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.

Neurological and Neuropsychiatric Impacts of COVID-19 Pandemic.

BACKGROUND: Albeit primarily a disease of respiratory tract, the 2019 coronavirus infectious disease (COVID-19) has been found to have causal association with a plethora of neurological, neuropsychiatric and psychological effects. This review aims to analyze them with a discussion of evolving therapeutic recommendations. METHODS: PubMed and Google Scholar were searched from 1 January 2020 to 30 May 2020 with the following key terms: "COVID-19", "SARS-CoV-2", "pandemic", "neuro-COVID", "stroke-COVID", "epilepsy-COVID", "COVID-encephalopathy", "SARS-CoV-2-encephalitis", "SARS-CoV-2-rhabdomyolysis", "COVID-demyelinating disease", "neurological manifestations", "psychosocial manifestations", "treatment recommendations", "COVID-19 and therapeutic changes", "psychiatry", "marginalised", "telemedicine", "mental health", "quarantine", "infodemic" and "social media". A few newspaper reports related to COVID-19 and psychosocial impacts have also been added as per context. RESULTS: Neurological and neuropsychiatric manifestations of COVID-19 are abundant. Clinical features of both central and peripheral nervous system involvement are evident. These have been categorically analyzed briefly with literature support. Most of the psychological effects are secondary to pandemic-associated regulatory, socioeconomic and psychosocial changes. CONCLUSION: Neurological and neuropsychiatric manifestations of this disease are only beginning to unravel. This demands a wide index of suspicion for prompt diagnosis of SARS-CoV-2 to prevent further complications and mortality.

Les impacts neurologiques et neuropsychiatriques d'une infection à la COVID-19. CONTEXTE: Bien qu'il s'agisse principalement d'une maladie des voies respiratoires, la maladie infectieuse à coronavirus apparue en 2019 (COVID-19) s'est avérée avoir un lien de causalité avec une pléthore d'impacts d'ordre neurologique, neuropsychiatrique et psychologique. Cette étude entend donc analyser ces impacts tout en discutant l'évolution des recommandations thérapeutiques se rapportant à cette maladie. MÉTHODES: Les bases de données PubMed et Google Scholar ont été interrogées entre les 1er janvier et 30 mai 2020. Les termes clés suivants ont été utilisés : « COVID-19 ¼, « SRAS ­ CoV-2 ¼, « Pandémie ¼, « Neuro ­ COVID ¼, « AVC ­ COVID ¼, « Épilepsie ­ COVID ¼, « COVID ­ encéphalopathie ¼, « SRAS ­ CoV-2 ­ encéphalite ¼, « SRAS ­ CoV-2 ­ rhabdomyolyse ¼, « COVID ­ maladie démyélinisante ¼, « Manifestations neurologiques ¼, « Manifestations psychosociales ¼, « Recommandations thérapeutiques ¼, « COVID-19 et changement thérapeutiques ¼, « Psychiatrie ¼, « Marginalisés ¼, « Télémédecine ¼, « Santé mentale ¼, « Quarantaine ¼, « Infodémique ¼ et « Médias sociaux ¼. De plus, quelques articles de journaux relatifs à la pandémie de COVID-19 et à ses impacts psychosociaux ont également été ajoutés en fonction du contexte. RÉSULTATS: Il appert que les manifestations neurologiques et neuropsychiatriques des infections à la COVID-19 sont nombreuses. Les caractéristiques cliniques d'une implication des systèmes nerveux central et périphérique sautent désormais aux yeux. Ces caractéristiques ont fait l'objet d'une brève analyse systématique à l'aide de publications scientifiques. En outre, la plupart des impacts d'ordre psychologique de cette pandémie se sont révélés moins apparents que les changements réglementaires, socioéconomiques et psychosociaux. CONCLUSION: Les manifestations neurologiques et neuropsychiatriques de cette maladie ne font que commencer à être élucidées. Cela exige donc une capacité accrue de vigilance en vue d'un diagnostic rapide, et ce, afin de prévenir des complications additionnelles et une mortalité accrue.

Appearance of extrapyramidal symptoms in adolescent psychiatry patients during COVID-19 infection.

Since the start of the pandemic, there has been an increase in the incidence of psychiatric morbidity among those infected with coronavirus disease 2019 (COVID-19) and those indirectly affected by COVID-19. There has been a considerable increase in the number of individuals with such psychiatric conditions as depression, acute stress disorders, anxiety, and posttraumatic stress disorder (PTSD). About one-third of patients with COVID-19 are reported to have developed short and long-term neuropsychiatric conditions such as delirium, agitation, altered consciousness, hypoxic encephalopathy encephalitis, dysexecutive syndrome, cerebrovascular complications (e.g., stroke), hypoxic encephalopathy, convulsions, neuromuscular dysfunction, demyelinating processes, or parkinsonism through several pathophysiological mechanisms. Nevertheless, as the pandemic progressed, data on neuropsychiatric manifestations implied that the pathologic capacity of COVID-19 and its association with the onset and/or exacerbation of psychiatric morbidity indicate that COVID-19 is potentially related to neuropsychiatric involvement. Patients with existing mental disorders under psychotropic treatment exposed to the COVID-19 infection have been represented by an increased risk of worsened psychiatric symptoms and expanded drug side effects. The present study aimed to describe five pediatric patients with various psychiatric illness that experienced COVID-19 infection and had potentially associated neuropsychiatric involvement, such as exacerbation of underlying psychiatric symptoms and extrapyramidal side effects. To the best of our knowledge, the present study is the first to describe adolescents with COVID-19 infection that presented with a series of manifestations in the form of an increase in extrapyramidal symptoms (EPS)  during exacerbation of underlying psychiatric disease.

Brain hypoxia caused by respiratory obstruction which should not be forgotten in COVID-19 disease.

DISCUSSION: None. The authors declare that there are no potential conflicts of interest.

Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia.

Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies.

Mild Poikilocapnic Hypoxia Increases Very Low Frequency Haemoglobin Oxygenation Oscillations in Prefrontal Cortex (preprint)

The aim of the study was to investigate the effect of mild cerebral hypoxia on haemoglobin oxygenation (HbO2), cerebrospinal fluid dynamics and cardiovascular physiology. To achieve this goal, four signals were recorded simultaneously: blood pressure, ECG, HbO2 from right hemisphere and changes of SAS width from left hemisphere. Signals were registered from 30 healthy, young participants (2 females and 28 males, BMI = 24.5 ± 2.3 kg/m2, age 30.8 ± 13.4 years). We analysed the recorded signals using wavelet transform (WT).  We demonstrated for the first time that in healthy subjects exposed to mild poikilokapnic hypoxia that there were increases in very low frequency HbO2 oscillations (< 0.052 Hz) in prefrontal cortex.  Additionally, SAS fluctuation diminishes in the whole frequency range which could be explained by brain oedema. Consequently the study provides insight into mechanisms governing brain response to a mild hypoxic challenge. Our study supports the notion that HbO2 and SAS width monitoring might be beneficial for patients with acute lung disease, including SARS-CoV-2. 

Severe diabetic ketoacidosis precipitated by COVID-19 in pediatric patients: Two case reports. / Cetoacidosis diabética severa precipitada por COVID-19 en pacientes pediátricos: reporte de dos casos.

INTRODUCTION: The association of COVID-19 with diabetes mellitus is bidirectional. In one direction, diabetes mellitus is associated with an increased risk of severe COVID-19. In the opposite direction, in patients with COVID-19 new-onset diabetes mellitus, severe diabetic ketoacidosis and severe metabolic complications have been described. CLINICAL CASE: This report describes two patients with diabetes mellitus who came to our hospital with ketoacidosis resulting from new-onset diabetes mellitus. We describe the clinical course and the management approach during the COVID-19 pandemic. CONCLUSION: COVID-19 is associated with metabolic complications such as severe diabetic ketoacidosis.

INTRODUCCIÓN: La relación entre la enfermedad por el coronavirus de 2019 (COVID-19) secundaria a SARS-CoV-2 y la diabetes mellitus es bidireccional. Por un lado, la diabetes mellitus se asocia con un mayor riesgo de COVID-19 grave. Por otro lado, en pacientes con COVID-19 se han observado diabetes mellitus de nueva aparición con presentaciones de cetoacidosis diabética y complicaciones metabólicas graves de dicha presentación. CASOS CLÍNICOS: En este informe, describimos a dos pacientes pediátricos con diabetes mellitus que acudieron a nuestro hospital con cetoacidosis diabética, de debut inicial. Describimos la evolución y el manejo clínico y terapéutico durante la pandemia de COVID-19. CONCLUSIÓN: La infección por COVID-19 puede precipitar complicaciones como cetoacidosis diabética severa.

Delayed post-hypoxic leukoencephalopathy in an adult with COVID-19.

As the novel coronavirus, SARS-CoV-2, has enveloped the world in a pandemic, it has become clear that the symptoms extend far beyond the respiratory system and have particularly caused a wide range of neurologic CNS complications, including diffuse leukoencephalopathy. Here, we describe a case of a 59-year-old male with severe COVID-19 infection who developed severe encephalopathy, which persisted well after his acute infection had subsided and had begun to improve from his respiratory dysfunction. He was found to have diffuse leukoencephalopathy with concomitant diffusion restriction on MR imaging. This case represents a delayed onset of leukoencephalopathy secondary to hypoxia in a small but growing cohort of COVID-related leukoencephalopathy due to similarities in imaging features and lack of superior alternate diagnosis. Patient's clinical improvement suggests reversibility with likely pathology being demyelination rather than infarction.

Surveillance Study of Acute Neurological Manifestations among 439 Egyptian Patients with COVID-19 in Assiut and Aswan University Hospitals.

BACKGROUND: COVID-19 can be accompanied by acute neurological complications of both central and peripheral nervous systems (CNS and PNS). In this study, we estimate the frequency of such complications among hospital inpatients with COVID-19 in Assiut and Aswan university hospitals. MATERIALS AND METHODS: We screened all patients with suspected COVID-19 admitted from 1 June to 10 August 2020 to the university hospitals of Assiut and Aswan in Upper Egypt. Clinical and laboratory tests, CT/MRI of the chest and brain, and neurophysiology study were performed for each patient if indicated. RESULTS: 439 patients had confirmed/probable COVID-19; neurological manifestations occurred in 222. Of these, 117 had acute neurological disease and the remainder had nonspecific neuropsychiatric symptoms such as headache, vertigo, and depression. The CNS was affected in 75 patients: 55 had stroke and the others had convulsions (5), encephalitis (6), hypoxic encephalopathy (4), cord myelopathy (2), relapse of multiple sclerosis (2), and meningoencephalitis (1). The PNS was affected in 42 patients: the majority had anosmia and ageusia (31) and the others had Guillain-Barré syndrome (4), peripheral neuropathy (3), myasthenia gravis (MG, 2), or myositis (2). Fever, respiratory symptoms, and headache were the most common general symptoms. Hypertension, diabetes mellitus, and ischemic heart disease were the most common comorbidities in patients with CNS affection. CONCLUSION: In COVID-19, both the CNS and PNS are affected. Stroke was the most common complication for CNS, and anosmia and/or ageusia were common for PNS diseases. However, there were 6 cases of encephalitis, 2 cases of spinal cord myelopathy, 2 cases of MG, and 2 cases of myositis.

The growth factor/ cytokine midkine may participate to cytokine storm and contribute to the pathogenesis of SARS-CoV-2 infected patients (preprint)

The current coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in Wuhan, China and has rapidly become global challenges, creating major challenges to health systems in almost every country in the world it has turned into a pandemic. COVID-19 poses a risky clinical situation that can range from mild illness to severe respiratory failure requiring admission to intensive care. It is known to cause cytokine storm in some critically ill patients. However, more and more evidence showed that there is a dramatic increase in cytokine levels in patients diagnosed with COVID-19. Midkine (MK) is involved in various physiological and pathological processes, which some of them are desired and beneficial such as controlling tissue repair and antimicrobial effects, but some others are harmful such as promoting inflammation, carcinogenesis and chemo-resistance. Also, MK is expressed in inflammatory cells and released by endothelial cells under hypoxic conditions. Considering all this information, there are strong data that MK, an important cytokine known to increase in inflammatory diseases, may overexpressed in patients who are positive for COVID-19. The overexpression of MK reveals a picture leading to fibrosis in the lung damage. Therefore, questions arise about how the concentration of MK changes in CoVID-19 patients and can we use it as an inflammation biomarker or in the treatment protocol in the future.

Pathophysiology of Psychiatric Symptoms in COVID-19 and Biomarkers (IL-6, Platelets, Ferritin, Lymphopenia and Urea) (preprint)

Most of the studies on the COVID-19 pandemic produced by the SARS-CoV-2 reported neuropsychiatric symptoms only as part of the manifestations of the disease in its terminal phase. However, there are neuropsychiatric symptoms since the beginning of the disease. Several investigations have indicated a direct relationship between chronic diseases such as human immunodeficiency virus (HIV), tuberculosis, SARS, MERS, Ebola and SARS 2003 with mental disorders such as depression. Neuropsychiatric disorders can occur due to different mechanisms, such as cerebral hypoxia, cytokine storm due to exaggerated immune response and encephalitis due to direct brain infection. Nervous system involvement leads to poor prognosis of COVID-19.

Helmet CPAP to treat hypoxic pneumonia outside the ICU: an observational study during the COVID-19 outbreak (preprint)

Background: Respiratory failure due to COVID-19 pneumonia is associated with high mortality and may overwhelm health care systems, due to the surge patients requiring advanced respiratory support. Shortage of intensive care unit (ICU) beds required many patients to be treated outside the ICU despite severe gas exchange impairment. Helmet is as effective interface to provide Continuous Positive Airway Pressure (CPAP) non-invasively. We report data about the usefulness of helmet CPAP during pandemic, either as an effective treatment, a bridge to intubation or a rescue therapy for patients with care limitations (DNI). Methods: In this observational study we collected data regarding patients failing standard oxygen therapy (i.e. non-rebreathing mask) due to COVID-19 pneumonia treated with a free flow helmet CPAP system. Patients’ data were recorded before, at initiation of CPAP treatment and once a day, thereafter. CPAP failure was defined as a composite outcome of intubation or death. Results: A total of 306 patients were included; 42% were deemed as DNI. Helmet CPAP treatment was successful in 69% of the full-treatment and 28% of the DNI patients ( P< 0.001). With helmet CPAP, PaO 2 /FiO 2 ratio doubled from about 100 to 200 mmHg ( P< 0.001); respiratory rate decreased from 28 [22-32] to 24 [20-29] breaths per minute, P <0.001). C-Reactive Protein, time to oxygen mask failure, age, PaO 2 /FiO 2 during CPAP, number of comorbidities were independently associated with CPAP failure. Helmet CPAP was maintained for 6 [3-9] days, almost continuously during the first two days. None of the full treatment patients died before intubation in the wards. Conclusions: : Helmet CPAP treatment is feasible for several days outside the ICU, despite persistent impairment in gas exchange. It was used, without escalating to intubation, in the majority of full treatment patients after standard oxygen therapy failed. DNI patients could benefit from helmet CPAP as rescue therapy to improve survival. Trial Registration: NCT04424992

Selective Neuronal Mitochondrial Targeting in SARS-CoV-2 Infection Affects Cognitive Processes to Induce 'Brain Fog' and Results in Behavioral Changes that Favor Viral Survival.

Alterations in brain functioning, especially in regions associated with cognition, can result from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and are predicted to result in various psychiatric diseases. Recent studies have shown that SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) can directly or indirectly affect the central nervous system (CNS). Therefore, diseases associated with sequelae of COVID-19, or 'long COVID', also include serious long-term mental and cognitive changes, including the condition recently termed 'brain fog'. Hypoxia in the microenvironment of select brain areas may benefit the reproductive capacity of the virus. It is possible that in areas of cerebral hypoxia, neuronal cell energy metabolism may become compromised after integration of the viral genome, resulting in mitochondrial dysfunction. Because of their need for constant high metabolism, cerebral tissues require an immediate and constant supply of oxygen. In hypoxic conditions, neurons with the highest oxygen demand become dysfunctional. The resulting cognitive impairment benefits viral spread, as infected individuals exhibit behaviors that reduce protection against infection. The effects of compromised mitochondrial function may also be an evolutionary advantage for SARS-CoV-2 in terms of host interaction. A high viral load in patients with COVID-19 that involves the CNS results in the compromise of neurons with high-level energy metabolism. Therefore, we propose that selective neuronal mitochondrial targeting in SARS-CoV-2 infection affects cognitive processes to induce 'brain fog' and results in behavioral changes that favor viral propagation. Cognitive changes associated with COVID-19 will have increasing significance for patient diagnosis, prognosis, and long-term care.

Indirect impacts of the COVID-19 pandemic at two tertiary neonatal units in Zimbabwe and Malawi: an interrupted time series analysis (preprint)

ABSTRACT Background Deaths from COVID-19 have exceeded 1.8 million globally (January 2020). We examined trends in markers of neonatal care before and during the pandemic at two tertiary neonatal units in Zimbabwe and Malawi. Methods We analysed data collected prospectively via the NeoTree app at Sally Mugabe Central Hospital (SMCH), Zimbabwe, and Kamuzu Central Hospital (KCH), Malawi. Neonates admitted from 1 June 2019 to 25 September 2020 were included. We modelled the impact of the first cases of COVID-19 (Zimbabwe: 20 March 2020; Malawi: 3 April 2020) on number of admissions, gestational age and birth weight, source of admission referrals, prevalence of neonatal encephalopathy, and overall mortality. Findings The study included 3,450 neonates at SMCH and 3,350 neonates at KCH. Admission numbers at SMCH did not initially change after the first case of COVID-19 but fell by 48% during a nurses’ strike (Relative risk (RR) 0·52, 95%CI 0·40-0·68, p < 0·002). At KCH, admissions dropped by 42% (RR 0·58; 95%CI 0·48-0·70; p < 0·001) soon after the first case of COVID-19. At KCH, gestational age and birth weight decreased slightly (1 week, 300 grams), outside referrals dropped by 28%, and there was a slight weekly increase in mortality. No changes in these outcomes were found at SMCH. Interpretation The indirect impacts of COVID-19 are context-specific. While this study provides vital evidence to inform health providers and policy makers, national data are required to ascertain the true impacts of the pandemic on newborn health. Funding International Child Health Group, Wellcome Trust. RESEARCH IN CONTEXT Evidence before this study We searched PubMed for evidence of the indirect impact of the COVID-19 pandemic on neonatal care in low-income settings using the search terms neonat* or newborn , and COVID-19 or SARS-CoV 2 or coronavirus , and the Cochrane low and middle income country (LMIC) filters, with no language limits between 01.10.2019 and 21.11.20. While there has been a decrease in global neonatal mortality rates, the smaller improvements seen in low-income settings are threatened by the direct and indirect impact of the COVID-19 pandemic. A modelling study of this threat predicted between 250000-1.1 million extra neonatal deaths as a result of decreased service provision and access in LMICs. A webinar and survey of frontline maternal/newborn healthcare workers in >60 countries reported a decline in both service attendance and in quality of service across the ante-, peri- and post-natal journey. Reporting fear of attending services, and difficulty in access, and a decrease in service quality due to exacerbation of existing service weaknesses, confusion over guidelines and understaffing. Similar findings were reported in a survey of healthcare workers providing childhood and maternal vaccines in LMICs. One study to date has reported data from Nepal describing an increase in stillbirths and neonatal deaths, with institutional deliveries nearly halved during lockdown. Added value of this study To our knowledge, this is the first and only study in Sub-Saharan Africa describing the impact of COVID-19 pandemic on health service access and outcomes for newborns in two countries. We analysed data from the digital quality improvement and data collection tool, the NeoTree, to carry out an interrupted time series analysis of newborn admission rates, gestational age, birth weight, diagnosis of hypoxic ischaemic encephalopathy and mortality from two large hospitals in Malawi and Zimbabwe ( n ∼7000 babies). We found that the indirect impacts of COVID-19 were context-specific. In Sally Mugabe Central Hospital, Zimbabwe, initial resilience was demonstrated in that there was no evidence of change in mortality, birth weight or gestational age. In comparison, at Kamuzu Central Hospital, Malawi, soon after the first case of COVID-19, the data revealed a fall in admissions (by 42%), gestational age (1 week), birth weight (300 grams), and outside referrals (by 28%), and there was a slight weekly increase in mortality (2%). In the Zimbabwean hospital, admission numbers did not initially change after the first case of COVID-19 but fell by 48% during a nurses’ strike, which in itself was in response to challenges exacerbated by the pandemic. Implications of all the available evidence Our data confirms the reports from frontline healthcare workers of a perceived decline in neonatal service access and provision in LMICs. Digital routine healthcare data capture enabled rapid profiling of indirect impacts of COVID-19 on newborn care and outcomes in two tertiary referral hospitals, Malawi and Zimbabwe. While a decrease in service access was seen in both countries, the impacts on care provided and outcome differed by national context. Health systems strengthening, for example digital data capture, may assist in planning context-specific mitigation efforts.

Special considerations in the assessment of catastrophic brain injury and determination of brain death in patients with SARS-CoV-2.

INTRODUCTION: The coronavirus disease 2019 (Covid-19) pandemic has led to challenges in provision of care, clinical assessment and communication with families. The unique considerations associated with evaluation of catastrophic brain injury and death by neurologic criteria in patients with Covid-19 infection have not been examined. METHODS: We describe the evaluation of six patients hospitalized at a health network in New York City in April 2020 who had Covid-19, were comatose and had absent brainstem reflexes. RESULTS: Four males and two females with a median age of 58.5 (IQR 47-68) were evaluated for catastrophic brain injury due to stroke and/or global anoxic injury at a median of 14 days (IQR 13-18) after admission for acute respiratory failure due to Covid-19. All patients had hypotension requiring vasopressors and had been treated with sedative/narcotic drips for ventilator dyssynchrony. Among these patients, 5 had received paralytics. Apnea testing was performed for 1 patient due to the decision to withdraw treatment (n = 2), concern for inability to tolerate testing (n = 2) and observation of spontaneous respirations (n = 1). The apnea test was aborted due to hypoxia and hypotension. After ancillary testing, death was declared in three patients based on neurologic criteria and in three patients based on cardiopulmonary criteria (after withdrawal of support (n = 2) or cardiopulmonary arrest (n = 1)). A family member was able to visit 5/6 patients prior to cardiopulmonary arrest/discontinuation of organ support. CONCLUSION: It is feasible to evaluate patients with catastrophic brain injury and declare brain death despite the Covid-19 pandemic, but this requires unique considerations.

Neurological Associations of COVID-19 (preprint)

Background: The COVID-19 pandemic, caused by SARS-CoV-2, is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. Based on knowledge of other coronaviruses, especially those that caused the SARS and MERS epidemics, we might expect to see rare cases of central nervous system (CNS) and peripheral nervous system (PNS) disease caused by SARS-CoV-2.Recent developments: A growing number of case reports and series describe a wide array of neurological manifestations, but many lack detail, reflecting the challenge of studying such patients. Encephalopathy is relatively common, being reported for 93 patients in total, including 16 (7.5%) of 214 hospitalised COVID-19 patients in Wuhan, China, and 40 (69%) of 58 in intensive care with COVID-19 in France. Encephalitis has been described in 8 patients to date, and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 is detected in the cerebrospinal fluid of some patients. Anosmia and ageusia are common and may occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication, with cohort studies reporting stroke in 1.6-6% of hospitalised COVID-19 cases. So far, 88 patients have been described, mostly with ischaemic stroke, who frequently have vascular events in the context of a pro-inflammatory hypercoagulable state with elevated CRP, D-dimer, and ferritin.Where next?: Careful clinical, diagnostic and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish non-specific complications of severe disease, such as hypoxic encephalopathy and critical care neuropathy, from those caused directly or indirectly by the virus; these include infectious, para- and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barré syndrome. Recognising SARS-CoV-2 neurological disease in patients whose respiratory infection is mild or asymptomatic may prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will remain small. However, these patients may be left with severe neurological sequelae. With so much of the population infected, the overall number of neurological patients, and their associated health, social and economic costs, may be large. Healthcare planners and policymakers must prepare for this eventuality. The many ongoing studies investigating the neurological association will increase our knowledge base.