key: cord-284829-dge21g0g
authors: Dinakaran, Damodharan; Manjunatha, Narayana; Naveen Kumar, Channaveerachari; Suresh, Bada Math
title: Neuropsychiatric aspects of COVID-19 Pandemic: A Selective Review
date: 2020-05-30
journal: Asian J Psychiatr
DOI: 10.1016/j.ajp.2020.102188
sha: 
doc_id: 284829
cord_uid: dge21g0g

Corona virus disease (COVID-19) has been declared as a controllable pandemic by the World Health Organization (WHO). COVID-19 though is a predominantly respiratory illness; it can also affect brain and other organs like kidneys, heart and liver. Neuropsychiatric manifestations are common during viral pandemics but are not effectively addressed. Fever and cough are common symptoms only in infected individuals but headache and sleep disturbances are common even in uninfected general public. In this selective review, the authors report the available evidence of neuropsychiatric morbidity during the current COVID-19 crisis. The authors also discuss the postulated neuronal mechanisms of the corona virus infection sequelae.

A meta-analysis conducted on the studies from the current outbreak had suggested that fever (88%) and cough (58%) are predominant complaints and overall 20% of the infected individuals needed intensive care unit admission (1). Hypertension (17%), diabetes (8%) and cardiovascular diseases (5%) were common co-morbidities (2) . Bilateral pneumonia on chest radiograph (ground glass pattern) (73%), decreased albumin (78%), High C-reactive pattern (58%), high lactate dehydrogenase (57%) and lymphopenia (43%) were the prevalent laboratory findings (1). Early reports on case fatality rates varies widely between 0.15% and 5% (3) . Though emerging reports are reassuring, it is important to note that not all the countries across the world are adequately enabled to provide effective responses against the virus (4, 5) . Global coordination is important to provide a coherent response to this challenge (5) . It is essential to understand the varied presentation of this illness to equip oneself to handle the potential crisis. In this selective review, the authors present the neuropsychiatric manifestations and postulated mechanisms of COVID-19.

The authors searched PUBMED and EBSCO independently with the following search terms "COVID-19" "AND", "Neurology", "Mental health", "Neuropsychiatry", "Delirium" and "Psychosis". The authors identified 188 manuscripts. The search was restricted to manuscripts in English language and time (till May 8 th 2020). After removing duplications, review articles, commentaries, opinion letters and manuscripts not relevant to neuropsychiatry, animal studies, and other newer manuscripts from cross-references were added and the total unique manuscripts identified for the final review were "12". Synthesis of information from these manuscripts is provided below.

Neurological manifestations could be secondary to direct neuroinvasion by the corona virus. Similar to many respiratory viruses, Corona viruses are observed to have direct effects on neuronal systems (6) (7) (8) . The spread could happen through haematogenous route but most commonly reported entry is through the olfactory neural pathway (9) . This invasion could result in meningitis, encephalopathy or at minor instances seizures (7, 10). Direct invasion might be possible through the activation of Angiotensin Converting Enzyme 2 (ACE-2) receptor expressed in both capillary and neuronal endothelium (9, 11) . Secondary immune alterations are hypothesized to underlie the chronic neuropsychiatric sequelae (12) (13) (14) . Dysregulated immune response that might result in excessive inflammation is postulated to play an important role in the severity of the infection (13, 15) . Possible direct medullary neuron destruction might precipitate respiratory failure in severely ill patients (16, 17) . Altered sensorium or delirium might be secondary to direct neuroinvasion by virus, central immune activation, secondary to multi organ failure, hypoxia, metabolic derangements and treatment related (9, 18) . Additionally, patients also exhibit increased prothrombin time and coagulopathy that ultimately might contribute to thrombosis or hemorrhage (19) .

Stress during virus outbreak is postulated to activate hypothalamo-pituitary-adrenal axis releasing increased levels of steroids. Steroids released impairs the immune system functioning and might precipitate the infection or worsen the severity. Viral infection further leads to neurasthenia and chronic fatigue. Psychiatric symptoms could also manifest secondary to side effects of drugs used to treat COVID-19 like oseltamivir, corticosteroids and interferons (20) (21) (22) . A pharmacovigilance study had reported significant neuropsychiatric adverse effects like amnesia, delirium, hallucinations, depression and loss of consciousness associated with exposure to chloroquine (23) . Chloroquine and other antiviral drugs can cause toxic neuropathy and myopathy (24, 25) .

SARS-CoV-2 virus is primarily a respiratory virus that has a predilection towards lower respiratory tract. Though the most common presentation is a self limiting viral illness with fever and dry cough, severe infection is reported in 15-20% of the affected population (26) . Lungs are involved in more than two-thirds of patients with severe infection. Pneumonia with ground glass opacities in middle and lower lobes of lungs are reportedly characteristic of the infection. In about 5% of the severely ill patients, Acute Respiratory Distress Syndrome (ARDS), Multi organ involvement and septic shock leads to further clinical deterioration. Case fatality rate ranges between 2-3% and elderly individuals with medical co-morbidities are more vulnerable to develop fatal illness (26) . Other organs involved include but not limited to kidneys, liver and heart. These organs are involved in about 15-30% of severely ill patients (27) .

Headache and myalgia are commonly noted in COVID-19. In mild to moderate infection, headache, altered smell and taste, cough, asthenia and myalgia are the most common symptoms (28) . There are reports of encephalopathy (29) , encephalitis (30), meningitis (31), stroke (32-35), seizures, dysexecutive syndrome, neuromuscular disorders, Guillain Barre syndrome and other neuropathies. Neurological manifestations are reported in one hospital based study from China (36) . 78 out of 214 admitted patients (36%) were identified to exhibit one or more neurological symptoms. Such presentations were analyzed broadly under illness effects on central nervous system, peripheral nervous system and musculo-skeletal system. Central nervous system symptoms include dizziness (16%), headache (13%), altered sensorium (8%) and cerebro vascular events (3%). Reduced taste (5%) and reduced smell (5%) perceptions are peripheral nervous system manifestations. Myalgia with significant muscle injury happened in 12% of admitted patients (36) .

A multicentre European study had reported olfactory and gustatory dysfunction in 85% and 88% of mild/moderately ill patients respectively (37) . Smell and taste disorders were reportedly more common in COVID-19 patients than in influenza (38). Acute brainstem dysfunction has been reported during the 2 nd week of COVID-19 illness (30) . Aberrant immune response to COVID-19 might lead to neuro-ophthalmological manifestations like Miller-Fisher Syndrome and polyneuritis cranialis (39, 40). Acute polyradiculopathy (Guillain Barre Syndrome -GBS) has been reported related to SARS-CoV-2 infection (41) (42) (43) (44) (45) (46) . Another study from China had showed that among the deceased patients, 22% had altered sensorium and 20% exhibited features of hypoxic encephalopathy (47) .

The neuropsychiatric sequelae of currently evolving COVID-19 pandemic are still unclear. However, there is a growing concern about a crashing wave of neuropsychiatric burden (48) . Such neuropsychiatric manifestations include encephalopathy (49) , delirium (50) (51) (52) (53) , mild cognitive impairment (54) , mood swings (31), insomnia (55, 56) , suicide (57) and psychosis (48, 57, 58) . Existing evidence suggest 0.9-4% of infected individuals develop psychotic spectrum disorders. Psychosis may be secondary to viral illness, treatment provided and increased psychosocial stress during pandemics (59). Neuropsychiatric sequelae of COVID-19 are discussed in Table- 1.

Patients with pre-existing mental illness who develop COVID-19 and individuals developing mental health concerns during the pandemic are advised to be treated with psychotropic drugs along with the standard treatment for the viral illness. The following drugs are suggested as safe considering the tolerability and minimal drug interactions: Benzodiazepines (oxazepam and lorazepam), antidepressants (citalopram and escitalopram), antipsychotics (olanzapine) and mood stabilizer (valproate) (60) . Delirium is one of the atypical presentations of the COVID-19 illness (52) . In most instances, delirium is poorly assessed and inadequately intervened (18, 61). Assessment using a standard tool and identifying the precipitating factors are essential in delirium management (62). Benzodiazepines are to be avoided and among antipsychotics, quetiapine is preferred especially in elderly (62) and oral haloperidol (0.5-1mg) otherwise (63) . Additionally, melatonin is suggested for sleep wake rhythm and consciousness disturbances and in severely ill individuals (64) .

The COVID-19 pandemic is still evolving and the medical fraternity is posed with huge challenge. Neurological manifestations are common. Immune alterations, hypoxic brain injury, available treatment options and psychosocial stress might potentially lead to a wave of neuropsychiatric sequelae. Improved attention to the possible neuropsychiatric consequences of SARS-CoV-2 viral infection might aid in early identification and better management.

Financial disclosure: Nil

No funding or research grant was received in the course of study, research or assembly of the manuscript titled "Neuropsychiatric aspects of COVID-19 Pandemic: A Selective Review"

Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel medicine and infectious disease

Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis

Early estimation of the case fatality rate of COVID-19 in mainland China: a data-driven analysis

Health security capacities in the context of COVID-19 outbreak: an analysis of International Health Regulations annual report data from 182 countries. The Lancet

The COVID-19 pandemic, personal reflections on editorial responsibility

Human coronaviruses: viral and cellular factors involved in neuroinvasiveness and neuropathogenesis

Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System? Viruses

Does SARS-Cov-2 invade the brain? Translational lessons from animal models

Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, behavior, and immunity. 2020. 10

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Coronavirus immunoreactivity in individuals with a recent onset of psychotic symptoms

Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Neurological Implications of COVID-19

Letter to the Editor Regarding the Viewpoint "Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanism

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

COVID-19: what if the brain had a role in causing the deaths? European journal of neurology

COVID-19: ICU delirium management during SARS-CoV-2 pandemic

Potential neurological symptoms of COVID-19

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. The Lancet

Analysis of Neuropsychiatric Adverse Events in Patients Treated with Oseltamivir in Spontaneous Adverse Event Reports

Neuropsychiatric Symptoms in the Pediatric Population After Administration of Oseltamivir

Neuropsychiatric adverse events of chloroquine: a realworld pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database. Bioscience trends

A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine

Clinical and Epidemiological Characteristics of 1,420 European Patients with mild-to-moderate Coronavirus Disease

Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy. Cureus

Lessons of the month 1: A case of rhombencephalitis as a rare complication of acute COVID-19 infection

Emergency Room Neurology in times of COVID-19: Malignant Ischemic Stroke and SARS-COV2 Infection

Characteristics of ischaemic stroke associated with COVID-19

COVID-19 presenting as stroke. Brain, behavior, and immunity

Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study

Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study

Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study

Miller Fisher Syndrome and polyneuritis cranialis in COVID-19

COVID-19 presenting with ophthalmoparesis from cranial nerve palsy

Guillain-Barre syndrome following COVID-19: new infection, old complication? Journal of neurology

Guillain-Barre syndrome related to COVID-19 infection

Covid-19 and Guillain-Barre syndrome: More than a coincidence! Revue neurologique

COVID-19 may induce Guillain-Barre syndrome. Revue neurologique

Guillain-Barre syndrome associated with SARS-CoV-2 infection: causality or coincidence? The Lancet Neurology

Guillain Barre syndrome associated with COVID-19 infection: A case report

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain, behavior, and immunity

Encephalitis as a clinical manifestation of COVID-19. Brain, behavior, and immunity

A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases

COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features

A Unique Presentation of Delirium in a Patient with Otherwise Asymptomatic COVID-19

Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles

Neurologic features in severe SARS-CoV-2 infection

Do psychiatric patients experience more psychiatric symptoms during COVID-19 pandemic and lockdown? A case-control study with service and research implications for immunopsychiatry

Severe psychological distress among epilepsy patients during the COVID-19 outbreak in southwest China

Reactive psychoses in the context of the COVID-19 pandemic: Clinical perspectives from a case series

Psychosis in a patient with anxiety related to COVID-19: A case report

The potential impact of COVID-19 on psychosis: A rapid review of contemporary epidemic and pandemic research

Treatment concerns for psychiatric symptoms in patients with COVID-19 with or without psychiatric disorders. The British journal of psychiatry : the journal of mental science

MANAGEMENT OF OLDER PEOPLE DURING THE COVID-19 OUTBREAK: RECOMMENDATIONS FROM AN ITALIAN EXPERIENCE

Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines

Delirium and sleep disturbances in COVID-19: a possible role for melatonin in hospitalized patients? Sleep Medicine

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