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Two new research studies focus on the neurologic issues that present in patients with COVID-19: One proposes that the disease that starts in the respiratory tract brings on coagulopathy and stroke risk, while the other asserts that, so far, the neurologic effects of the virus does not appear to involve direct invasion of the central nervous system.

Two new studies attempt to bring into focus neurological issues that present in patients with COVID-19: One proposes that the disease that starts in the respiratory tract brings on coagulopathy and stroke risk, and another asserts that, so far, the virus' neurologic effects do not appear to involve direct invasion of the central nervous system (CNS).

The studies represent two of the latest publications in the expanding literature on the virus and its neurological manifestations, which reflect an updated understanding that COVID-19 is not merely a respiratory phenomenon.

In an August 10 online report in the Journal of Neuroimaging, the authors proposed a cascade of events they say could be taking place in COVID-19 patients after the virus escapes the respiratory system and gets into the bloodstream, a process they say points to the potential for specific modes of therapy tailored to different steps in the cascade.

The authorstwo of whom are associated with a company that has developed a tool that, once approved, could be used to treat the type of patients they describesay that after the virus enters the alveolus of the lung, it causes inflammation that damages the thin membrane between the alveolus and the adjacent lung capillary, or the blood-air barrier.

Then a potentially disastrous string of events begins, first with the development of endothelial dysfunction. This happens, they say, in one of two ways: Either the virus enters endothelial cells directly, or damaging angiotensin II accumulates because their usual docks, angiotensin-converting enzyme 2 (ACE2) receptors, become occupied by the virus, which has a high affinity for the receptors. The angiotensin II leads to oxidative stress and oxidation of the typically circular Beta2glycoprotein1 (B2GP1) but becomes unwound into a J shape.

At that point, the authors posit, there is an opening on B2GP1 for antiphospholipid antibody complexes, associated with thrombotic tendencies, to form. The lack of non-oxidized B2GP1 to competitively bind von Willebrand Factor leads to platelet adhesion and platelet attachment to sub-endothelial collagen, and then to platelet activation and aggregation in the setting of the thrombosis-friendly antiphospholipid antibodies. In the worst cases, the resulting clots lead to pulmonary emboli or stroke from large vessel occlusion.

Vallabh Janardhan, MD, the paper's lead author and a stroke and interventional neurologist at the Medical Center of Plano, said that a proper understanding of the process points to opportunities to intervene therapeuticallywith antiplatelet, antithrombotic, and antifibrinolytic therapy, and if necessary, with clot-removal devices.

In some cases, you don't have all day to dissolve the clothalf the brain will die, he said. So you need to go pull out the clot with clot-removal devices and initiate blood thinners, so it doesn't re-clot.

With his brother Vikram Janardhan, he co-founded Insera Therapeutics, which has developed a clot-removal system using intermittent or cyclicalrather than continuoussuction designed to be gentler on the vessel and for better removal of clots.

We believe, yes, there was a lot of attention towards ventilators early onthat's because we didn't connect the dots at that time, Vikram Janardhan said. Now that we're connecting the dots, there are other therapeutics that are a better fit in reducing mortality than an exclusive concern on the number of ventilators.

Insera's device is approved in Europe but not the United States and is not yet commercially launched.

We fully anticipate and hope the vaccines will be out and available before our therapy is ready worldwide, Vikram Janardhan said.

The other paper, which was published in the August 19 issue of Cell, conveys the broad scope of the neurological manifestations seen in COVID-19 patients.

Neurological abnormalities have been described in 30 percent of patients. But the most frequent neurological problemsespecially malaise, dizziness, and headachetend to be confined to non-specific abnormalities in patients experiencing mild COVID-19, said lead author Constantino Iadecola, MD, director of the Feil Family Brain and Mind Research Institute at Weill Cornell. Among those with more severe diseases requiring hospitalization, neurological manifestations are more severewith ischemic stroke and encephalopathy, for example, Dr. Iadecola said.

While serious neurological complications have been reported in patients with otherwise mild COVID-19, the most severe complications occur in critically ill patients and are associated with significantly higher mortality, he said.

COVID-19 is a much more aggressive disease, he said, noting that to date, no convincing evidence shows that the virus directly infiltrates neurons.

There's no evidence that this is a neurotropic virus, he said. In the case of the loss of smell, he said, some cells in the nasal cavity, such as epithelial cells, might become infected, but there is no definitive evidence that the nerves themselves are invaded.

Most of the neurological problems seen in COVID-19 patients, he said, result from systemic effects on the virus, Dr. Iadecola said.

He cautioned, though, that the data that has been published so far has mostly come from the most serious cases.

We're not going to know maybe until a year from now when you look at the population as a whole, the real mortality, the real incidence of neurological manifestations, and the most prevalent neurological manifestations, he said. Because now we know only the patient who gets very, very sick and goes to the hospital and may be intubated.

The most pressing research questions remaining, he said, include whether neurological manifestations of COVID-19 reflect brain invasion, whether the brain contributes to immune dysregulation and respiratory failure, and the long-term neurological consequences of the virus.

He urged centers treating COVID-19 patients to establish systems to track patients longitudinally.

The mortality from the COVID-19 virus may not be extremely high, he said, but a lot of people are getting infected. Evidence from other viral infections suggests that even if you have a mild infection .... there could be long-term neuropsychiatric effects that range from anxiety, PTSD, and depression, to cognitive impairment.

The message for clinicians, he said, is to be aware that the major complications that come from this are most likely due to whatever is going on elsewhere in the body, especially the hypercoagulable state and hypoxia. That's what the evidence so far suggests. They've got to pay almost more attention to what goes on outside the brain because most likely what goes on in the brain may be a reflection of that. And then pay attention to the sequelaewhatever it is going to be coming up in the next several months.

Be very attentive to the patients, he continued. Ask general questionsabout their mood, sleep pattern, appetite, social life, and whether they've gone back to work, he suggested.

As the acute phase resolves, quality of life is going to be paramount, Dr. Costantino said.

Adnan I. Qureshi, MD, FAAN, professor of clinical neurology at the University of Minnesota, who has studied COVID-19, said there are two main ways the virus can affect the CNS. One is a direct effect by the virus or inflammation affecting neuronal cells and the blood-brain barrier. These patients can get encephalitis or have demyelination, but it's unclear whether there is any treatment except for a therapy that can suppress the excessive inflammation, such as IL-6 inhibitors.

The second is through blood-clotting mechanisms, he said.

Some large studies, including one of ours, [published in July in the International Journal of Stroke], has shown that patients who develop ischemic stroke with COVID-19 are at risk due to older age and high prevalence of hypertension, diabetes mellitus, and hyperlipidemia. Therefore, these patients have other cardiovascular risk factors for ischemic stroke. COVID-19 may simply be a precipitant like other respiratory and systemic infections.

Important pending questions, Dr. Qureshi said, include how to best manage neurological patients, since focusing on neurological aspects alone might not be enough; the effect of remdesivir and convalescent serum; the role of anticoagulation in those with stroke risk; and the length of time stroke risk lasts after the infection.

Drs. Vallabh and Vikram Janardhan report receiving grants from the National Science Foundation and Insera Therapeutics. Dr. Vallabh Janardhan has also received grants from the Society of Vascular and Interventional Neurology. In addition, he and his brother, Dr. Vikram Janardhan, have 20 patents pending with the US Patent and Trademark Office and more than 65 patents in the US and worldwide issue.

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