Coagulopathy and Brain Injury Pathogenesis in Post-Covid-19 Syndrome.

The post-COVID neurological syndrome has been coined, which describes the functional and structural sequelae of coronavirus infection disease-19 (COVID-19) in the brain. Mild/severe manifestations of the post-COVID neurological syndrome have been identified in approximately 33.00% of COVID-19 survivors. The presence of neurological complications after COVID allowed neuropathologists to investigate in-depth the role of viral infection in neurons. The pathophysiology of the post-COVID neurological syndrome involved the development of a systematic response, including coagulopathy characterized by the formation of microthrombi. Coagulopathy, an old term for a new disease, describes the discrepancy between pro-coagulant and anticoagulant systems due to overexpression of pro-coagulant substances and or their receptors in addition to suppression of the anticoagulant molecules and or their receptors. Vascular endothelial cells and hepatocytes play a central role in the regulation of hemostasis that is disrupted during the acute phase response (APR) of coronavirus-19 (COVID-19). Currently, coagulopathy and inflammation are termed together since both form a complementary system, indicated by the elevation of inflammatory biomarkers (APR) and fibrinolysis biomarkers (D-dimer/fibrin). The later events of the post-COVID neurological syndrome are primarily induced by coagulopathy and direct viral tropism. Therefore, the paper introduces the hypothesis of coagulopathy induced post-COVID neurological syndrome.

ARDS associated acute brain injury: from the lung to the brain.

A complex interrelation between lung and brain in patients with acute lung injury (ALI) has been established by experimental and clinical studies during the last decades. Although, acute brain injury represents one of the most common insufficiencies in patients with ALI and acute respiratory distress syndrome (ARDS), the underlying pathophysiology of the observed crosstalk remains poorly understood due to its complexity. Specifically, it involves numerous pathophysiological parameters such as hypoxemia, neurological adverse events of lung protective ventilation, hypotension, disruption of the BBB, and neuroinflammation in such a manner that the brain of ARDS patients-especially hippocampus-becomes very vulnerable to develop secondary lung-mediated acute brain injury. A protective ventilator strategy could reduce or even minimize further systemic release of inflammatory mediators and thus maintain brain homeostasis. On the other hand, mechanical ventilation with low tidal volumes may lead to self-inflicted lung injury, hypercapnia and subsequent cerebral vasodilatation, increased cerebral blood flow, and intracranial hypertension. Therefore, by describing the pathophysiology of ARDS-associated acute brain injury we aim to highlight and discuss the possible influence of mechanical ventilation on ALI-associated acute brain injury.

Outcomes of infants with hypoxic-ischemic encephalopathy during COVID-19 pandemic lockdown in Canada: a cohort study.

PURPOSE: To evaluate change in the severity of hypoxic-ischemic encephalopathy (HIE) and associated morbidities between pre- and during COVID-19 pandemic periods in Canada. METHODS: We conducted a retrospective cohort study extracting the data from level-3 NICUs participating in Canadian Neonatal Network (CNN). The primary outcome was a composite of death in the first week after birth and/or stage 3 HIE (Sarnat and Sarnat). Secondary outcomes included rate and severity of HIE among admitted neonates, overall mortality, brain injury on magnetic resonance imaging (MRI), neonates requiring resuscitation, organ dysfunction, and therapeutic hypothermia (TH) usage. We included 1591 neonates with gestational age ≥ 36 weeks with HIE during the specified periods: pandemic cohort from April 1st to December 31st of 2020; pre-pandemic cohort between April 1st and December 31st of 2017, 2018, and 2019. We calculated the odds ratio (OR) and confidence intervals (CI). RESULTS: We observed no significant difference in the primary outcome (15% vs. 16%; OR 1.08; 95%CI 0.78-1.48), mortality in the first week after birth (6% vs. 6%; OR 1.10, 95%CI 0.69-1.75), neonates requiring resuscitation, organ dysfunction, TH usage, or rate of brain injury. In the ad hoc analysis, per 1000 live births, there was an increase in the rate of infants with HIE and TH use. CONCLUSIONS: Severity of HIE, associated morbidities, and mortality were not significantly different during the pandemic lockdown compared to a pre-pandemic period in Canada. Anticipated risks and difficulties in accessing healthcare have not increased the mortality and morbidities in neonates with HIE in Canada.

Prolonged Unconsciousness is Common in COVID-19 and Associated with Hypoxemia.

OBJECTIVE: The purpose of this study was to estimate the time to recovery of command-following and associations between hypoxemia with time to recovery of command-following. METHODS: In this multicenter, retrospective, cohort study during the initial surge of the United States' pandemic (March-July 2020) we estimate the time from intubation to recovery of command-following, using Kaplan Meier cumulative-incidence curves and Cox proportional hazard models. Patients were included if they were admitted to 1 of 3 hospitals because of severe coronavirus disease 2019 (COVID-19), required endotracheal intubation for at least 7 days, and experienced impairment of consciousness (Glasgow Coma Scale motor score <6). RESULTS: Five hundred seventy-one patients of the 795 patients recovered command-following. The median time to recovery of command-following was 30 days (95% confidence interval [CI] = 27-32 days). Median time to recovery of command-following increased by 16 days for patients with at least one episode of an arterial partial pressure of oxygen (PaO2 ) value ≤55 mmHg (p < 0.001), and 25% recovered ≥10 days after cessation of mechanical ventilation. The time to recovery of command-following  was associated with hypoxemia (PaO2 ≤55 mmHg hazard ratio [HR] = 0.56, 95% CI = 0.46-0.68; PaO2 ≤70 HR = 0.88, 95% CI = 0.85-0.91), and each additional day of hypoxemia decreased the likelihood of recovery, accounting for confounders including sedation. These findings were confirmed among patients without any imagining evidence of structural brain injury (n = 199), and in a non-overlapping second surge cohort (N = 427, October 2020 to April 2021). INTERPRETATION: Survivors of severe COVID-19 commonly recover consciousness weeks after cessation of mechanical ventilation. Long recovery periods are associated with more severe hypoxemia. This relationship is not explained by sedation or brain injury identified on clinical imaging and should inform decisions about life-sustaining therapies. ANN NEUROL 2022;91:740-755.

Effects of COVID-19 pandemic on intensive rehabilitation after severe acquired brain injuries.

PURPOSE: COVID-19 pandemic has affected most components of health systems including rehabilitation. The study aims to compare demographic and clinical data of patients admitted to an intensive rehabilitation unit (IRU) after severe acquired brain injuries (sABIs), before and during the pandemic. MATERIALS AND METHODS: In this observational retrospective study, all patients admitted to the IRU between 2017 and 2020 were included. Demographics were collected, as well as data from the clinical and functional assessment at admission and discharge from the IRU. Patients were grouped in years starting from March 2017, and the 2020/21 cohort was compared to those admitted between March 2017/18, 2018/19, and 2019/20. Lastly, the pooled cohort March 2017 to March 2020 was compared with the COVID-19 year alone. RESULTS: This study included 251 patients (F: 96 (38%): median age 68 years [IQR = 19.25], median time post-onset at admission: 42 days, [IQR = 23]). In comparison with the pre-pandemic years, a significant increase of hemorrhagic strokes (p < 0.001) and a decrease of traumatic brain injuries (p = 0.048), a reduction of the number of patients with a prolonged disorder of consciousness admitted to the IRU (p < 0.001) and a lower length of stay (p < 0.001) were observed in 2020/21. CONCLUSIONS: These differences in the case mix of sABI patients admitted to IRU may be considered another side-effect of the pandemic. Facing this health emergency, rehabilitation specialists need to adapt readily to the changing clinical and functional needs of patients' addressing the IRUs.

Brain injury, endothelial injury and inflammatory markers are elevated and express sex-specific alterations after COVID-19.

OBJECTIVE: Although COVID-19 is a respiratory disease, all organs can be affected including the brain. To date, specific investigations of brain injury markers (BIM) and endothelial injury markers (EIM) have been limited. Additionally, a male bias in disease severity and mortality after COVID-19 is evident globally. Sex differences in the immune response to COVID-19 may mediate this disparity. We investigated BIM, EIM and inflammatory cytokine/chemokine (CC) levels after COVID-19 and in across sexes. METHODS: Plasma samples from 57 subjects at < 48 h of COVID-19 hospitalization, and 20 matched controls were interrogated for the levels of six BIMs-including GFAP, S100B, Syndecan-1, UCHLI, MAP2 and NSE, two EIMs-including sICAM1 and sVCAM1. Additionally, several cytokines/chemokines were analyzed by multiplex. Statistical and bioinformatics methods were used to measure differences in the marker profiles across (a) COVID-19 vs. controls and (b) men vs. women. RESULTS: Three BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNFα were significantly (p < 0.05) elevated in the COVID-19 cohort compared to controls. Bioinformatics analysis reveal a stronger positive association between BIM/CC/EIMs in the COVID-19 cohort. Analysis across sex revealed that several BIMs and CCs including NSE, IL10, IL15 and IL8 were significantly (p < 0.05) higher in men compared to women. Men also expressed a more robust BIM/ EIM/CC association profile compared to women. CONCLUSION: The acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization are suggestive of brain and endothelial injury. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.

COVID-19 mental health impact among children with early brain injury and associated conditions.

This study describes the impact of COVID-19 among a clinical research sample of children with early brain injury and associated conditions. Between March 2020 and March 2021, 64 children and their parents participated. Children ranged in age between 3 and 14 years (M = 6 years, 3 months; SD = 2 years, 4 months) with a range of diagnoses (i.e., neonatal stroke, hypoxic ischemic encephalopathy (HIE), congenital heart disease (CHD) and preterm birth (<32 weeks)). The abbreviated CoRonavIrus Health Impact Survey (CRISIS) was completed by parents as part of their child's routine intake for neuropsychological services. Questions included COVID-19 specific ratings of child mental health impact, child, and parent stressors, with open-ended questions regarding negative and positive COVID-19 related changes. Over 40% of parents described moderate to extreme influence of COVID-19 on their child's mental health. Common child stressors reported included restrictions on leaving the home and social isolation. Among parents, the most common stress reported was caring for their child's education and daily activities. Children's mental health impact was associated with social isolation, parent mental health, COVID-19 economic concern, and number of siblings in the home. Child's age, sex, brain injury severity, or intellectual functioning were not associated with reported COVID-19 mental health impact. Some COVID-19 positives were identified, namely increased quality family time. Findings reflect the significant pandemic mental health impact among neurologically at-risk children and their families. Implications to future clinical needs and considerations for neuropsychological practice are discussed.

[Effectiveness, adherence and usability of a teleneurorehabilitation programme to ensure continuity of care for patients with acquired brain injury during the COVID-19 pandemic]. / Efectividad, adhesión y usabilidad de un programa de teleneurorrehabilitación para garantizar la continuidad de cuidados en pacientes con daño cerebral adquirido durante la pandemia originada por la COVID-19.

INTRODUCTION: The health pandemic brought about by SARS-CoV-2 (COVID-19) has limited access to neurorehabilitation programmes for many patients who have suffered stroke, traumatic brain injury or acquired brain damage due to some other cause. As telerehabilitation allows for the provision of care in situations of social distancing, it may mitigate the negative effects of confinement. The aim of this study was to determine the efficacy, adherence and usability of a teleneurorehabilitation intervention for patients with acquired brain injury. PATIENTS AND METHODS: All patients included in a face-to-face neurorehabilitation programme at the time of the declaration of the state of alarm in Spain due to COVID-19 and who agreed to participate in the study were included in a teleneurorehabilitation programme. The effectiveness of the programme, understood as an improvement in independence, was quantified with the Barthel index. Adherence to the programme and usability of the tool were explored through questionnaires. RESULTS: Altogether, 46 patients, accounting for 70.6% of the total, participated in the study. Participants significantly improved their independence and showed an improvement in the Barthel index between the start (77.3 ± 28.6) and the end of the programme (82.3 ± 26). Adherence to the intervention was very high (8.1 ± 2.2 out of 10) and the online sessions were the most highly rated content. The tool used showed a high usability (50.1 ± 9.9 out of 60) and could be used without assistance by more than half the participants. CONCLUSION: The teleneurorehabilitation intervention was found to be effective in improving patients' independence, and promoted a high degree of adherence and usability.

TITLE: Efectividad, adhesión y usabilidad de un programa de teleneurorrehabilitación para garantizar la continuidad de cuidados en pacientes con daño cerebral adquirido durante la pandemia originada por la COVID-19.Introducción. La pandemia sanitaria originada por el SARS-CoV-2 (COVID-19) ha limitado el acceso a programas de neurorrehabilitación de muchos pacientes que han sufrido ictus, traumatismos craneoencefálicos o un daño cerebral adquirido por otra causa. Dado que la telerrehabilitación permite la provisión de cuidados en situaciones de distanciamiento social, podría atenuar los efectos negativos del confinamiento. El objetivo de este estudio fue determinar la eficacia, la adhesión y la usabilidad de una intervención de teleneurorrehabilitación dirigida a pacientes con daño cerebral adquirido. Pacientes y métodos. Todos los pacientes incluidos en un programa de neurorrehabilitación presencial en el momento de la declaración del estado de alarma en España con motivo de la COVID-19 y que aceptaron participar en el estudio fueron incluidos en un programa de teleneurorrehabilitación. La eficacia del programa, entendida como una mejora en la independencia, se cuantificó con el índice de Barthel. La adhesión al programa y la usabilidad de la herramienta se investigaron mediante cuestionarios. Resultados. Un total de 146 pacientes, el 70,6% del total, participó en el estudio. Los participantes mejoraron significativamente su independencia y mostraron una mejoría en el índice de Barthel entre el inicio (77,3 ± 28,6) y el fin del programa (82,3 ± 26). La intervención tuvo una gran adhesión (8,1 ± 2,2 sobre 10) y las sesiones en línea fueron el contenido mejor valorado. La herramienta utilizada mostró una elevada usabilidad (50,1 ± 9,9 sobre 60) y pudo ser utilizada sin ayuda por más de la mitad de los participantes. Conclusión. La intervención de teleneurorrehabilitación resultó ser eficaz para mejorar la independencia de los pacientes, y promovió una elevada adhesión y usabilidad.

Focused Management of Patients With Severe Acute Brain Injury and ARDS.

Considering the COVID-19 pandemic where concomitant occurrence of ARDS and severe acute brain injury (sABI) has increasingly coemerged, we synthesize existing data regarding the simultaneous management of both conditions. Our aim is to provide readers with fundamental principles and concepts for the management of sABI and ARDS, and highlight challenges and conflicts encountered while managing concurrent disease. Up to 40% of patients with sABI can develop ARDS. Although there are trials and guidelines to support the mainstays of treatment for ARDS and sABI independently, guidance on concomitant management is limited. Treatment strategies aimed at managing severe ARDS may at times conflict with the management of sABI. In this narrative review, we discuss the physiological basis and risks involved during simultaneous management of ARDS and sABI, summarize evidence for treatment decisions, and demonstrate these principles using hypothetical case scenarios. Use of invasive or noninvasive monitoring to assess brain and lung physiology may facilitate goal-directed treatment strategies with the potential to improve outcome. Understanding the pathophysiology and key treatment concepts for comanagement of these conditions is critical to optimizing care in this high-acuity patient population.

Letter to the editor: COVID in patients with brain injury with a disorder of consciousness: a pathogenetic theory.

We recently published in this journal (Caronni and colleagues, Brain Injury, 2021-04-16) the first description of the spread of the SARS-CoV-2 infection in a cohort of brain injured patients with a disorder of consciousness (DOC). Surprisingly enough we showed that, in these patients, the COVID was moderate and did not result in fatalities. The pathogenesis of the COVID is characterized by the profound dysregulation of the immune system. To explain our findings, we speculated that the immunosuppression due to the brain injury could be protective against the development of the COVID in patients with DOC. More recently, a second group of authors (Marino and colleagues, PLoSOne, 2021-06-30) described the course of the COVID in an independent cohort of patients with DOC. Since our results were quite unexpected, we have been very comforted by the data reported by Marino and colleagues. Moreover, these data also offer a unique opportunity to further evaluate our theory regarding the COVID pathogenesis in patients with DOC. In the current Letter to the Editor it is shown that the independent data presented by Marino and colleagues do support our theory. Waiting for larger cohorts to further test it (and in case falsify it), our interpretation seems to remain valid.

Stress Response Is the Main Trigger of Sporadic Amyloidoses.

Amyloidoses are a group of diseases associated with the formation of pathological protein fibrils with cross-ß structures. Approximately 5-10% of the cases of these diseases are determined by amyloidogenic mutations, as well as by transmission of infectious amyloids (prions) between organisms. The most common group of so-called sporadic amyloidoses is associated with abnormal aggregation of wild-type proteins. Some sporadic amyloidoses are known to be induced only against the background of certain pathologies, but in some cases the cause of amyloidosis is unclear. It is assumed that these diseases often occur by accident. Here we present facts and hypotheses about the association of sporadic amyloidoses with vascular pathologies, trauma, oxidative stress, cancer, metabolic diseases, chronic infections and COVID-19. Generalization of current data shows that all sporadic amyloidoses can be regarded as a secondary event occurring against the background of diseases provoking a cellular stress response. Various factors causing the stress response provoke protein overproduction, a local increase in the concentration or modifications, which contributes to amyloidogenesis. Progress in the treatment of vascular, metabolic and infectious diseases, as well as cancers, should lead to a significant reduction in the risk of sporadic amyloidoses.

Clinical course of SARS-CoV-2 infection in patients with severe acquired brain injury and a disorder of consciousness: an observational study.

Purpose: SARS-CoV-2 infection can cause the coronavirus disease (COVID), ranging from flu-like symptoms to interstitial pneumonia. Mortality is high in COVID pneumonia and it is the highest among the frailest. COVID could be particularly serious in patients with severe acquired brain injury (SABI), such as those with a disorder of consciousness. We here describe a cohort of patients with a disorder of consciousness exposed to SARS-CoV-2 early after their SABI.Materials and methods: The full cohort of 11 patients with SABI hospitalized in March 2020 in the IRCCS Fondazione Don Gnocchi rehabilitation (Milan, Italy) was recruited. Participants received SARS-CoV-2 testing and different clinical and laboratory data were collected.Results: Six patients contracted SARS-CoV-2 and four of them developed the COVID. Of these, one patient had ground-glass opacities on the chest CT scan, while the remaining three developed consolidations. No patient died and the overall respiratory involvement was mild, requiring in the worst cases low-flow oxygen.Conclusions: Here we report the clinical course of a cohort of patients with SABI exposed to SARS-CoV-2. The infection spread among patients and caused COVID in some of them. Unexpectedly, COVID was moderate, caused at most mild respiratory distress and did not result in fatalities.

Neuroprotective effects of flavone luteolin in neuroinflammation and neurotrauma.

Neuroinflammation leads to neurodegeneration, cognitive defects, and neurodegenerative disorders. Neurotrauma/traumatic brain injury (TBI) can cause activation of glial cells, neurons, and neuroimmune cells in the brain to release neuroinflammatory mediators. Neurotrauma leads to immediate primary brain damage (direct damage), neuroinflammatory responses, neuroinflammation, and late secondary brain damage (indirect) through neuroinflammatory mechanism. Secondary brain damage leads to chronic inflammation and the onset and progression of neurodegenerative diseases. Currently, there are no effective and specific therapeutic options to treat these brain damages or neurodegenerative diseases. Flavone luteolin is an important natural polyphenol present in several plants that show anti-inflammatory, antioxidant, anticancer, cytoprotective, and macrophage polarization effects. In this short review article, we have reviewed the neuroprotective effects of luteolin in neurotrauma and neurodegenerative disorders and pathways involved in this mechanism. We have collected data for this study from publications in the PubMed using the keywords luteolin and mast cells, neuroinflammation, neurodegenerative diseases, and TBI. Recent reports suggest that luteolin suppresses systemic and neuroinflammatory responses in Coronavirus disease 2019 (COVID-19). Studies have shown that luteolin exhibits neuroprotective effects through various mechanisms, including suppressing immune cell activation, such as mast cells, and inflammatory mediators released from these cells. In addition, luteolin can suppress neuroinflammatory response, activation of microglia and astrocytes, oxidative stress, neuroinflammation, and the severity of neuroinflammatory diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and TBI pathogenesis. In conclusion, luteolin can improve cognitive decline and enhance neuroprotection in neurodegenerative diseases, TBI, and stroke.

Chest CT-scan finding of asymptomatic COVID-19 pneumonia: a prospective 542 patients' single center study.

Since asymptomatic infections as "covert transmitter", and some patients can progress rapidly in the short term, it is essential to pay attention to the diagnosis and surveillance of asymptomatic patients with SARS-COV2 infection. CT scan has great value in screening and detecting patients with COVID-19 pneumonia, especially in the highly suspected or probable asymptomatic cases with negative RT-PCR for SARS-COV2. This study aimed to detect incidentally COVID-19 pneumonia on medical imaging for patients consulting for other reasons.

ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of diabetes insipidus and hyponatraemia.

COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counseling, with relevance for patients with diabetes insipidus (DI) or hyponatraemia. The main complication of desmopressin treatment in DI is dilutional hyponatraemia. Since plasma sodium monitoring is not always possible in times of COVID-19, we recommend to delay the desmopressin dose once a week until aquaresis occurs allowing excess retained water to be excreted. Patients should measure their body weight daily. Patients with DI admitted to the hospital with COVID-19 have a high risk for mortality due to volume depletion. Specialists must supervise fluid replacement and dosing of desmopressin. Patients after pituitary surgery should drink to thirst and measure their body weight daily to early recognize the development of the postoperative syndrome of inappropriate antidiuresis (SIAD). They should know hyponatraemia symptoms. The prevalence of hyponatraemia in patients with pneumonia due to COVID-19 is not yet known, but seems to be low. In contrast, hypernatraemia may develop in COVID-19 patients in ICU, from different multifactorial reasons, for example, due to insensible water losses from pyrexia, increased respiration rate and use of diuretics. Hypernatraemic dehydration may contribute to the high risk of acute kidney injury in COVID-19. IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary oedema.