Infection | Brain

Evidence Suggests COVID-19 Might Have Neuropsychiatric Aftereffects

“Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19?” psychiatrists ask — and why immune system regulation is important for brain health.

The COVID-19 pandemic has created much psychological distress. Coupled with the virus's ability to cause neurological symptoms like encephalitis, loss of smell and taste, meningitis, etc. — what else could SARS-CoV-2 be doing to the mind?

A recent review published in Brain, Behavior, and Immunity discusses just that. “Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms” is the paper’s title — written by Emily Troyer, MD, and her psychiatrist colleagues at the University of California San Diego.

History of Virus Pandemics and Neuropsychiatric Sequelae

During the 18th and 19th centuries after the influenza pandemic, there was a drastic rise in cases of schizophrenia, sleep disorders, anxiety, depression, psychosis, delirium, and suicidality. Scientists called this “psychoses of influenza” — and indeed, influenza is known to invade the brain.

Another recent review, titled “COVID-19: Considering the prevalence of schizophrenia in the coming decades,” has also examined the relationship between virus pandemics and the birth of schizophrenic individuals in the subsequent generation — warning that the same pattern might repeat.

During the early 20th-century, after the Spanish flu pandemic, cases of encephalitis lethargica spiked globally. It’s a form of inflammatory brain disease accompanied by Parkinsonism, catatonic schizophrenia, psychosis, and excessive sleepiness. “Almost 100 years after the encephalitis lethargica epidemic, its etiology remains enigmatic, raising the possibility of a recurrence…in a future influenza pandemic,” writes Sherman McCall, MD, at the US Army Medical Research Institute of Infectious Diseases.

During the 2009 influenza H1N1 pandemic — as well as other coronavirus epidemics (SARS-CoV-1 in 2003 and MERS-CoV in 2012) — neuropsychiatric sequelae also happened in several cases. These include seizures, encephalitis, encephalopathy, Guillain-Barre syndrome, neuromuscular issues, and excessive sleepiness. And all of these, except sleepiness, have already occurred in the current COVID-19 pandemic.

SARS survivors are also more likely to develop neuropsychiatric disorders at 31–50 months post-infection, compared to the non-infected. The data shows that 54.5% of SARS survivors had PTSD, 39% had depression, 36.4% had pain disorder, 32.5% had panic disorder, and 15.6% had obsessive-compulsive disorder. Whereas the prevalence of these disorders was only 3% before the SARS epidemic.

“Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19?”

Understanding the Neuroimmunology of Infections

From previous pandemics and epidemics, it’s evident that neuropsychiatric symptoms can occur after a neuroinvasive virus infection like the influenza virus and coronaviruses. “Acute and delayed neuropsychiatric sequelae have been associated with past viral pandemics,” Dr. Troyer and colleagues said.

The delay can range from weeks (in case of neuromuscular problems) or decades (in case of schizophrenia in the next generation) following the onset of virus infection, Dr. Troyer added. How do these viruses harm the brain? Researchers have proposed two firm mechanisms and a third speculative one:

1. Virus-induced neuro-immunopathology

2. Virus-induced neuropathology

3. Gut-brain axis intervention (largely speculative)

[1] For one, immune responses against the virus can persist even when the virus is gone. Persistent inflammation slowly degenerates cells, including neurons and the blood-brain barrier. “Respiratory viruses may damage the central nervous system as a result of misdirected host immune responses that could be associated with autoimmunity in susceptible individuals [called] virus-induced neuro-immunopathology,” explains Marc Desforges, Ph.D., and fellow neurovirologists in a 2019 paper titled,

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

[2] Second, viruses can establish dormancy (or latency) in neurons — meaning that it “sleeps” in the neuronal genome. Latent viruses can reactivate and become infective again when the immune system is less vigilant. And neural and immune cells can serve as reservoirs for coronaviruses latency. When virus replication directly attacks the nervous system, it’s called “virus-induced neuropathology,” the neurovirologists added.

[3] The third but rather far-fetched mechanism is via the gut-brain axis, which is involved in autoimmune and neuropsychiatric disorders. ACE-2 receptors — that SARS-CoV-2 binds to — are also expressed in the gut epithelial cells. About 40% of COVID-19 patients showed gastrointestinal distress. And, most importantly, virus shedding has been shown to occur in the feces of COVID-19 patients at about five weeks post-infection.

“SARS-CoV-2 [may] precipitates changes in gut microbial composition, which could be involved in the pathogenesis of neuropsychiatric symptoms via the gut-brain axis,” Dr. Troyer and colleagues hypothesized.

On Prevention

Nobody knows if the COVID-19 pandemic will lead to lifelong neuropsychiatric sequelae. But researchers think this is possible considering what had happened in past virus pandemics and epidemics, Dr. Troyer said. “The delayed or chronic effects of this pandemic, particularly on public mental health, will not be fully appreciated for several years.”

Because of this, longitudinal evaluations of COVID-19 patients for any neuropsychiatric sequelae must be conducted. This would be of utmost importance for disease monitoring and early treatment of neuropsychiatric symptoms to mitigate the disease burden associated with COVID-19, Dr. Troyer and colleagues concluded.

While there’s that, the possible neuropsychiatric sequela only happens as a result of an aberrant immune response that compromises the brain function, as discussed above. How the immune system is regulated also depends, in part, on lifestyle choices such as physical exercise and adequate nutrition (and many others), says the exercise and nutrition immunologist, Glen Davidson. And a well-regulated immune system and brain health are tightly integrated — during both the brain and immune system development in children and functional maintenance across life.