The Neurochemical Evidence for CNS Injury in Moderate COVID-19

​ COVID-19 damages neurons in a significant fraction of patients, even among those without clinical neurological symptoms, according to a new study in the June 16 online issue of Neurology. The evidence comes from measurement of neurofilament light chain (NfL), a marker of neuronal injury, and glial fibrillary acidic protein (GFAp), a marker for as

COVID-19 damages neurons in a significant fraction of patients, even among those without clinical neurological symptoms, according to a new study in the June 16 online issue of Neurology.

The evidence comes from measurement of neurofilament light chain (NfL), a marker of neuronal injury, and glial fibrillary acidic protein (GFAp), a marker for astrocyte activation, in the plasma of 47 COVID-19 patients across the severity spectrum.

"These findings are important because they are some of the first data to suggest that in otherwise neurologically asymptomatic patients, there could be under-appreciated injury in the central nervous system," said Serena Spudich, MD, professor of neurology and division chief of neurological infections and global neurology at Yale University School of Medicine in New Haven, CT, who was not involved in the study.

"A relatively large number of COVID-19 patients have some neurological involvement, such as confusion, but on the other hand, these are patients who are severely ill," so it has been difficult to know whether the disease is causing actual injury to the central nervous system, said lead study author Magnus Gisslen, MD, PhD, professor of infectious diseases at the University of Gothenburg, Sweden, and chief physician at Sahlgrenska University Hospital.

To date, out of concern for transmission, there has been little post-mortem examination of the CNS to assess the effects of infection in patients dying of the disease.

Study Details

To assess the potential of direct damage to the CNS, Dr. Gisslen and colleagues measured plasma levels of NfL and GFAp in COVID-19 patients, including 20 with mild, nine with moderate, and 18 with severe disease. They defined mild disease as not requiring hospitalization, moderate disease as requiring hospitalization and supplemental oxygen, and severe disease as requiring intubation and mechanical ventilation, or in one case, dying from the disease before treatment commenced.

The ages of patients ranged from 37 to 72 years; about two-thirds were male. As seen more broadly with the disease, more severely affected patients tended to have more comorbid conditions, including hypertension, heart disease, obesity, and diabetes.

Four of the severely affected patients displayed confusion before admission to the intensive care unit, and one had had a single seizure before ICU admission, with no signs of seizure activity the following day. Because of the concern for transmission, no MRIs were done, and full neurologic exams were not performed, Dr. Gisslen noted.

GFAp and NfL were assessed in plasma samples, a more recent technique than assessing the same markers in cerebrospinal fluid. Both are widely accepted markers of CNS injury; elevation of NfL is seen in multiple neurodegenerative diseases as well as ischemic stroke. Samples were taken at a mean of 13 days after onset of symptoms. Levels in COVID-19 patients were compared to those in age-matched healthy controls.

As expected, levels of both markers correlated with age, in both patients and controls. Plasma GFAp was elevated in patients with both moderate and severe disease compared to controls (204, 206, and 141 picograms/milliliter, respectively; p=0.03 for moderate and p=0.001 for severe), while NfL was significantly elevated in patients with severe disease compared to controls (32.7 and 13.1 pg/mL, respectively; p<0.001).

A second assessment, at a median of 13 days after the first, was performed in a subset of patients. In the severely affected patients, GFAp decreased while NfL increased. No changes in either marker were seen over time in either less severely affected group.

The results suggest that astrocytic activation may be a common and early feature in most cases of COVID-19, Dr. Gesslen said, while neuronal injury may occur later and in the more severely affected patients.

Much remains unclear, he added, including the likely outcome for affected patients, and whether the virus is causing damage through direct infection of neurons or astrocytes, or instead is acting indirectly. "We really don't know yet," Dr. Gesslen said. Direct invasion of the CNS seems unlikely, he said, because the cellular receptor the virus relies on to enter cells is expressed at very low levels in the CNS. Hypoxia due to respiratory failure, microthrombotic events, or immune activation-mediated damage seem more likely to him. "But this remains an open question," he added.

Neither is it known whether the neurofilament marker will revert to normal levels over time, but work is underway to track that in COVID-19 patients. "It will be very interesting to see if corticosteroid treatment affect these markers," Dr. Gesslen said.

Expert Commentary

"This is an important paper, because these two markers are reflecting central nervous system injury," commented Paola Cinque, MD, PhD, professor of infectious diseases and senior physician in the neurovirology unit at San Raffaele Scientific Institute in Milan, Italy. "However, it does not tell us about the mechanism. Hypoxemia may be the most probable one."

"It is also not yet possible to correlate these signs of injury with the type and severity of neurologic symptoms reported in COVID-19 patients," he said, adding, "Those associations will have to come over time."

The clinical picture remains concerning, said Pranusha Pinna, DO, a neurology resident at Rush University Medical Center and first author on a recent large case series on neurologic manifestations in COVID-19 patients.

"Patients who have been critically ill with COVID-19 may have a hard time regaining function," she said. "We are seeing a lot of requests for consults about that. Unfortunately, it is very difficult to comment on prognosis when the underlying cause of the neurologic symptoms is a disease we don't understand very well. The finding of biochemical manifestations of the illness reported here is important, although its meaning is still unclear."

Given the number of patients worldwide whose illness has met the criterion in this paper for moderate disease—hospitalized but without intubation—there may be a significant public health implication from these findings, Dr. Spudich of Yale said.

"Whenever we see neuronal injury, we know some brain cells are taking a hit," Dr. Spudich continued, "so I think the clinical implications of this paper is that if there is neuronal injury, whether or not the patient presents with severe neurological symptoms, there may be consequences for how the brain functions after recovery. Will there be long-term effects in these patients? That is an important question for us as neurologists.

Disclosures: Drs. Gisslen, Pinna, Cinque, and Spudich have no relevant disclosures.

Link Up for More Information:

Kanberg N, Ashton NJ, Andersson LM, et al. Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19. Neurology 2020; Epub 2020 Jun 16.

Pinna P, Grewal P, Hall JP, et al. Neurological manifestations and COVID-19: Experiences from a tertiary care center at the Frontline. J Neurol Sci 2020;415:116969