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.

Systemic Inflammation Is Associated With Neurologic Involvement in Pediatric Inflammatory Multisystem Syndrome Associated With SARS-CoV-2.

OBJECTIVE: Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a severe immune-mediated disorder. We aim to report the neurologic features of children with PIMS-TS. METHODS: We identified children presenting to a large children's hospital with PIMS-TS from March to June 2020 and performed a retrospective medical note review, identifying clinical and investigative features alongside short-term outcome of children presenting with neurologic symptoms. RESULTS: Seventy-five patients with PIMS-TS were identified, 9 (12%) had neurologic involvement: altered conciseness (3), behavioral changes (3), focal neurology deficits (2), persistent headaches (2), hallucinations (2), excessive sleepiness (1), and new-onset focal seizures (1). Four patients had cranial images abnormalities. At 3-month follow-up, 1 child had died, 1 had hemiparesis, 3 had behavioral changes, and 4 completely recovered. Systemic inflammatory and prothrombotic markers were higher in patients with neurologic involvement (mean highest CRP 267 vs 202 mg/L, p = 0.05; procalcitonin 30.65 vs 13.11 µg/L, p = 0.04; fibrinogen 7.04 vs 6.17 g/L, p = 0.07; d-dimers 19.68 vs 7.35 mg/L, p = 0.005). Among patients with neurologic involvement, these markers were higher in those without full recovery at 3 months (ferritin 2284 vs 283 µg/L, p = 0.05; d-dimers 30.34 vs 6.37 mg/L, p = 0.04). Patients with and without neurologic involvement shared similar risk factors for PIMS-TS (Black, Asian and Minority Ethnic ethnicity 78% vs 70%, obese/overweight 56% vs 42%). CONCLUSIONS: Broad neurologic features were found in 12% patients with PIMS-TS. By 3-month follow-up, half of these surviving children had recovered fully without neurologic impairment. Significantly higher systemic inflammatory markers were identified in children with neurologic involvement and in those who had not recovered fully.

COVID-19-related neuropathology and microglial activation in elderly with and without dementia.

The actual role of SARS-CoV-2 in brain damage remains controversial due to lack of matched controls. We aim to highlight to what extent is neuropathology determined by SARS-CoV-2 or by pre-existing conditions. Findings of 9 Coronavirus disease 2019 (COVID-19) cases and 6 matched non-COVID controls (mean age 79 y/o) were compared. Brains were analyzed through immunohistochemistry to detect SARS-CoV-2, lymphocytes, astrocytes, endothelium, and microglia. A semi-quantitative scoring was applied to grade microglial activation. Thal-Braak stages and the presence of small vessel disease were determined in all cases. COVID-19 cases had a relatively short clinical course (0-32 days; mean: 10 days), and did not undergo mechanical ventilation. Five patients with neurocognitive disorder had delirium. All COVID-19 cases showed non-SARS-CoV-2-specific changes including hypoxic-agonal alterations, and a variable degree of neurodegeneration and/or pre-existent SVD. The neuroinflammatory picture was dominated by ameboid CD68 positive microglia, while only scant lymphocytic presence and very few traces of SARS-CoV-2 were detected. Microglial activation in the brainstem was significantly greater in COVID-19 cases (p = 0.046). Instead, microglial hyperactivation in the frontal cortex and hippocampus was clearly associated to AD pathology (p = 0.001), regardless of the SARS-CoV-2 infection. In COVID-19 cases complicated by delirium (all with neurocognitive disorders), there was a significant enhancement of microglia in the hippocampus (p = 0.048). Although higher in cases with both Alzheimer's pathology and COVID-19, cortical neuroinflammation is not related to COVID-19 per se but mostly to pre-existing neurodegeneration. COVID-19 brains seem to manifest a boosting of innate immunity with microglial reinforcement, and adaptive immunity suppression with low number of brain lymphocytes probably related to systemic lymphopenia. Thus, no neuropathological evidence of SARS-CoV-2-specific encephalitis is detectable. The microglial hyperactivation in the brainstem, and in the hippocampus of COVID-19 patients with delirium, appears as a specific topographical phenomenon, and probably represents the neuropathological basis of the "COVID-19 encephalopathic syndrome" in the elderly.

Emerging Evidence for Neuropsycho-Consequences of COVID-19.

The pandemic novel coronavirus disease (COVID-19) has become a global concern in which the respiratory system is not the only one involved. Previous researches have presented the common clinical manifestations including respiratory symptoms (i.e., fever and cough), fatigue and myalgia. However, there is limited evidence for neurological and psychological influences of SARS-CoV-2. In this review, we discuss the common neurological manifestations of COVID-19 including acute cerebrovascular disease (i.e., cerebral hemorrhage) and muscle ache. Possible viral transmission to the nervous system may occur via circulation, an upper nasal transcribrial route and/or conjunctival route. Moreover, we cannot ignore the psychological influence on the public, medical staff and confirmed patients. Dealing with public psychological barriers and performing psychological crisis intervention are an important part of public health interventions.

Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 "long haulers".

OBJECTIVE: Most SARS-CoV-2-infected individuals never require hospitalization. However, some develop prolonged symptoms. We sought to characterize the spectrum of neurologic manifestations in non-hospitalized Covid-19 "long haulers". METHODS: This is a prospective study of the first 100 consecutive patients (50 SARS-CoV-2 laboratory-positive (SARS-CoV-2+ ) and 50 laboratory-negative (SARS-CoV-2- ) individuals) presenting to our Neuro-Covid-19 clinic between May and November 2020. Due to early pandemic testing limitations, patients were included if they met Infectious Diseases Society of America symptoms of Covid-19, were never hospitalized for pneumonia or hypoxemia, and had neurologic symptoms lasting over 6 weeks. We recorded the frequency of neurologic symptoms and analyzed patient-reported quality of life measures and standardized cognitive assessments. RESULTS: Mean age was 43.2 ± 11.3 years, 70% were female, and 48% were evaluated in televisits. The most frequent comorbidities were depression/anxiety (42%) and autoimmune disease (16%). The main neurologic manifestations were: "brain fog" (81%), headache (68%), numbness/tingling (60%), dysgeusia (59%), anosmia (55%), and myalgias (55%), with only anosmia being more frequent in SARS-CoV-2+ than SARS-CoV-2- patients (37/50 [74%] vs. 18/50 [36%]; p < 0.001). Moreover, 85% also experienced fatigue. There was no correlation between time from disease onset and subjective impression of recovery. Both groups exhibited impaired quality of life in cognitive and fatigue domains. SARS-CoV-2+ patients performed worse in attention and working memory cognitive tasks compared to a demographic-matched US population (T-score 41.5 [37, 48.25] and 43 [37.5, 48.75], respectively; both p < 0.01). INTERPRETATION: Non-hospitalized Covid-19 "long haulers" experience prominent and persistent "brain fog" and fatigue that affect their cognition and quality of life.

Persons with Co-Existing Neurological Disorders: Risk Analysis, Considerations and Management in COVID-19 Pandemic.

Increasing reports of neurological symptoms in COVID-19 patient's warrant clinicians to adopt and define the standardized diagnostic and managing protocols in order to investigate the linkage of neurological symptoms in COVID-19. Encephalitis, anosmia, acute cerebrovascular disease and ageusia are some of the emerging neurological manifestations which are reported in several cohort studies on hospitalized patients with COVID-19. Although the COVID-19 pandemic is primarily associated with infection of the respiratory tract system, but measures like lockdown and restricted physical movements to control the spread of this infection will certainly have neurobehavioural implications. Additionally, some of the patients with pre-existing neurological manifestations like epilepsy, Parkinson's and Alzheimer's disease are more prone to infection and demand extra care as well as improvised treatment. In this review, we have focused on the neurovirological clinical manifestations associated with the COVID-19 pandemic. Although the prevalence of neurovirological manifestations is rare increasing reports cannot be ignored and needs to be discussed thoroughly with respect to risk analysis and considerations for developing a management strategy. This also helps in defining the burden of neurological disorders associated with COVID-19 patients.

Manifestations and impact of the COVID-19 pandemic in neuroinflammatory diseases.

OBJECTIVE: To report initial results of a planned multicenter year-long prospective study examining the risk and impact of COVID-19 among persons with neuroinflammatory disorders (NID), particularly multiple sclerosis (MS). METHODS: In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of suspected COVID-19 in persons with NID (PwNID) and change in their neurological care. RESULTS: Our cohort included 1115 participants (630 NID, 98% MS; 485 reference) as of 30 April 2020. 202 (18%) participants, residing in areas with high COVID-19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID-19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID-19 were younger, more racially diverse, and reported more depression and liver disease. PwNID had the same rate of suspected COVID-19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of PwNID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID-19 (ORadj  = 1.45, 1.17-1.84). INTERPRETATIONS: Our study of real-time, patient-reported experience during the COVID-19 pandemic complements physician-reported MS case registries which capture an excess of severe cases. Overall, PwNID seem to have a risk of suspected COVID-19 similar to the reference population.

The Brain on COVID-19.

In March 2020 -still the early days of the U.K.'s COVID-19 crisis-Rhys Thomas, a neurologist at Newcastle University, got a call at home from a concerned colleague. The colleague's cousin was hospitalized, critically ill with COVID-19, and had developed brainstem encephalitis, a severe inflammatory condition of the brain causing a suite of symptoms, from eye problems to balance problems and drowsiness. He wanted to know if Thomas knew anything about these conditions. At the time, the research coming out of Wuhan, China, only suggested a mild whiff of neurological symptoms-headache, dizziness, and the loss of taste and smell. Clearly the virus could affect the brain in some ways, but it wasn't, Thomas thought then, anything serious. But this report sounded much more concerning. Symptoms like this patient's would mean the virus was accessing more of the nervous system than scientists originally thought.

Changes of perceptions and behaviours during the phases of COVID-19 pandemic in German elderly people with neurological disorders: an observational study using telephone interviews.

OBJECTIVES: Describing perceived limitations in everyday life, psychological burden and approval to easing of measures during the COVID-19 phases in elderly people with neurological disorders. DESIGN: Observational, prospective study SETTING: This is a monocentric study conducted at a university hospital in Germany. PARTICIPANTS: Overall, 452 elderly people participated in the NeuroGerAdh study (DRKS00016774) and were interviewed by telephone between 18 March and 30 August 2020. RESULTS: Overall, 307 (67.9%) patients had relevant limitations in daily life due to the measures. These limitations significantly decreased during the pandemic phases. At the beginning of the pandemic, people complained about restricted social contacts and mobility, which were the most common reasons for perceived limitations in daily life. Later, since June 2020, wearing a mouth-nose mask had become the main reason for perceived limitations. In the elastic net regularisation, model higher perceived limitations in daily life were among others associated with younger age and earlier pandemic phases. Higher psychological burden was mainly associated with early pandemic phase, younger age and depression.The perceived psychological burden decreased as the pandemic phases passed, even though the reasons for psychological burden (anxiety or fear of infection, insecurity and concerns) did not remarkably change during the phases. From 16 June 2020, the patients were asked whether they approve the easing of measures. Sixty-seven of 136 patients (49.3%) approved and 55 (40.4%) did not. The common reasons for disapproval were fear of increased risk of infection and irresponsible behaviour of other people. CONCLUSION: While limitations in daily life decreased during the study period, anxiety remains a common psychological burden in elderly sick people, and this needs special attention. Accordingly, most people do not approve easing of measures. Special strategies are needed to cope with changing measures during the COVID-19 pandemic.

Environmental Issues and Neurological Manifestations Associated with COVID-19 Pandemic: New Aspects of the Disease?

Coronavirus (SARS-CoV-2) emerged in China in December 2019 and rapidly caused a global health pandemic. Current evidence seems to suggest a possible link with ecosystem disequilibrium and even air pollution. The primary manifestations affect respiratory and circulatory systems, but neurological features are also being reported through case reports and case series. We summarize neurological symptoms and complications associated with COVID-19. We have searched for original articles published in PubMed/Medline, PubMed Central and Google Scholar using the following keywords: "COVID-19", "Coronavirus", "pandemic", "SARS-COV-2", "neurology", "neurological", "complications" and "manifestations". We found around 1000 publications addressing the issue of neurological conditions associated with COVID-19 infection. Amongst those, headache and dizziness are the most common reported symptoms followed by encephalopathy and delirium, while the most frequent complications are cerebrovascular accidents, Guillain-Barré syndrome, acute transverse myelitis, and acute encephalitis. Specific symptoms affecting the peripheral nervous system such as hyposmia and dysgeusia are the most common manifestations recorded in the selected studies. Interestingly, it was noted that these kinds of neurological symptoms might precede the typical features, such as fever and cough, in COVID patients. Neurological symptoms and complications associated with COVID-19 should be considered as a part of the clinical features of this novel global pandemic.

The psychiatric and neuropsychiatric repercussions associated with severe infections of COVID-19 and other coronaviruses.

INTRODUCTION: It is known that viral infections are epidemiologically prevalent and some of them are harmful to the central nervous system (CNS) due to the development of neuropsychiatric syndromes which affect the cognitive, affective, behavioral and perceptual domains. OBJECTIVE: To carry out a comprehensive analysis of the psychiatric and neuropsychiatric repercussions of COVID-19 based on epidemiological, pathophysiological and clinical foundations observed in previous and recent pandemic events, and also to make a proposition about effective therapeutic interventions to help tackle this serious public health problem, more specifically in its neuropsychiatric developments. METHOD: This current literature review has utilized literature reserves and scientific search engines MEDLINE, EMBASE and Web of Science. The search terms included, "SARS-CoV-2", "etiology," "psychiatric and neuropsychiatric repercussions", "severe infections" "COVID-19". Specific choices of unique papers from each of the searches were identified. The inclusion criteria were relevance and availability of full-text. Papers were excluded on the basis of relevance and non-availability of full-text. Papers were identified in the general literature reserve as pertinent to the search terms. RESULTS: The main psychiatric and neuropsychiatric repercussions analyzed were depression, anxiety, post-traumatic stress disorder, psychosis, nonspecific neurological symptoms, delirium, cerebrovascular complications, encephalopathies, neuromuscular disorders, anosmia and ageusia. CONCLUSION: The psychiatric and neuropsychiatric symptoms of acute respiratory syndromes can appear during or after the infectious stage. Among the risk factors pointed out for such effects are the female gender, health professionals, presence of avascular necrosis and distressing pain.

Dyspnea perception and neurological symptoms in non-severe COVID-19 patients.

INTRODUCTION: The relationship between dyspnea and COVID-19 is unknown. In COVID-19 patients, the higher prevalence of neurological symptoms and the lack of dyspnea may suggest common underlying pathogenetic mechanisms. The aim of this preliminary study is to address whether there is a lack of dyspnea in COVID-19 patients and if there is a relationship between neurological symptoms and the perception of dyspnea. METHODS: A structured interview regarding the occurrence of subjective neurological symptoms was performed and coupled with a questionnaire about the intensity and qualities of dyspnea. Respiratory rate (RR) and an arterial blood gas on room air were concurrently evaluated. RESULTS: Twenty-two patients (age 68.4 ± 13.9 years, 13 males and 9 females) were included and divided into two groups according to the Borg dyspnea scale: dyspneic patients BU ≥ 1(DYSP) and non-dyspneic patients BU < 1 (NDYSP). The prevalence of dyspnea overall was 31.8%. The prevalence of neurological symptoms, dyspnea descriptors, RR, pH, PaCO2, PaO2, or lactate was similar between groups. CONCLUSION: This study confirms that the prevalence of dyspnea is low in non-severe COVID-19 patients, but contrary to our hypothesis of a relationship between shortness of breath and neurological symptoms, we have not been able to find any evidence of an impairment in dyspnea perception, either in the DYSP or NDYSP group.