On the plausibility of late neuropsychiatric manifestations associated with the COVID-19 pandemic

Highlights

• •Virus-host interactions in COVID-19 pandemic is a substrate for the emergence of late neurological manifestations
• •Occurrence subacute autoimmune disorders after COVID-19 suggests the risk of late neurological autoimmune disturbance
• •Global monitoring is important to uncover emergence of late neuropsychiatric manifestations

Dear Sir

Recognition of the association between acute and subacute different neuropsychiatric manifestations with the infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic, is progressively being recognized [1]. The potential emergence of late onset neuropsychiatric manifestations after infection with SARS-CoV-2 remains to be discussed. After the “Spanish” influenza pandemic in the 20th century, an outbreak of encephalitis lethargica (EL) [2], a neuropsychiatric disorder of possible autoimmune origin emerged occurring soon after the acute phase or at some time later [3]. It's worthwhile to highlight that manifestations of EL such as sleep disturbance, fatigue, psychosis, catatonia, movement disorders among others were identified in previous historical epidemics since the 15th century [3]. Molecular mimicry leading to damage of the brainstem respiratory pace-maker [4] and occurrence of neurological autoimmune disorders after SARS-CoV-2 infection (Gillian Barré syndrome and its variants) [5,6] are indicative of the potential inducer of autoimmunity involving the nervous system on the long-term.

Apart from a single study showing an association of seropositivity for specific coronavirus (HCoV-NL63) with chronic mood disorder [7], nothing is known about the possibility of late neuropsychiatric manifestations associated with coronavirus infections.

The is indirect evidence (Fig. 1 ) supporting the biological pathophysiology of late occurrence of neuropsychiatric manifestations after SARS-CoV-2 infection.

Fig. 1.

Schematic representation of potential mechanisms involved in the occurrence of late neuropsychiatric complications.

Proinflammatory cytokines such as the interleukin-6 (IL-6) [8] or tumour necrosis factor alpha (TNF-α) ⁹ are associated with development of late onset neuropsychiatric manifestations. COVID-19 is associated with systemic inflammatory storm with a massive release of cytokines, chemokines, including IL-6 and TNF-α ¹⁰ . Delirium it's not rare in patients with COVID-19 [1], suggesting that at least acutely, significant break of blood brain barrier and neuroinflammation occurs. Latent viral chronic brain infection caused by viruses, per example the human herpes virus 6 infections or the measle virus are associated with late cognitive and behaviour disturbances [9,10]. In murine models, coronaviruses can invade the brain and cause chronic infection [11,12]. The presence of coronavirus was demonstrated in the brain tissue in a single patient after SARS-CoV infection [13]. Very low levels of SARS-CoV-2 was detected in very few patients who died from COVID-19 [14]. Despite the inexistence of documented cases of 2019-nCoV chronic brain infection, the invasiveness and neurotropism of the virus [15],obliges to leave this possibility open.

SARS-CoV-2 is worldwide distributed and affecting people with different genetic background. The virus itself, is also genetically adapting to humans [16]. Hence, in the context of an infinitude of virus-host interactions, the possibility of late neuropsychiatric manifestations after SARS-CoV-2 infection should be considered. Careful monitoring of chronic or late neuropsychiatric manifestations is important to uncover mechanisms of the disease and guide interventions to prevent. Most patients with SARS-CoV-2 infection are asymptomatic and the durability of serological markers of infection is unknow. This might preclude studies based on serological status. Due to the large variability of SARS-CoV-2 infection prevalence between sites, ecological studies might be a promising design to address patterns of occurrence of late neuropsychiatric manifestations.