Article In Brief
New findings show that one-third of COVID-19 patients have a neurologic or psychiatric diagnosis within six months.
A third of patients diagnosed with COVID-19 had a psychiatric or neurologic disorder within six months, including depression, anxiety, strokes, and dementia, according to a report appearing in the April 6 online Lancet Psychiatry.
Researchers who looked at ICD-10 codes from more than 230,000 electronic health records from the TriNetX database— which includes anonymous data from 62 health-care organizations, primarily in the US, comprising 81 million patients—also found that among COVID patients admitted to an intensive care unit (ICU), the incidence of developing a psychiatric or neurologic disorder rose to 46 percent and was higher yet for those who were diagnosed with encephalopathy resulting from COVID-19.
Patients in the study were 10 years of age or older, diagnosed with COVID-19 in or after January 2020, and were still alive in December 2020. Medical records for these patients were compared against those of more than 105,000 patients with influenza and over 236,000 with any respiratory tract infection. The researchers found increased hazard ratios for patients with COVID-19 compared with other respiratory tract infections, but not with influenza.
The most common post-COVID diagnosis was any anxiety disorder (17.4 percent, CI: 17.04-17.74), followed by any mood disorder (13.7 percent, CI: 13.35-13.99). Other diagnoses included psychotic disorder (1.40 percent, CI: 1.30-1.51), ischemic stroke (2.1 percent, CI: 1.97-2.23), intracranial hemorrhage (0.6 percent, CI: 0.50-0.63), and among patients over 65, dementia (0.7 percent, CI: 0.59-0.75).
When researchers looked at outcomes for patients who had been admitted to the ICU, the incidence rates increased—for instance, 19.2 percent had anxiety disorders, 15.4 had mood disorders, 2.7 percent (CI: 2.24-3.16) had intracranial hemorrhage, nearly 7 percent had ischemic stroke (CI: 6.17-7.76), and 1.74 percent had dementia (CI: 1.34-2.30). In patients over 65 with encephalopathy, first-time diagnosis of dementia rose to 5 percent, according to the findings.
The authors noted that as compared with neurologic disorders, common psychiatric disorders such as mood and anxiety disorders showed a weaker relationship with the markers of COVID-19 severity in terms of incidence or hazard ratios. “This might indicate that their occurrence reflects, at least partly, the psychological and other implications of a COVID-19 diagnosis rather than being a direct manifestation of the illness,” they wrote.
The authors noted that one study limitation included reliance on ICD-10 codes in the electronic health records to interpret diagnoses—the diagnoses themselves were not validated, and some of the records were incomplete, they noted.
In addition, the authors warned that analysis involving encephalopathy—which involved delirium and related conditions—should be interpreted carefully. “Even among patients who were hospitalized, only about 11 percent received this diagnosis, whereas much higher rates would be expected. Under-recording of delirium during acute illness is well known and probably means that the diagnosed cases had prominent or sustained features; as such, results for this group should not be generalized to all patients with COVID-19 who experience delirium.”
Lead researcher Paul Harrison, FRCPsych, professor of neurology at Oxford University, noted that “the associations between COVID-19 and cerebrovascular and neurodegenerative diagnoses are concerning, and more information about the severity and subsequent course of these diseases is required.”
In comments to Neurology Today, Dr. Harrison surmised that the mechanism behind the neurologic disorders post-COVID “could be a direct effect of the virus. We know COVID can get into the brain via the olfactory nerves, but we don't know what if any damage it causes when it's there,” he noted. “Another, perhaps most likely, possibility is that the disorders are related to the inflammatory and thrombotic response to the virus. There may also be an autoimmune basis to some disorders,” adding that targeted research is needed to further illuminate these possibilities.
Future research, he noted, would ideally investigate the timing of dementia onset in the study group. “It is possible that some cases were in fact present before COVID but brought to light due to the medical attention.” Dr. Harrison said that he'd like to learn more about the clinical picture and nature of the dementia. “For instance, are we seeing a vascular dementia related to stroke, or does it have a different etiology?”
The Burden of COVID-19 Complications
Severe syndromes observed in the Lancet article, such as ischemic stroke and intracranial hemorrhage, are rare in survivors of COVID-19, noted Pria Anand, MD, who is chief in the division of hospitalist neurology and assistant professor in the division of neuro-infectious diseases at Boston University School of Medicine. Such syndromes can happen in the setting of acute COVID-19 due to inflammation and issues with blood clotting, said Dr. Anand.
“More often, the neurologic symptoms we see in patients with so-called ‘long COVID’ or post-acute sequelae of COVID are not as clearly defined and include complications like headaches, difficulty thinking or concentrating, muscle aches, insomnia, or fatigue alongside systemic symptoms like shortness of breath,” Dr. Anand said. “Interestingly, we're seeing these symptoms even in patients who had mild initial infection and did not require critical care or even hospitalization.”
She also noted that psychiatric symptoms like anxiety and depression are also common in survivors of COVID-19 and that “some of these symptoms may be compounded by stressors like isolation and quarantine, or by the trauma of hospitalization.”
Dr. Anand advised that any patient with neurologic symptoms post- COVID-19 should have a thorough neurologic history and examination, and that the evaluation and management of most of these symptoms are like that of patients without post-COVID syndrome.
“For instance, a patient with cognitive complaints after COVID-19 should be screened with bedside cognitive testing such as a Montreal Cognitive Assessment and might benefit from formal neuropsychological or speech/cognitive therapy evaluation and management,” she said. While it will be difficult to predict all the needs of patients with post-COVID syndrome, she said, one approach would be to focus resources on rehabilitation services—physical, occupational, and speech or cognitive therapy, neuropsychological testing and management, and other services designed to improve patients' functional status.
Given the magnitude of COVID cases across the US and the world, “the burden of these (neurologic) symptoms is likely to be enormous. Although post-COVID symptoms are more subtle and less fulminant than the acute complications of severe COVID, they affect a tremendous number of patients, even those who only had mild COVID initially, and they can have devastating consequences, such as keeping someone from returning to work or school or leaving them reliant on a family member or other caregiver,” she said.
Fighting an Invisible Enemy
Sherry Chou, MD, associate professor of critical care medicine, neurology, and neurosurgery at the University of Pittsburgh told Neurology Today that during the first year of the COVID-19 pandemic, clinicians were mostly focused on keeping patients alive. “Now, we are interested in helping patients do well once they survive COVID-19,” said Dr. Chou, who leads the Global Consortium Study of Neurological Dysfunction in COVID-19 (GCS-NeuroCOVID), an international, multicenter study on neurological dysfunctions in COVID-19 patients.
Dr. Chou, who is a neurointensivist, said that during the pandemic, many of her patients with COVID-19 had been on a ventilator and needed a long hospitalization. “People would say they beat COVID. But then some return with new, severe problems such as stroke, confusion, or brain injury from cardiac arrest,” she said.
In her role as lead investigator of the GCS-NeuroCOVID, Dr. Chou has also heard from a number of people who are less severely ill but disabled with chronic headaches, or “are extraordinarily fatigued to the point where they cannot carry on with life's activities—these are people who used to be very high functioning and would hold down busy jobs.” Many complained of what has now become known as ‘brain fog’ months after testing positive for the virus, she noted.
Dr. Chou said she believes the Lancet Psychiatry paper is important for many reasons, as it gives readers an idea of the magnitude of the problems involving long-term neurologic and psychiatric conditions following COVID-19. However, she pointed out that the reliance on diagnostic codes means that “if there is a syndrome that doesn't yet exist or hasn't yet been defined, we won't have a code for it—for instance, I don't think we have a diagnostic code for brain fog. We have a lot of work to do, and between physicians and scientists, we will be able to learn more about why patients develop these disabling neurologic conditions, and then we can figure out how to improve patients' functionality and ease their symptoms.”
As a first step, researchers must first determine the timing, frequency, and magnitude of neurologic complications and get the information to clinicians and providers treating patients with COVID-19 so the symptoms can be detected and then treated appropriately. “We need to know what we are up against as we fight this invisible enemy,” she said.
Improving the specificity of the tools to measure post-COVID symptoms such as brain fog, chronic headache, and severe fatigue will also become central to effective treatment, she said. “If we study these post-COVID syndromes and find that they are similar to chronic and severe headaches, fatigue, and cognitive problems that we've seen before SARS-CoV-2 was part of our world, then this pandemic may help us to understand this other disease we've known about, but didn't fully understand,” she observed. “Either way, I think we stand to learn a lot from this pandemic and from this virus.”
Jennifer Frontera, MD, who has researched the neurological complications of COVID-19 and is a professor in the department of neurology at NYU Grossman School of Medicine, agrees with that assessment.
“We have to figure out what is mechanistically underpinning this, and from there, we can look at therapeutic strategies,” Dr. Frontera said. “COVID may worsen symptoms of an underlying neurodegenerative disease—or extricate the underlying neurodegenerative disease,” adding that there are viruses and neuroinflammatory viruses that can cause cognitive. With severe COVID cases, she pointed out, patients will be exposed to a whole host of other neurologic complications related to critical illness. Problems such as intracranial microhemorrhages could be exacerbated by hypoxia, for instance. “These could be secondary effects of COVID or just effects of being critically ill,” she said.
“Dementia has been one of the most interesting post-COVID stories,” she said, noting brain fog has emerged as a major complaint in some of her recent research. “[Brain fog] is debilitating because people feel like they cannot perform at their jobs. It is quite concerning because cognitive impairment impacts every aspect of one's life and eventually impacts societal productivity,” she said.
Dr. Frontera pointed out that “post-COVID clinics” were popping up around the US designed to focus on the issues that impact COVID survivors. “At NYU, we have neurologists and psychiatrists who are specifically interested in managing post-COVID chronic fatigue-like complications.” The post-COVID treatment teams combine disciplines of pulmonology, cardiology, neurology, psychiatry, and rehabilitative medicine, she noted. “There have been a lot of new clinical and research collaborations that have formed because of the multi-system effects of COVID,” she said, adding, “Unfortunately, I think we are going to be dealing with COVID and the fallout from COVID for quite some time.”
Drs. Harrison, Anand, Chou, and Frontera had no disclosures.