key: cord-0967879-isdsestc
authors: Hosseini, Akram A.; Shetty, Ashit K.; Sprigg, Nikola; Auer, Dorothee P.; Constantinescu, Cris S.
title: Delirium as a presenting feature in COVID-19: neuroinvasive infection or autoimmune encephalopathy?
date: 2020-06-09
journal: Brain Behav Immun
DOI: 10.1016/j.bbi.2020.06.012
sha: dc31216af4049421a8149e54bd429e01e18f18de
doc_id: 967879
cord_uid: isdsestc

nan

The most common symptoms of COVID-19 are related to systemic and respiratory involvement. 1 We report two cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) infection with acute onset of altered mental status and delirium with normal respiration and metabolic balance in the first 48 hours. Informed consent for publication was obtained from both patients.

A 46-year-old male presented with two days history of headache followed by acute hypoactive delirium, disinhibition, confusion, but no fever, cough, or systemic manifestations. He had no previous medical or psychiatric illness, smoking, alcohol or illicit drug use. He was apyrexic but encephalopathic, nonverbal, and unable to follow commands.

There was no weakness, but he had ankle clonus, brisk reflexes and Babinski's sign. Baseline brain CT and blood tests were unremarkable (Table 1) . Nasopharyngeal swab real-time reverse-transcriptase-polymerase-chain-reaction (rRT-PCR) test was positive for SARS-CoV2.

After 2 days, he developed fever and status epilepticus requiring sedation, neuromuscular blockade and intubation. The fraction of inspired oxygen (FiO2) remained at 21% and no additional respiratory support was needed. Chest X-ray only showed patchy consolidation without significant progression on subsequent imaging. Cerebrospinal fluid (CSF) showed mildly raised protein and oligoclonal bands, and was negative for SARS-CoV2.

Neuromuscular blockade was withdrawn on day 5, when the new symptom of cough emerged. Despite normal brain CT at 48 hours, MRI on day 6 showed three hyperintense foci on diffusion-weighted images, but no overt restriction, consistent with T2-shine-through suggesting cellular infiltration/inflammation or small infarcts ( Figure 1 ). The presistent diffusion-weighted hyperintensity on subsequent MRI supported neuroinflammation. Cranial arteries were normal on CT angiogram. Empirical treatment included Ceftriaxone, Aciclovir and Sodium Valproate. .

He noted hyposmia and dysgeusia during the convolescence. Despite improvement after a week, he had impaired verbal fluecy, linguistic abstraction, phrase repetition, and delayed recall memory. He scored 20/30 on Montreal Cognitive Assessment on day 8.

A 79-year-old female was admitted to hospital following a seizure resulting in injuries to her face. According to her relatives, the symptoms started a few hours earlier with confusion and verbal communication difficulties. There was no preceding illness. She had no fever, cough, or respiratory symptoms at presentation. Vital signs were normal. There were no sensory or motor deficits. She had dysphasia and impaired orientation, attention and memory. The first brain MRI only showed chronic small vessel ischemic changes. Chest CT scan only demonstrated bilateral pleural effusion.

After 60 hours, she had two generalized seizures, followed by fever and low oxygen saturation. Neurological examination confirmed poor mental state, with Glasgow Coma Scale scores between 8 and 13. Repeat blood tests showed hyponatremia. The second nasopharyngeal sample rRT-PCR was positive for SARS-CoV2. CSF revealed normal constituents (Table 1) . CT scan and repeat brain MRI showed new changes in the limbic system with partial diffusion restriction, suggestive of limbic encephalitis ( Figure 2 ).

The patient's persistent delirium improved over 10 days with mild respiratory symptoms, hyposmia and dysgeusia. On day 15, she scored 19/30 on Montreal Cognitive Assessment with impaired verbal fluency, repetition, abstraction, and delayed recall memory.

There is emerging evidence that SARS-CoV2 can present with neurological features and concomitant encephalopathy. 1,2 However, there is currently no report of limbic encephalitis associated with COVID-19 that presented with delirium in the absence of respiratory, metabolic or systemic features, while patients may be hidden sources of spreading the virus in busy clinical settings.

The detection of SARS-CoV2 in the CSF in a patient with meningo-encephalitis supports neurotropic and neuroinvasive potential of the virus 2 presumably through the blood vesselrich meninges once the blood brain barrier is damaged. 3 The evidence of SARS-CoV2 viral particles in brain capillary endothelial cells of an infected patient suggests hematogenous CNS entry. 4 The olfactory neuronal pathway could explain hyposmia. 5 Angiotensinconverting enzyme 2 (ACE2) receptors of vascular endothelium in respiratory system and meningeal capillaries can be the binding target for SARS-CoV2 proteins. 6 In the absence of detectable virus in the CSF, it is plausible that SARS-CoV2 causes an immunologic response that results in parenchymal inflammatory injury, cerebral edema and clinical manifestations of encephalopathy. 7 The presence of oligoclonal bands in one of our patient's CSF and serum supports immune-mediated response that is not restricted to intrathecal production of immunoglobulins. Increased interleukin-6 in severe SARS-Cov2 disease highlights the occurrence of immunologic response and indicates intracranial cytokine storms. 8 Post-infection or non-infectious autoimmune encephalitis are known to be associated with antibodies against neuronal cell-surface or synaptic proteins. 9 The clinical phenotype similarly includes neurological and psychiatric presentations without CSF pleocytosis, and early immunotherapy improves outcome. 9 In patients with recent episodes of psychosis, higher prevalence of antibodies against four coronaviruses strains are reported 10 , which supports the possibility of SARS-CoV2 encephalopathy and psychosis. It is unknown if immunotherapy is required to improve neurocognitive outcome in patients with SARS- 

Neurologic manifestations of hospitalized patients with coronavirus disease

A first case of meningitis/encephalitis associated with SARS-Coronavirus-2

Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms

Central Nervous System Involvement by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2)

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

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

Nervous system involvement after infection with COVID-19 and other coronaviruses

COVID-19: consider cytokine storm syndromes and immunosuppression

We acknowledge the help from Dr Rob Dineen, Dr Yasser Falah, Dr