The future of neurologic care in the COVID era

By Naveed Saleh, MD, MS | Medically reviewed by Alison Christy, MD, PhD

Published March 21, 2024

Key Takeaways

Neurological sequelae occur in about 14% of patients with COVID-19.
Neurological complications include strokes, cognitive disorders, and mental health issues, possibly linked to calcium buildup and protein aggregation.
Treatment with dexamethasone and remdesivir may reduce neurological complications, and dietary changes could also help mitigate risks.

SARS-CoV-2 infection typically affects the lungs, but studies have shown that other organ systems also experience damage. Damage to the neurological system following infection can even occur in patients with mild illness.

Long-term adverse neurological effects of COVID-19 are an emerging area of study in the context of global health, with implications for the future of neurologic care. Let’s take a closer look.

Rates of neurological disorders

According to the results of a prospective, observational study published in Neurology, neurologic disorders were present in 13.5% of patients with COVID-19 during the study timeframe.^[] Many of these disorders occurred commonly in patients with critical illness. Of note, although Guillan-Barré syndrome was observed, encephalitis, meningitis, or myelitis secondary to SARS-CoV-2 infection did not occur.

Overall, neurological disorders associated with SARS-CoV-2 infection predicted in-hospital mortality and decreased the chances of discharge.

Ultimately, the relationship between SARS-CoV-2 and post-acute and long-term health effects should be considered in the context of infection-associated chronic illnesses.

VA researchers who followed COVID-19 patients found that, despite a decline in post-acute sequelae by 2 years, the cumulative burden of health loss persisted in patients who had been either hospitalized or not hospitalized during the acute infection.^[]

The authors proposed that viral and nonviral diseases may result in post-acute and chronic disease, writing that “there is likely a bidirectional nexus between noncommunicable diseases and infectious diseases, in that noncommunicable disease[s] often increase the risk of infection and adverse outcomes after infection and that a viral infection may lead to the emergence of new-onset noncommunicable disease.”

ACE-2

The relationship between the nervous system and SARS-CoV-2 is not yet well-established, but we know that the SARS-CoV-2 spike protein is highly attracted to the angiotensin-converting enzyme 2 (ACE-2) receptor and could be pivotal in neurologic pathology.

ACE-2 protein has recently been identified at the level of neurons and glial cells in several studies, as reported in ACS Omega.^[] This could lead to direct infection of neurons by SARS-CoV-2. Involvement of the ACE-2 protein in other areas of the body could also affect the brain indirectly, by increasing risk for hemorrhagic stroke.

“Although uncommon, there have also been reports of hemorrhagic stroke associated with COVID-19,” wrote the authors of a literature review in the Journal of Integrative Neuroscience.^[] “The proposed mechanisms include a blood pressure increase caused by infection leading to a reduction in [ACE-2] levels that results in an imbalance of the renin-angiotensin system ultimately manifesting inflammation and vasoconstriction.”

“Coagulopathy, as demonstrated by elevated prothrombin time (PT), has also been posited as a factor contributing to [hemorrhagic] stroke in patients with COVID-19,” they elaborated. “Other neurological conditions associated with COVID-19 include encephalopathy, anosmia, encephalitis, psychosis, brain fog, headache, depression, and anxiety.”

Calcium buildup

It is apparent that COVID-19 is associated with a wide range of neurological sequelae, including ischemic stroke, hemorrhagic stroke, peripheral nervous system disorders, disorders of cognition and memory, mental health disorders, migraines, seizures, and sensory disorders. One theory, according to the authors writing in ACS Omega, is that neurological function becomes compromised following infection with SARS-CoV-2 due to the antagonism of hydrogen bonding.

SARS-CoV-2 consists of proteins containing high concentrations of valine and glycine, which attracts calcium and other divalent cations. Calcium buildup alters the proteome by allowing for the synthesis of proteins rich in amino acids with calcium affinity. The formation of insoluble, stiff calcium oxalate and its aggregates could result in cellular stress and senescence.

Neurodegenerative risk factors include the presence of α-synuclein, amyloid β, or tau- also are rich in valine plus glycine residues. Aβ40 and Aβ42, two peptide fragments of amyloid β, possess nearly 30% valine plus glycine.

“Together with long-COVID factors, they form extensive aggregates with calcium oxalate, compounding neurological and perhaps non-neurological symptoms,” wrote the ACS Omega authors. “Biochemical aggregates consisting of proteins and small, insoluble, and stiff molecules generate stresses and result in cell death.”

Potential interventions

Research shows that in patients hospitalized with severe COVID-19, treatment with dexamethasone, remdesivir, or both decreases frequency of neurological complications. The largest benefit was observed in those receiving both drugs.^[]

Remdesivir prevents viral replication, whereas dexamethasone is hypothesized to prevent neurological complications by mitigating hyperinflammatory organ injury.

Diet may also play a role in preventing the neurological sequelae of COVID-19, posit the authors in ACS Omega.

“Strong anions, for instance Cl–, antagonize calcium oxalate by disrupting secondary chemical bonding among proteins and insoluble salts and solubilize insoluble and stiff molecules,” they said. “To address changes in the proteome and sequelae of COVID-19, amino acids antagonizing valine plus glycine, for example, lysine or particular amino acids capable of hydrogen bonding, can be adopted in the dietary regimen at a modest amount to improve physical health.”

What this means for you

Although the underlying mechanisms contributing to the neurological and neuropsychiatric repercussions of COVID-19 remain to be elucidated, the buildup of calcium salts could play a role. The depletion of the renin-angiotensin system secondary to hypertension—ultimately increasing inflammation and vasoconstriction—could also play a role. Potential interventions to decrease the potential public health burden of such complications include the administration of dexamethasone and remdesivir at the onset of SARS-Cov-2 infection, as well as dietary change.