie» bezeichnet wird. Ebenfalls wurde in Berichten erwähnt, dass es an einem klaren Zusammenhang zwischen dem klinischen Schweregrad der Erkrankung und der von den Patienten berichteten Schwere der Atemnot fehlt. Die zerebralen Komplikationen von COVID-19 sind weitgehend nachgewiesen, mit einer hohen Prävalenz akuter Enzephalopathien, die möglicherweise die Verarbeitung afferenter Signale oder die absteigende Modulation von Atemnotsignalen beeinträchtigen könnte. In dieser Übersichtsarbeit möchten wir die an der Atemnot beteiligten Mechanismen hervorheben und die Pathophysiologie von COVID-19 und den bekannten Auswirkungen der Erkrankung auf die Interaktion von Gehirn und Lunge zusammenfassen. Anschließend stellen wir Hypothesen für die Veränderung der Wahrnehmung von Atemnot bei COVID-19-Patienten auf und schlagen Möglichkeiten vor, mit denen dieses Phänomen weiter erforscht werden könnte.

[Neurology : what's new in 2021]. / Neurologie.

In 2021, we assisted to the publication of new diagnostic criteria, classifications, and guidelines (CIDP, brain tumors, auto-immune encephalitis). Several studies helped to define the pharmacological management of focal and generalized epileptic seizures and epilepsy in pregnant women. The availability of biomarkers and the approval of immunotherapies are modifying the landscape of dementia management. Endovascular interventions without previous thrombolysis seems to be effective in anterior circulation acute ischemic stroke (AIS) and severe posterior circulation AIS. Neurologic complications of Sars-CoV-2 infection were further studied, as well as the efficacy of vaccines in immunosuppressed patients. New molecules and techniques show promising results for the treatment of migraine and cluster headache.

L'année 2021 a été marquée par la publication des nouveaux critères diagnostiques, classifications et guidelines (polyradiculonévrite inflammatoire démyélinisante chronique, tumeurs cérébrales, encéphalites autoimmunes). L'attitude thérapeutique dans les épilepsies focales ou généralisées et l'épilepsie chez la femme enceinte a été mieux définie. Les marqueurs biologiques et les immunothérapies modifient le paysage de la prise en charge des démences. Le traitement endovasculaire des AVC de la circulation antérieure semble efficace indépendamment d'une thrombolyse préalable, ainsi qu'en cas d'AVC sévère de la circulation postérieure. Les complications neurologiques du SARS-CoV-2 ont été éclaircies et l'efficacité des vaccins étudiée chez les patients immunosupprimés. Plusieurs nouvelles molécules et techniques montrent des résultats prometteurs pour les migraines et céphalées en grappe.

Decrease in pain perception during acute SARS-CoV-2 infection: a case series.

ABSTRACT: Many reports have described pain appearance or an increase of chronic pain concomitant to severe acute respiratory syndrome coronavirus 2 infection. Here, we describe the cases of 3 patients with chronic cancer pain, in which COVID-19 was associated with a dramatic reduction or disappearance of pain. Pain reappeared after recovery from COVID-19. Neurological imaging and pathological findings, when available, were inconclusive. To the best of our knowledge, this is the first case series reporting an acute reduction in pain perception in COVID-19. We believe further investigation is mandatory because it could shed new light on the mechanisms of pain perception and modulation.

C-reactive protein and white matter microstructural changes in COVID-19 patients with encephalopathy.

Encephalopathy is a neurological complication of COVID-19. The objective of this exploratory study is to investigate the link between systemic inflammation and brain microstructural changes (measured by diffusion-weighted imaging) in patients with COVID-19 encephalopathy. 20 patients with COVID-19 encephalopathy (age: 67.3 [Formula: see text] 10.0 years; 90% men) hospitalized in the Geneva University Hospitals for a SARS-CoV-2 infection between March and May 2020 were included in this retrospective cohort study. COVID-19 encephalopathy was diagnosed following a comprehensive neurobiological evaluation, excluding common causes of delirium, such as hypoxemic or metabolic encephalopathy. We investigated the correlation between systemic inflammation (measured by systemic C-reactive protein (CRP)) and brain microstructural changes in radiologically normal white matter (measured by apparent diffusion coefficient (ADC)) in nine spatially widespread regions of the white matter previously associated with delirium. Systemic inflammation (CRP = 60.8 ± 50.0 mg/L) was positively correlated with ADC values in the anterior corona radiata (p = 0.0089), genu of the corpus callosum (p = 0.0064) and external capsule (p = 0.0086) after adjusting for patients' age. No statistically significant association between CRP and ADC was found in the other six white matter regions. Our findings indicate high risk of white matter abnormalities in COVID-19 encephalopathy patients with high peripheral inflammatory markers, suggesting aggressive imaging monitoring may be warranted in these patients. Future studies should clarify a possible specificity of the spatial patterns of CRP-white matter microstructure association in COVID-19 encephalopathy patients and disentangle the role of individual cytokines on brain inflammatory mechanisms.

Breathlessness and COVID-19: A Call for Research.

Breathlessness, also known as dyspnoea, is a debilitating and frequent symptom. Several reports have highlighted the lack of dyspnoea in a subgroup of patients suffering from COVID-19, sometimes referred to as "silent" or "happy hyp-oxaemia." Reports have also mentioned the absence of a clear relationship between the clinical severity of the disease and levels of breathlessness reported by patients. The cerebral complications of COVID-19 have been largely demonstrated with a high prevalence of an acute encephalopathy that could possibly affect the processing of afferent signals or top-down modulation of breathlessness signals. In this review, we aim to highlight the mechanisms involved in breathlessness and summarize the pathophysiology of COVID-19 and its known effects on the brain-lung interaction. We then offer hypotheses for the alteration of breathlessness perception in COVID-19 patients and suggest ways of further researching this phenomenon.

Myoclonus and Cerebellar Ataxia Associated with SARS-CoV-2 Infection: Case Report and Review of the Literature.

The current SARS-CoV-2/COVID-19 pandemic has led to a global health crisis. The clinical spectrum of SARS-CoV-2 infection ranges from asymptomatic infection to critical illness affecting almost every organ including the central and peripheral nervous systems. Myoclonus, a less expected and relatively unusual neurological complication, together with ataxia, has lately been associated with SARS-CoV-2 infection. We describe the case of a 67-year-old male patient, admitted to our hospital for interstitial bilateral pneumonia due to SARS-CoV-2 infection, who progressively developed general myoclonus and later cerebellar ataxia and gait disturbance. Given the timeline from COVID-19 systemic symptoms to neurological manifestations and the normal results of extensive and non-conclusive diagnostic work-up (blood test, lumbar puncture, EEG, cerebral MRI), a para-infectious encephalopathy related to SARS-CoV-2 was contemplated and a high dose of methylprednisolone was started with prompt symptom improvement. Further investigation and neuroepidemiological studies are needed to help define the mechanism of neuroinvasion and the entire spectrum of neurological manifestations of SARS-CoV-2 infection, even in mildly affected patients, in terms of prevention, treatment and possible neurological sequelae. LEARNING POINTS: SARS-CoV-2 infection can be related to neurological symptoms and sequelae.Myoclonus, specifically when associated with ataxia, might represent the expression of COVID-19-related encephalopathy.Myoclonus associated with SARS-CoV-2 infection mostly responds to treatment with steroids.