key: cord-0970233-63sj611c
authors: Forero‐Peña, David A.; Hernandez, Matthew M.; Mozo Herrera, Iriana Paola; Collado Espinal, Iván Bolívar; Páez Paz, Joselyn; Ferro, Carlos; Flora‐Noda, David M.; Maricuto, Andrea L.; Velásquez, Viledy L.; Camejo‐Avila, Natasha A.; Sordillo, Emilia M.; Delgado‐Noguera, Lourdes A.; Perez‐Garcia, Luis A.; Morantes Rodríguez, Carlos G.; Landaeta, María Eugenia; Paniz‐Mondolfi, Alberto E.
title: Remitting neuropsychiatric symptoms in COVID‐19 patients: Viral cause or drug effect?
date: 2021-11-19
journal: J Med Virol
DOI: 10.1002/jmv.27443
sha: 4a655e740adc895d83c44f90ca2960294aa70da2
doc_id: 970233
cord_uid: 63sj611c

Numerous reports of neuropsychiatric symptoms highlighted the pathologic potential of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and its relationship the onset and/or exacerbation of mental disease. However, coronavirus disease 2019 (COVID‐19) treatments, themselves, must be considered as potential catalysts for new‐onset neuropsychiatric symptoms in COVID‐19 patients. To date, immediate and long‐term neuropsychiatric complications following SARS‐CoV‐2 infection are currently unknown. Here we report on five patients with SARS‐CoV‐2 infection with possible associated neuropsychiatric involvement, following them clinically until resolution of their symptoms. We will also discuss the contributory roles of chloroquine and dexamethasone in these neuropsychiatric presentations.

In March 2020, a 58-year-old male pilot with no remarkable clinical history presented to the University Hospital of Caracas (UHC), Venezuela, with 6 days of fever (between 38.3°C and 39°C), headache, dry cough, and dysgeusia. Three weeks prior, he traveled to Spain, Dominican Republic, and Trinidad and Tobago before returning to Caracas. His wife reported that the family had noticed changes in the patient's behavior, including intermittent anxiety and logorrhea. At presentation (Day 0), the patient was fully alert, was auto-and allopsychic oriented, and had an unremarkable neurologic examination. A nasopharyngeal specimen was submitted to the Rafael Rangel National Hygiene Institute, where SARS-CoV-2 infection was confirmed using real-time reverse transcription polymerase chain reaction (rRT-PCR). The patient was managed supportively as an outpatient, and his fever and respiratory symptoms were selflimited and resolved at Day 5. However, at Day 12, he returned to the hospital and presented with increased anxiety. He was afebrile (36.5°C) and vital signs were stable. A repeat nasopharyngeal specimen was still positive for SARS-CoV-2, and he was admitted. He was treated with CQ 155 mg orally every 12 h for 7 days, plus enoxaparin 40 mg subcutaneously every 24 h for 10 days, per Venezuelan Ministry of Health guidelines. 4 During his hospital course, he remained afebrile, and his vital signs were stable. However, he demonstrated increased anxiety and spent multiple hours on his smartphone researching COVID-19 disease and believed he understood the detailed mechanisms of his infection; however, he was not evaluated by psychiatry during his course. He was discharged at Day 26 after two consecutive nasal swabs tested negative for SARS-CoV-2.

At Day 56, the patient was brought back to the hospital by his wife, who reported worsening psychiatric symptoms since the previous discharge. Specifically, he presented with insomnia, pressured rate of speech, and logorrhea and recently had developed ideas of self-harm and grandiose delusions which warranted readmission. Of note, additional history revealed that he had been hospitalized 30 years prior for similar manic symptoms, but was discharged without a definitive diagnosis there were no recurrences of psychiatric symptoms until the current episode.

At initial evaluation, the patient was afebrile and vital signs were stable (Table 1 ). In addition, the patient was oriented to person, place, and time, but he was hyperalert and restless. Although he was cooperative, his speech was loud, jittery, reiterative, logorrheic, and abnormally fast. He presented with an inappropriately elevated mood commenting he was "better than ever" and with grandiose delusions remarking he was "like God" and "[had] the cure for the COVID-19 pandemic." He also experienced delusions characterized by a belief that the government and healthcare workers sought to persecute him for his reportedly extensive knowledge about COVID-19. The patient was evaluated by psychiatry, who diagnosed him with a moderate manic episode, and he was initially treated with intramuscular diazepam 5 mg. A head magnetic resonance imaging (MRI) study showed no abnormalities, and cerebrospinal fluid (CSF) analysis was unremarkable for abnormalities in cell count or protein.

CSF and repeat samples from the nasopharynx were negative for SARS-CoV-2 by rRT-PCR. 5, 6 Of note, given that it was not possible to hospitalize him due to administrative limitations, he was discharged with a diagnosis of bipolar I disorder. He was treated on an outpatient basis with risperidone 2 mg orally every 12 h, valproic acid 500 mg orally every 12 h, and clonazepam 2 mg orally every 24 h. He adhered to this medical regimen and his symptoms resolved completely 1 month after discharge. subtypes have been associated with chronic demyelinating diseases such as multiple sclerosis. 10, 11 Currently, studies that investigate the psychiatric impacts of delirium, 20 acute mania, 21 or acute psychosis. 16, 17 In this case series, we report several scenarios which highlight the onset of neuropsychiatric symptoms due to direct central ner- 

The neurologic pathogenesis and neurotropic potential of SARS-CoV-2 remain unclear. In addition to the wide distribution in the lungs, intestines, endothelium, and kidneys, the host cell receptor for SARS-CoV-2angiotensin converting enzyme 2 (ACE2)-has been identified in neurons, glia, and blood-brain barrier (BBB) capillary cells in the CNS. 22, 23 In addition, neuropilin-1 (NRP-1), which has been described as an alternative viral receptor to host cell entry, 24, 25 is found in the olfactory epithelium. 24 Given that SARS-CoV-1 has been shown to enter CNS cells, 26 it is attractive to speculate the same ability of SARS-CoV-2 particularly because of its high sequence homology to the SARS-CoV-1 receptor-binding domain. 27 Indeed, SARS-CoV-2 has demonstrated in vitro infectivity of human brain organoids 23 and in vivo infectivity of mice expressing human ACE2. 28 Moreover, the presence of blebbing viral particles in BBB endothelial cells and adjacent frontal lobe neurons suggests that SARS-CoV-2 could also disseminate hematogenously via paracellular, transcellular, or "trojan horse" mechanisms to reach the CNS and cause direct cytopathic effects. 29 and exacerbated cytotoxicity has been described in COVID-19 patients, 33 which have been associated with the onset of neurological and neuropsychiatric symptoms. 34 This pathogenic mechanism parallels the increased levels of acute-phase reactants (e.g., CRP) seen in previous case reports 15, 16 as well as two of the five patients presented (#2, #5) in this case series. Neuropsychiatric symptoms, including psychosis, grandiose delusions, paranoia, hallucinations, and even suicidality, have been described up to 8 weeks after ceasing CQ treatment. 37, 38 The pathogenesis of CQ-induced psychosis may be mediated-at least in part-by its dopaminergic, serotoninergic, and antimuscarinic effects in the CNS. 39 Cases of CQ-induced mania may present as druginduced psychosis, or behave more like an affective disorder. 40 Although most psychiatric side effects of CQ and hydroxychloroquine have been described in the setting of rheumatologic disease treatment, 38 two case reports describe psychosis and anxiety in COVID-19 patients treated with CQ, 41 and a global pharmacovigilance study found the use of hydroxychloroquine was associated with an increased risk of psychiatric disorders. 42 Interestingly, in four of the five patients presented (#1, #3, #4, and #5), the rapid onset of symptoms after initiation of the drug and remission shortly after discontinuation, support CQ as a potential trigger for their neuropsychiatric symptoms; however, the direct impacts of direct CNS infection by SARS-CoV-2 or the indirect effects of neuroinflammation secondary to COVID-19 cannot be excluded.

In the hyperinflammatory setting of SARS-CoV-2 infection, corticosteroids have been proposed as a component of treatment.

Although multiple studies have demonstrated their utility in treatment in the inpatient setting, 43, 44 its use has the potential to induce acute psychosis. 45, 46 Corticosteroid-induced psychosis is a rare but well-known disorder classified as a form of substance/medicationinduced psychotic disorder in the "Diagnostic and Statistical Manual of Mental Disorder". 47 Its pathophysiology remains poorly understood, but it is presumed to originate from an imbalance between glucocorticoid stimulation and mineralocorticoid receptor stimulation 48 and may be the result of glutamate-induced neuronal toxicity. 49 The majority of these patients usually develop symptoms within the first 2 weeks after initiation of corticosteroid therapy and cases are usually self-remitting after discontinuation of therapy, similar to what we observed in two of our cases (#2 and #4). 

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