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How can a respiratory pathogen like SARS-CoV-2 cause the nervous system to go haywire?

That's a question yet to be answered, observed Serena Spudich, MD, MA, of Yale University, and Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, in an essay in .

"Though COVID-19 is well known as a respiratory disease, neurological symptoms such as confusion, strokes, headaches, weakness, and nerve problems also occur in some patients around the time of the initial illness," Spudich told MedPage Today.

"Additionally, some people have difficulties with thinking, abnormal skin sensations, headaches, and other neurological symptoms for months after recovery from COVID-19," she continued. "Even patients with mild initial COVID-19 manifest a wide variety of persistent neurological and psychiatric symptoms, thus millions who have recovered from COVID-19 are at risk for these conditions."

The essay reviewed what's currently known about the effects of SARS-CoV-2 on the brain and what's still a mystery.

"Neurological complications are common, very diverse in presentation, and long lasting," Nath told MedPage Today. "They are largely immune-mediated, the brain endothelial cells being a major target."

"We do not have specific treatments for these illnesses, and the long-term consequences remain unknown," Nath noted. A concern is whether neurologic complications of COVID-19 could accelerate the process of neurodegenerative diseases, he added.

Clinical neurologic and psychiatric syndromes have emerged in studies of hospitalized COVID-19 patients, but little is known about their physiopathology. In their essay, Spudich and Nath discussed potential mechanisms for neurologic complications, including neuroinflammation, coagulopathy, neuronal injury, and possible viral infection in the central nervous system (CNS).

"Despite early speculation that SARS-CoV-2 may enter the CNS via migration through the nasal cavity and the olfactory pathway or trafficking across the blood-brain barrier, analysis of cerebrospinal fluid (CSF) from living patients with neuropsychiatric manifestations has almost uniformly failed to detect viral RNA by reverse transcription polymerase chain reaction," Spudich and Nath noted.

Instead, most evidence from CSF and brain tissue suggests that immune activation and inflammation within the CNS is the primary driver of neurologic disease in acute COVID-19, they said. Histopathological studies of brain tissue from patients who died with acute COVID-19 reveal only limited detection of SARS-CoV-2 nucleic acid or viral protein in the brain, consistent with findings in CSF from live patients, they noted.

What's also unknown is what drives the nervous system symptoms in long COVID. "Research is needed to understand whether longer-term neurologic and psychiatric symptoms that last in some people after recovery from acute COVID-19 -- nervous system long COVID -- relates to the persistence of immune and vascular abnormalities, or arises from other causes," Spudich said. "We also do not fully understand whether distinct SARS-CoV-2 variants or breakthrough cases after COVID-19 vaccination confer different risks for acute neurologic disorders or nervous system long COVID."

Since early in the pandemic, COVID-19 patients have described lingering symptoms after acute infection, including difficulty with memory and concentration, frequent headaches, alterations in skin sensation, autonomic dysfunction, and intractable fatigue. Many people with long COVID neurologic symptoms are under age 50 and were healthy and active prior to SARS-CoV-2 infection, Spudich and Nath noted. Most were never hospitalized for acute COVID-19 illness.

The at Yale is studying people with persistent post-COVID symptoms involving the nervous system with brain imaging, blood and spinal fluid assessments, and clinical tests. "Our multidisciplinary team applies state-of-the-art methods to look for signs of immune changes, vascular injury, and even ongoing presence of virus to reveal the underlying causes of nervous system long COVID, in order to develop targeted treatment," Spudich said.

"In the NIH intramural program, we are establishing a cohort of long COVID patients that will undergo deep phenotyping, and we are also in the process of starting a clinical trial using immunomodulatory drugs," Nath added.

"The COVID-19 pandemic has brought together patient groups, community members, clinicians, and investigators in an unprecedented manner to tackle the unexpected and emerging global neurological consequences of SARS-CoV-2," Spudich observed. "Discovery related to the effects of this viral infection in the nervous system may help to shed light on other infectious and immune-mediated disorders of the brain and nerves."

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