Neuropsychiatric aspects of long COVID: A comprehensive review

Although some patients have persistent symptoms or develop new symptoms following coronavirus disease 2019 (COVID-19) infection, neuropsychiatric aspects of long COVID are not well known. This review summarizes and provides an update on the neuropsychiatric dimensions of long COVID. Its neuropsychiatric manifestations commonly include fatigue, cognitive impairment, sleep disorders, depression, anxiety, and post-traumatic stress disorder. There are no specific tests for long COVID, but some characteristic findings such as hypometabolism on positron emission tomography have been reported. The possible mechanisms of long COVID include inflammation, ischemic effects, direct viral invasion, and social and environmental changes. Some patient characteristics and the severity and complications of acute COVID-19 infection may be associated with an increased risk of neuropsychiatric symptoms. Long COVID may resolve spontaneously or persist, depending on the type of neuropsychiatric symptoms. Although established treatments are lacking, various psychological and pharmacological treatments have been attempted. Vaccination against COVID-19 infection plays a key role in the prevention of long coronavirus disease. With differences among the SARS-CoV-2 variants, including the omicron variant, the aspects of long COVID are likely to change in the future. Further studies clarifying the aspects of long COVID to develop effective treatments are warranted.     

The three frontlines against COVID-19: Brain,Behavior, and Immunity

The pandemic outbreak of coronavirus disease 2019 (COVID-19) is raising global anxiety and fear of both real and perceived health threat from the virus. Overwhelming evidence shows infected patients experiencing neuropsychiatric complications, suggesting that the “psychoneuroimmunity” model might be beneficial in understanding the impact of the virus. Therefore, this Special Issue on “Immunopsychiatry of COVID-19 Pandemic” was launched immediately after the pandemic was declared, with the first paper accepted on the March 25th, 2020. A total of ninety-three papers were accepted, the last one was on the July 10th, 2020 when the initial acute phase started declining. The papers of this Special Issue have illuminated the social impact, psychopathology, neurological manifestation, immunity responses, and potential treatments and prevention on COVID-19. For example, anxiety disorders, mood disorders, and suicidal ideation are most common psychiatric manifestations. COVID-19 infection can have central and/or peripheral nervous system symptoms, including headache, sleep disorders, encephalopathy, and loss of taste and smell. A “three-steps” Neuro-COVID infection model (neuro-invasion, clearance and immune response) was established. The current therapeutic interventions for COVID-19 include supportive intervention, immunomodulatory agents, antiviral therapy, and plasma transfusion. Psychological support should be implemented, improving the psychological wellbeing, as well as to enhance psychoneuroimmunity against COVID-19.     

Does COVID-19 increase the risk of neuropsychiatric sequelae? Evidence from a mendelian randomization approach

Observational studies based on electronic health records (EHR) report an increased risk of neurological/neuropsychiatric sequelae for patients who have had coronavirus disease 2019 (COVID-19). However, these studies may suffer from biases such as unmeasured confounding, residual reverse causality, or lack of precision in EHR-based diagnoses. To rule out these biases, we tested causal links between COVID-19 and different potential neurological/neuropsychiatric sequelae through a two-sample Mendelian randomization analysis of summary statistics from large Genome-Wide Association Scans of susceptibility to COVID-19 and different neurological and neuropsychiatric disorders, including major depression, anxiety, schizophrenia, stroke, Parkinson’s and Alzheimer’s diseases. We found robust evidence suggesting that COVID-19 – notably the hospitalized and most severe forms – carries an increased risk of neuropsychiatric sequelae, particularly Alzheimer’s disease, and to a lesser extent anxiety disorder. In line with a large longitudinal EHR-based study, this evidence was stronger for more severe COVID-19 forms. These results call for a targeted screening strategy to tackle the post-COVID neuropsychiatric pandemic.     

SARS-CoV-2 involvement in central nervous system tissue damage

As the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to spread globally,it became evident that the SARS-CoV-2 virus infects multiple organs including the brain.Several clinical studies revealed that patients with COVID-19 infection experience an array of neurological signs ranging in severity from headaches to life-threatening strokes.Although the exact mechanism by which the SARS-CoV-2 virus directly impacts the brain is not fully understood,several theories have been suggested including direct and indirect pathways induced by the virus.One possible theory is the invasion of SARS-CoV-2 to the brain occurs either through the bloodstream or via the nerve endings which is considered to be the direct route.Such findings are based on studies reporting the presence of viral material in the cerebrospinal fluid and brain cells.Nevertheless,the indirect mechanisms,including blood-clotting abnormalities and prolonged activation of the immune system,can result in further tissue and organ damages seen during the course of the disease.This overview attempts to give a thorough insight into SARS-CoV-2 coronavirus neurological infection and highlights the possible mechanisms leading to the neurological manifestations observed in infected patients.     

Neurological Manifestations in Patients with COVID-19: Experiences from the Central Infectious Diseases Hospital in South Korea

Background and PurposeTo investigate the incidence and characteristics of neurological manifestations associated with coronavirus disease 2019 (COVID-19).MethodsWe reviewed the medical records of the consecutive patients with COVID-19 who were admitted to the central infectious diseases hospital designated for the treatment of COVID-19 in South Korea between March 2020 and September 2020. Newly developed neurological manifestations associated with COVID-19 were investigated. The frequency and clinical features of the neurological manifestations were analyzed according to disease severity, which was classified according to World Health Organization interim guidance.ResultsOf the 306 symptomatic patients, 186 (60.8%) developed at least one neurological manifestation during hospitalization. The most common neurological symptom was headache (n=102, 33.3%), followed by myalgia (n=96, 31.4%) and anosmia/ageusia (n=54, 17.6%). Acute stroke (all ischemic stroke) occurred in three (1.0%) patients, and new-onset seizures occurred in two (0.7%). Neurological manifestation was a presenting symptom of COVID-19 in 72 (23.5%) patients, and was the only symptom of COVID-19 in 12 (3.9%). Stroke, seizure, and impaired consciousness were significantly associated with severe to critical COVID-19, whereas headache and anosmia/ageusia were frequently found in patients with mild to moderate disease.ConclusionsNeurological manifestations were commonly observed in patients with COVID-19. During the current pandemic, when patients present with new-onset neurological symptoms, COVID-19 may be considered as part of the differential diagnosis. Attention to severe neurological complications is needed, especially in patients with severe or critical COVID-19.     

Creutzfeldt-Jakob disease in a man with COVID-19: SARS-CoV-2-accelerated neurodegeneration?

We describe a man whose first manifestations of Creutzfeldt-Jakob disease occurred in tandem with symptomatic onset of coronavirus disease 2019 (COVID-19). Drawing from recent data on prion disease pathogenesis and immune responses to SARS-CoV-2, we hypothesize that the cascade of systemic inflammatory mediators in response to the virus accelerated the pathogenesis of our patient’s prion disease. This hypothesis introduces the potential relationship between immune responses to the novel coronavirus and the hastening of preclinical or manifest neurodegenerative disorders. The global prevalence of both COVID-19 and neurodegenerative disorders adds urgency to the study of this potential relationship.     

Neurological post-acute sequelae of SARS-CoV-2 infection

The novel coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can have two phases: acute (generally 4 weeks after onset) and chronic (>4 weeks after onset). Both phases include a wide variety of signs and symptoms including neurological and psychiatric symptoms. The signs and symptoms that are considered sequelae of COVID-19 are termed post-COVID condition, long COVID-19, and post-acute sequelae of SARS-CoV-2 infection (PASC). PASC symptoms include fatigue, dyspnea, palpitation, dysosmia, subfever, hypertension, alopecia, sleep problems, loss of concentration, amnesia, numbness, pain, gastrointestinal symptoms, depression, and anxiety. Because the specific pathophysiology of PASC has not yet been clarified, there are no definite criteria of the condition, hence the World Health Organization's definition is quite broad. Consequently, it is difficult to correctly diagnose PASC. Approximately 50% of patients may show at least one PASC symptom up to 12 months after COVID-19 infection; however, the exact prevalence of PASC has not been determined. Despite extensive research in progress worldwide, there are currently no clear diagnostic methodologies or treatments for PASC. In this review, we discuss the currently available information on PASC and highlight the neurological sequelae of COVID-19 infection. Furthermore, we provide clinical suggestions for diagnosing and caring for patients with PASC based on our outpatient clinic experience.     

Legacy of neuropsychiatric symptoms associated with past COVID-19 infection: A cause of concern

Although primarily affecting the respiratory system, growing attention is being paid to the neuropsychiatric consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Acute and sub-acute neuropsychiatric manifestations of coronavirus disease 2019 (COVID-19) disease and their mechanisms are better studied and understood currently than they had been when the pandemic began; however, many months or years will be necessary to fully comprehend how significant the consequences of such complications will be. In this editorial, we discuss the possible long-term sequelae of the COVID-19 pandemic, deriving our considerations on experiences drawn from past coronaviruses’ outbreaks, such as the SARS and the middle east respiratory syndrome, and from the knowledge of the mechanisms of neurotropism and invasiveness of SARS-CoV-2. Acknowledging the global spread of COVID-19 and the vast number of people affected, to date amounting to many millions, the matter of this pandemic’s neuropsychiatric legacy appears concerning. Public health monitoring strategies and early interventions seem to be necessary to manage the possible emergence of a severe wave of neuropsychiatric distress among the survivors.     

Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms

The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals’ lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.     

Genetic disorders of thyroid metabolism and brain development

Normal thyroid metabolism is essential for human development, including the formation and functioning of the central and peripheral nervous system. Disorders of thyroid metabolism are increasingly recognized within the spectrum of paediatric neurological disorders. Both hypothyroid and hyperthyroid disease states (resulting from genetic and acquired aetiologies) can lead to characteristic neurological syndromes, with cognitive delay, extrapyramidal movement disorders, neuropsychiatric symptoms, and neuromuscular manifestations. In this review, the neurological manifestations of genetic disorders of thyroid metabolism are outlined, with particular focus on Allan‐Herndon‐Dudley syndrome and benign hereditary chorea. We report in detail the clinical features, major neurological and neuropsychiatric manifestations, molecular genetic findings, disease mechanisms, and therapeutic strategies for these emerging genetic ‘brain‐thyroid’ disorders.     

COVID-19, SARS and MERS: A neurological perspective

Central to COVID-19 pathophysiology is an acute respiratory infection primarily manifesting as pneumonia. Two months into the COVID-19 outbreak, however, a retrospective study in China involving more than 200 participants revealed a neurological component to COVID-19 in a subset of patients. The observed symptoms, the cause of which remains unclear, included impaired consciousness, skeletal muscle injury and acute cerebrovascular disease, and appeared more frequently in severe disease. Since then, findings from several studies have hinted at various possible neurological outcomes in COVID-19 patients. Here, we review the historical association between neurological complications and highly pathological coronaviruses including SARS-CoV, MERS-CoV and SARS-CoV-2. We draw from evidence derived from past coronavirus outbreaks, noting the similarities and differences between SARS and MERS, and the current COVID-19 pandemic. We end by briefly discussing possible mechanisms by which the coronavirus impacts on the human nervous system, as well as neurology-specific considerations that arise from the repercussions of COVID-19.     

Psychiatric signs and symptoms in treatable inborn errors of metabolism

Possible underlying organic causes of psychiatric symptoms can be overlooked in the clinical setting. It is important to increase awareness amongst psychiatric and neurological professionals with regard to certain inborn errors of metabolism as, in some cases, disease-specific therapies are available that can, for instance, treat underlying metabolic causes. The following article describes the basic pathophysiology, clinical and neurological features, and available diagnostic procedures of six treatable metabolic diseases that are associated with neuropsychiatric symptoms: Wilson’s disease, cerebrotendinous xanthomatosis, porphyrias, homocysteinemia, urea cycle disorders, and Niemann-Pick disease type C (NP-C). NP-C is taken as a particularly relevant example because, while it is traditionally considered to be a condition that presents with severe neurological and systemic manifestations in children, an increasing number of patients are being detected who have the adolescent- or adult-onset form, which is frequently associated with neuropsychiatric signs. A notable proportion of adult-onset cases have been reported where NP-C has mistakenly been diagnosed and treated as a psychiatric condition, usually based on patients’ initial presentation with psychotic or schizophrenia-like symptoms. Underlying organic causes of psychiatric disorders such as psychosis should be considered among patients with atypical symptoms and/or resistance to standard therapy. Alongside improved frameworks for additional multidisciplinary diagnostic work in patients with suspected organic disease, the development of convenient and affordable biochemical screening and/or diagnostic methods has enabled new ways to narrow down differential diagnoses.     

SARS-CoV-2-associated first episode of acute mania with psychotic features

Despite neuropsychiatric outcomes of SARS-CoV-2 infection are now under close scrutiny, psychoneuroimmunological characteristics of COVID-19 and precise pathophysiology of neuropsychiatric manifestations of the infection are still obscure. Moreover, there still exists a shortfall in demonstrating specific clinical manifestations of the brain involvement of the virus. Here, we presented a 33-year-old female patient with COVID-19, reporting acute-onset paranoid delusions symptoms, insomnia and irritability. Cranial MRI showed an hyperintense signal in the splenium of the corpus callosum with decreased apparent diffusion coefficient, which might possibly indicate the presence of cytotoxic edema related to the brain involvement of the infection. Following the completion of SARS-CoV-2 treatment, both cytotoxic edema and psychiatric symptoms resolved. In light of this report, we suggest that either heightened immune response and direct viral infection that SARS-CoV-2 may lead to such psychiatric manifestations and neuropsychiatric monitoring should be performed in patients with COVID-19. Prompt recognition of psychiatric consequences of COVID-19 may help clinicians provide guidance for differential diagnosis and manage them accordingly.     

Neuroimaging and neurologic findings in COVID-19 and other coronavirus infections: A systematic review in 116 patients

Various neurologic syndromes have been described in patients with COVID-19 and other coronavirus infections. In this paper, we systematically reviewed the available imaging findings of patients diagnosed with neurological symptoms associated with coronavirus infections. Diverse radiologic results in the context of different neurologic presentations have been demonstrated using CT and MRI. While many patients have normal imaging evaluations, some patients present with intra-axial and extra-axial abnormalities. Stroke (both ischemic and hemorrhagic), encephalomyelitis, meningitis, demyelinating disorders such as acute disseminated encephalomyelitis (ADEM), and encephalopathy have been reported. Familiarity with these radiologic patterns will guide radiologists and referring clinicians to consider coronavirus infections in patients with worsening or progressive neurologic findings, particularly during the current COVID-19 pandemic. As data on this topic is very limited, further research and investigation are required.     

Spectrum of neuropsychiatric manifestations in COVID-19

Corona Virus Disease 2019 (COVID-19) emerged in December 2019 from Wuhan, China. It typically presents with mild upper respiratory tract infection symptoms and may have life threatening complications, including acute respiratory distress syndrome, acute stroke, myocardial infarction, kidney failure, shock, and even death. Coronavirus infections are known to have neuroinvasive potential with consequent neuropsychiatric manifestations. We analyzed COVID-19 adult patients in the TriNetX database, which is a global health collaborative clinical research platform collecting real-time electronic medical records data from a network of health care organizations (HCOs) from January 20, 2020 to June 10th, 2020. 40,469 patients were diagnosed with COVID-19 among whom 9086 (22.5%) patients had neuropsychiatric manifestations. The most common neurologic manifestations included headache (3.7%) and sleep disorders (3.4%), Encephalopathy (2.3%), Stroke and transient ischemic attack (TIA) (1.0%) and 0.6% had seizures. Most common psychiatric manifestations included anxiety and other related disorders (4.6%), mood disorders (3.8%), while 0.2% patients had suicidal ideation. Early recognition and prompt management of neuropsychiatric manifestations in these patients have a potential to decrease overall morbidity and mortality.     

Acute myelitis and SARS-CoV-2 infection. A new etiology of myelitis?

The etiological agent of coronavirus disease-19 (COVID-19), SARS-coronavirus-2 (SARS-CoV-2), emerged in Wuhan, China, and quickly spread worldwide leading the World Health Organization (WHO) to recognize it not only as a pandemic but also as an important thread to public health. Beyond respiratory symptoms, new neurological manifestations are being identified such as headache, ageusia, anosmia, encephalitis or acute cerebrovascular disease. Here we report the case of an acute transverse myelitis (TM) in a patient with SARS-CoV-2 infection detected by the nasopharyngeal swab technique but not in cerebrospinal fluid (CSF) analysis. Anti-herpes simplex virus (HSV) 1 and varicella-zoster IgM antibodies were not detected in serum samples and spinal and brain magnetic resonance imaging (MRI) showed no abnormal findings. This case remarks that COVID-19 nervous system damage could be caused by immune-mediated mechanisms.     

Care for Patients with Stroke During the COVID-19 Pandemic: Physical Therapy and Rehabilitation Suggestions for Preventing Secondary Stroke

Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the development of the novel 2019 coronavirus disease (COVID-19) and associated clinical symptoms, which typically presents as an upper respiratory syndrome such as pneumonia. Growing evidence indicates an increased prevalence of neurological involvement (e.g., in the form of stroke) during virus infection. COVID-19 has been suggested to be more than a lung infection because it affects the vasculature of the lungs and other organs and increases the risk of thrombosis. Patients with stroke are vulnerable to secondary events as a result not only of their poor vascular condition but also of their lack of access to rehabilitation resources. Herein, we review current knowledge regarding the pathophysiology of COVID-19, its possible association with neurological involvement, and current drug therapies. Suggestions are also offered regarding the potential for current neurorehabilitation therapies to be taught and practiced at home.     

COVID-19-Associated Encephalopathy: Systematic Review of Case Reports

Background and PurposeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily attacks the respiratory system, but there are also several reports of the involvement of the central nervous system, with one of the manifestations being encephalopathy. The relatively new emergence of COVID-19 means that few studies have investigated the clinical profile of encephalopathy associated with this disease. This study aimed to determine the clinical profile, laboratory, and imaging results of encephalopathy associated with COVID-19.MethodsThree databases, namely PubMed/MEDLINE, Embase, and Scopus, were systematically searched for case reports and case series related to COVID-19-associated encephalopathy published from January 1, 2019 to July 20, 2020.ResultsThis review included 24 studies involving 33 cases. The most-reported neurological symptoms were disorientation/confusion (72.72%), decreased consciousness (54.54%), and seizures (27.27%). Laboratory examinations revealed increases in the C-reactive protein level (48.48%), the lactate dehydrogenase level (30.30%), and lymphopenia (27.27%). Brain imaging did not produce any pathological findings in 51.51% of the cases. Electroencephalography showed generalized slowing in 45.45% of the cases. Elevated protein (42.42%) and lymphocytosis (24.24%) were found in the cerebrospinal fluid. Fifteen patients were reportedly discharged from the hospital in a stable condition, while four cases of mortality were recorded.ConclusionsThe clinical, laboratory, and imaging findings in this review support the hypothesis that cerebral damage in COVID-19-associated encephalopathy is caused by cytokine-immune-mediated inflammation rather than by direct invasion.     

Potential mechanisms of cerebrovascular diseases in COVID-19 patients

Journal of NeuroVirology - Since the outbreak of coronavirus disease 2019 (COVID-19) in 2019, it is gaining worldwide attention at the moment. Apart from respiratory manifestations, neurological...     

Investigating the potential mechanisms of depression induced-by COVID-19 infection in patients

The new coronavirus (COVID-19) has emerged now in the world as a pandemic. The SARS-CoV-2 infection causes variant common symptoms, such as dry cough, tiredness, dyspnea, fever, myalgia, chills, headache, chest pain, and conjunctivitis. Different organs may be affected by COVID-19, such as the respiratory system, gastrointestinal tract, kidneys, and CNS. However, the information about the COVID-19 infection in the CNS is insufficient. We do know that the virus can enter the central nervous system (CNS) via different routes, causing symptoms such as dizziness, headache, seizures, loss of consciousness, and depression. Depression is the most common disorder among all neurological symptoms following COVID-19 infection, although the mechanism of COVID-19-induced depression is not yet clear.The aim of the present study is to investigate the probable mechanisms of COVID-19-induced depression.The reasons for depression in infected patients may be due to social and pathological factors including social quarantine, economic problems, stress, changes in the HPA axis, inflammation due to the entry of proinflammatory cytokines into the CNS, production of inflammatory cytokines by microglia, mitochondrial disorders, damage to the hippocampus, and malnutrition.By evaluating different factors involved in COVID-19-induced depression, we have concluded that depression can be minimized by controlling stress, preventing the cytokine storm with appropriate anti-inflammatory drugs, and proper nutrition.