Three Stages to COVID-19 Brain Damage, New Review

Neurologic sympoms of Covid 19

Since the Centers for Disease Control and Prevention (CDC) confirmed the first US case of novel coronavirus infection on January 20, much of the clinical focus has naturally centered on the virus' prodromal symptoms and severe respiratory effects.

However, US neurologists are now reporting that COVID-19 symptoms may also could include encephalopathy, ataxia, and other neurologic signs. [1]

"I am hearing about strokes, ataxia, myelitis, etc," Stephan Mayer, MD, a neurointensivist in Troy, Michigan, posted on Twitter on March 26.

Other possible signs and symptoms include subtle neurologic deficits, severe fatigue, trigeminal neuralgia, complete/severe anosmia, and myalgia as reported by clinicians who responded to the tweet.

Last week, as reported by by Medscape Medical News, the first presumptive case of encephalitis linked to COVID-19 was documented in a 58-year-old woman treated at Henry Ford Health System in Detroit.

Physicians who reported the acute necrotizing hemorrhagic encephalopathy case in the journal Radiology counseled neurologists to suspect the virus in patients presenting with altered levels of consciousness.

Researchers in China also reported the first presumptive case of Guillain-Barre syndrome associated with COVID-19. A 61-year-old woman initially presented with signs of the autoimmune neuropathy GBS, including leg weakness, and severe fatigue after returning from Wuhan, China. She did not initially present with the common COVID-19 symptoms of fever, cough, or chest pain.

Her muscle weakness and distal areflexia progressed over time. On day 8, the patient developed more characteristic COVID-19 signs, including 'ground glass' lung opacities, dry cough, and fever. She was treated with antivirals, immunoglobulins, and supportive care, recovering slowly until discharge on day 30.

"Our single-case report only suggests a possible association between GBS and SARS-CoV-2 infection. It may or may not have causal relationship. More cases with epidemiological data are necessary," senior author Sheng Chen, MD, PhD, told Medscape Medical News.

However, "we still suggest physicians who encounter acute GBS patients from pandemic areas protect themselves carefully and test for the virus on admission. If the results are positive, the patient needs to be isolated," added Chen, a neurologist at Shanghai Ruijin Hospital and Shanghai Jiao Tong University School of Medicine in China.

Neurologic presentations of COVID-19 "are not common, but could happen," Chen added. Headache, muscle weakness and myalgias have been documented in other patients in China, he said.

Early Days

Despite this growing number of anecdotal reports and observational data documenting neurologic effects, the majority of patients with COVID-19 do not present with such symptoms.

"Most COVID-19 patients we have seen have a normal neurological presentation. Abnormal neurological findings we have seen include loss of smell and taste sensation, and states of altered mental status including confusion, lethargy, and coma," Robert Stevens, MD, who focuses on neuroscience critical care at the Johns Hopkins School of Medicine in Baltimore, Maryland, told Medscape Medical News.

Other groups are reporting seizures, spinal cord disease, and brain stem disease. It has been suggested that brain stem dysfunction may account for the loss of hypoxic respiratory drive seen in a subset of patients with severe COVID-19 disease, he added.

However, Stevens, who plans to track neurologic outcomes in COVID-19 patients, also cautioned that it's still early and these case reports are preliminary.

"An important caveat is that our knowledge of the different neurological presentations reported in association with COVID-19 is purely descriptive. We know almost nothing about the potential interactions between COVID-19 and the nervous system," he noted.

He added it's likely that some of the neurologic phenomena in COVID-19 are not causally related to the virus.

"This is why we have decided to establish a multisite neuro-COVID-19 data registry, so that we can gain epidemiological and mechanistic insight on these phenomena," he said.

Nevertheless, in an online report February 27 in the Journal of Medical Virology, Yan-Chao Li, MD, and colleagues write that "increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system, inducing neurological diseases."

Li is affiliated with the Department of Histology and Embryology, College of Basic Medical Sciences, Norman Bethune College of Medicine, Jilin University, Changchun, China.

A Global View

Scientists observed SARS-CoV in the brains of infected people and animals, particularly the brainstem, they note. Given the similarity of SARS-CoV to SARS-CoV2, also known as COVID-19, the researchers suggest a similar invasive mechanism could be occurring in some patients.

Although it hasn't been proven, Li and colleagues suggest COVID-19 could act beyond receptors in the lungs, traveling via "a synapse‐connected route to the medullary cardiorespiratory center" in the brain. This action, in turn, could add to the acute respiratory failure observed in many people with COVID-19.

Other neurologists tracking and monitoring case reports of neurologic symptoms potentially related to COVID-19 include Mayer and Amelia Boehme, PhD, MSPH, an epidemiologist at Columbia University specializing in stroke and cardiovascular disease.

Boehme suggested on Twitter that the neurology community conduct a multicenter study to examine the relationship between the virus and neurologic symptoms/sequelae.

Medscape Medical News interviewed Michel Dib, MD, a neurologist at the Pitié Salpêtrière hospital in Paris, who said primary neurologic presentations of COVID-19 occur rarely — and primarily in older adults. As other clinicians note, these include confusion and disorientation. He also reports cases of encephalitis and one patient who initially presented with epilepsy.

Initial reports also came from neurologists in countries where COVID-19 struck first. For example, stroke, delirium, epileptic seizures and more are being treated by neurologists at the University of Brescia in Italy in a dedicated unit designed to treat both COVID-19 and neurologic syndromes, Alessandro Pezzini, MD, reported in Neurology Today, a publication of the American Academy of Neurology.

Pezzini notes that the mechanisms behind the observed increase in vascular complications warrant further investigation. He and colleagues are planning a multicenter study in Italy to dive deeper into the central nervous system effects of COVID-19 infection.

Clinicians in China also report neurologic symptoms in some patients. A study of 221 consecutive COVID-19 patients in Wuhan revealed 11 patients developed acute ischemic stroke, one experienced cerebral venous sinus thrombosis, and another experienced cerebral hemorrhage.

Older age and more severe disease were associated with a greater likelihood for cerebrovascular disease, the authors report.

Chen and Li have disclosed no relevant financial relationships.

Three Stages to COVID-19

Three-Stage Classification [2], [3]

Stage 1

The extent of SARS-CoV-2 binding to the ACE2 receptors is limited to the nasal and gustatory epithelial cells, with the cytokine storm remaining "low and controlled." During this stage, patients may experience smell or taste impairments, but often recover without any interventions.

Stage 2

A "robust immune response" is activated by the virus, leading to inflammation in the blood vessels, increased hypercoagulability factors, and the formation of blood clots in cerebral arteries and veins. The patient may therefore experience either large or small strokes.

Additional stage 2 symptoms include fatigue, hemiplegia, sensory loss, double vision, tetraplegia, aphasia, or ataxia.

Stage 3

The cytokine storm in the blood vessels is so severe that it causes an "explosive inflammatory response" and penetrates the blood–brain barrier, leading to the entry of cytokines, blood components, and viral particles into the brain parenchyma and causing neuronal cell death and encephalitis.

This stage can be characterized by seizures, confusion, delirium, coma, loss of consciousness, or death.

"Patients in stage 3 are more likely to have long-term consequences, because there is evidence that the virus particles have actually penetrated the brain, and we know that SARS-CoV-2 can remain dormant in neurons for many years," said Fotuhi.

"Studies of coronaviruses have shown a link between the viruses and the risk of multiple sclerosis or Parkinson's disease even decades later," he added.

"Based on several reports in recent months, between 36% to 55% of patients with COVID-19 that are hospitalized have some neurological symptoms, but if you don't look for them, you won't see them," Fotuhi noted.

As a result, patients should be monitored over time after discharge, as they may develop cognitive dysfunction down the road.

Additionally, "it is imperative for patients [hospitalized with COVID-19] to get a baseline MRI before leaving the hospital so that we have a starting point for future evaluation and treatment," said Fotuhi.

"The good news is that neurological manifestations of COVID-19 are treatable," and "can improve with intensive training," including lifestyle changes—such as a heart-healthy diet, regular physical activity, stress reduction, improved sleep, biofeedback, and brain rehabilitation," Fotuhi added.

Routine MRI Not Necessary

Kenneth Tyler, MD, chair of the Department of Neurology at the University of Colorado School of Medicine, disagreed that all hospitalized patients with COVID-19 should routinely receive an MRI.

"Whenever you are using a piece of equipment on patients who are COVID-19 infected, you risk introducing the infection to uninfected patients," he told Medscape Medical News.

Instead, "the indication is in patients who develop unexplained neurological manifestations — altered mental status or focal seizures, for example —because in those cases, you do need to understand whether there are underlying structural abnormalities," said Tyler, who was not involved in the review.

Also commenting on the review for Medscape Medical News, Vanja Douglas, MD, associate professor of clinical neurology, University of California San Francisco, described the review as "thorough" and suggested it may "help us understand how to design observational studies to test whether the associations are due to severe respiratory illness or are specific to SARS-CoV-2 infection."

Douglas, who was not involved in the review, added that it is "helpful in giving us a sense of which neurologic syndromes have been observed in COVID-19 patients, and therefore which patients neurologists may want to screen more carefully during the pandemic."

The study had no specific funding. Fotuhi has disclosed no relevant financial relationships. Coauthor Cyrus Raji reports consulting fees as a member of the scientific advisory board for Brainreader ApS and reports royalties for expert witness consultation in conjunction with Neurevolution LLC. Tyler and Douglas have disclosed no relevant financial relationships.