Some COVID-19 patients have brain complications, study suggests

Authors: Mary Van Beusekom | News Writer | CIDRAP News  | Jun 26, 2020

Some COVID-19 patients, including those younger than 60 years old, appear to develop neurologic and neuropsychiatric complications such as stroke, brain inflammation, psychosis, and dementia-like symptoms, according to a study published yesterday in The Lancet Psychiatry.

The early-stage study of 153 hospitalized patients with confirmed, probable, or possible COVID-19 in the United Kingdom (UK) from Apr 2 to 26 identified 125 patients with complete data, of whom 77 (62%) had a stroke.

Of 125 patients, 114 (92%) had confirmed coronavirus infection, 5 (4%) had probable infection, and 5 (4%) were classified as possibly infected.

Stroke, encephalopathy, psychiatric diagnoses

Fifty-seven of 77 stroke patients (74%) had an ischemic stroke caused by a blood clot in the brain, 9 (12%) had a stroke caused by a brain hemorrhage, and 1 (1%) had a stroke caused by inflammation in the brain’s blood vessels. Sixty-one of the 77 stroke patients for whom age was available (82%) were older than 60 years.

Thirty-nine of 125 patients (31%) had behavioral changes indicative of an altered mental state, of whom 9 (23%) had unspecified brain dysfunction known as encephalopathy, and 7 (18%) had brain inflammation, or encephalitis.

The remaining 23 patients with altered mental states had psychiatric diagnoses, including 10 with new-onset psychosis, 7 with depression or anxiety, and 6 with a dementia-like syndrome. Only 2 patients (9%) had exacerbations of a chronic mental illness, although the authors noted that they cannot exclude the possibility that cases classified as new were simply undiagnosed before the pandemic.

Of the 37 of 39 COVID-19 patients with an altered mental state for whom age was available, 18 (49%) were younger than 60 years, which could be because they were more likely to be referred to a psychiatrist or other specialist, while physicians may be likely to attribute confusion or behavioral changes in older patients to delirium without further investigation, the authors said.

Altered mental states in younger patients

While altered mental states are not uncommon in hospitalized patients with infections, especially those requiring intensive care, they occur most often in older patients.

“In this study, we observed a disproportionate number of neuropsychiatric presentations in younger patients and a predominance of cerebrovascular complications in older patients, which might reflect the state of health of the cerebral vasculature and associated risk factors, exacerbated by critical illness in older patients,” the authors said.

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Long-Term Neurologic Symptoms Emerge in COVID-19

— Hospitalized patients show deficits including cognitive impairment 6 months later

Authors: by Judy George, Senior Staff Writer, MedPage Today January 7, 2021share to facebookshare to twittershare to linkedinemail article

Long-term neurologic manifestations were seen in more than a third of patients hospitalized with SARS-CoV-2 infection, a prospective study in Italy showed.

In a group of hospitalized COVID-19 patients with no prior neurologic disease, 37.4% showed abnormalities on neurologic exam 6 months later — most commonly cognitive deficits, hyposmia, and postural tremor — according to Alessandro Padovani, MD, PhD, of the University of Brescia, and co-authors. The findings were reported in a medRxiv preprint and have not undergone peer review.

Patients also noted fatigue, memory impairment, and sleep disorders, Padovani said. “The severity of SARS-CoV-2 infection was an important predictor, together with age and premorbid condition, of long-term neurological symptoms and features in the cohort.”

The findings are important for long-term management of COVID-19 patients, he told MedPage Today. “They showed that the severity of SARS-CoV-2 infection may impact on neurological sequelae, but also that the symptoms reported do not always reflect neurological features at examination.”

The study is one of the first to look specifically for new long-term neurologic manifestations in COVID-19 patients who were hospitalized. Earlier research showed that 87% of patients hospitalized with COVID-19 reported persistence of at least one lingering symptom, notably fatigue and dyspnea, 60 days after discharge. Fatigue and dyspnea also were the most prevalent symptoms reported during infection and at 3-month follow-up in an analysis of both hospitalized and non-hospitalized COVID-19 patients.

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The Impact of COVID-19 on Developing Neurologic Disorders

Authors: Piotr Tekiela,  View ORCID ProfileJennifer J. Majersik

One of the greatest challenges of treating a new virus is the lack of information about it. When little is known about a virus, patients affected by it, as well as their families, are left with uncertainty. In an article appearing in this issue of Neurology®, Dr. Frontera and her team aimed to determine how often patients hospitalized with coronavirus disease 2019 (COVID-19) developed new neurologic disorders.1 They then compared several key outcomes in treatment between patients who developed a new neurologic disorder due to COVID-19 and those who did not. These included discharges to home, ventilator use, length of hospital stay, and in-hospital deaths. These findings can help us understand which groups of people may be more likely to develop more severe disease after having COVID-19, as well as what their prognosis is likely to be.

How Was the Study Done?

The study was run during the first wave of the COVID-19 pandemic, from March 10 through May 20, 2020, in 4 hospitals in the New York City metropolitan area. The researchers set strict guidelines for the type of patients they would include in the study. Patients had to be adults with a laboratory-confirmed severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. They also had to have been admitted to the hospital at some point during the duration of their illness. Patients who were only seen in an emergency department or at an outpatient clinic were not included in the study.

There are 3 major strengths of this study that set it apart from other studies. First, patients were excluded if they were not tested for SARS-CoV-2 or if they tested negative for the virus. Second, all of the neurologic diagnoses made during the study were determined by a neurologist. Lastly, only new diagnoses of neurologic disease were included in the study. If someone had a neurologic disorder that was known before hospitalization due to COVID-19, that diagnosis was not counted in the study results. This improved the accuracy of diagnosing new neurologic complications that appeared to be caused by COVID-19.

What Were the Results?

A total of 4,491 patients were hospitalized with COVID-19 at the 4 hospitals involved in the study. Of those patients, 606 (13.5%) developed a new neurologic disorder, as diagnosed by a neurologist. These disorders included a confused state in 51% (called a toxic-metabolic encephalopathy), stroke in 14%, seizures in 12%, and brain injury due to lack of oxygen or blood flow (called hypoxic or ischemic disorders) in 11% (see below to learn more about these disorders). The researchers did not find any infections in the brain (such as meningitis or encephalitis) or in the spinal cord (myelitis) in these patients. The patients at highest risk of developing a neurologic disease were older and more likely to be male, White, or diabetic.

For most patients (54%) who developed a neurologic disorder, the disorder appeared about 2 days after the initial COVID-19 symptoms (fever, cough, nausea, vomiting, or diarrhea) arose. In 43% of patients, neurologic problems developed at approximately the same time as their initial COVID-19 symptoms. Only 2% of patients developed neurologic symptoms before onset of the common COVID-19 symptoms.

Development of new neurologic disease was associated with worse outcomes overall. Patients who developed a neurologic disorder along with COVID-19 were 28% less likely to be discharged home from the hospital and 38% more likely to die (either from the illness or from the neurologic disorder). Further, they spent 6 more days on a ventilator and 4 more days in the hospital than patients who did not develop a new neurologic disorder.

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How COVID-19 Affects the Brain

Authors: Maura Boldrini, MD, PhD1,2Peter D. Canoll, MD, PhD3Robyn S. Klein, MD, PhD4,5,6

COVID-19 has resulted in more than 120 million cases and 2.6 million deaths to date. Respiratory and gastrointestinal symptoms are accompanied by short- and long-term neuropsychiatric symptoms (NPs) and long-term brain sequelae.

Some patients present with anosmia, cognitive and attention deficits (ie, brain fog), new-onset anxiety, depression, psychosis, seizures, and even suicidal behavior.1,2 These present before, during, and after respiratory symptoms and are unrelated to respiratory insufficiency,1 suggesting independent brain damage. Follow-ups conducted in Germany and the United Kingdom found post–COVID-19 NPs in 20% to 70% of patients, even in young adults, and lasting months after respiratory symptoms resolved,1 suggesting brain involvement persists.

Entering through angiotensin-converting enzyme 2 receptors,2 SARS-CoV-2 can damage endothelial cells leading to inflammation, thrombi, and brain damage. Moreover, systemic inflammation leads to decreased monoamines and trophic factors and activation of microglia, resulting in increased glutamate and N-methyl-d-aspartate (NMDA)3 and excitotoxicity (Figure). These insults induce new-onset or re-exacerbation of preexisting NPs.

Brain Vascular Injury, Neurotransmitter System Dysfunction, Thrombotic Events, Neuronal Damage, and Neuropsychiatric Symptoms

A, SARS-CoV-2 invades endothelial cells via transmembrane angiotensin-converting enzyme 2 (ACE2) receptor, enabled by transmembrane protease, serine 2 (TMPRSS2). B, Cytokine elevation and microglia activation result in increased kynurenine, quinolinic acid, and glutamate, and neurotransmitter depletion. C, Coagulation cascade and elevation of von Willebrand factor (vWF) lead to thrombotic events. D, Altered neurotransmission, excitotoxicity by increased glutamate, and hypoxic injury contribute to neuronal dysfunction and loss. E, Neuropsychiatric symptoms differ depending on the Brodmann area involved. IL indicates interleukin; NMDA, N-methyl-d-aspartate; TNF, tumor necrosis factor.

Does the Virus Invade the Brain?

SARS-CoV-2 is known to penetrate the olfactory mucosa, causing loss of smell, and may enter the brain, migrating from the cribriform plate along the olfactory tract2 or through vagal or trigeminal pathways; however, definitive evidence for this is lacking. SARS-CoV-2 could pass the blood-brain barrier (BBB) because inflammatory cytokines induce BBB instability or via monocytes.4 It could reach brain tissue via circumventricular organs (CVOs), midline structures around the third and fourth ventricles, that monitor blood and cerebral spinal fluid content via fenestrated capillaries lacking the junctional proteins expressed in the BBB. Viral RNA was detected by reverse transcription–quantitative real-time polymerase chain reaction but not by in situ hybridization in medulla and cerebellum,2 located next to the area postrema, a CVO that controls emetic responses to toxins. SARS-CoV-2 protein has been found in brain vascular endothelium but not in neurons or glia.2 Thus, detected viral RNA may represent contamination by vasculature in leptomeninges and Virchow-Robin spaces. Histopathologic analysis of whole human brain showed microglial nodules and phagocytosis of neurons (neuronophagia) in brain stem and less frequently in cortex and limbic structures, associated with sparse lymphocytic infiltration, and no correlations between histopathologic findings and levels of viral messenger RNA in the same brain.5 While ageusia, nausea, and vomiting may be related to CVO and brain stem viral invasion, other short-term and long-lasting NPs are more likely due to neuroinflammation and hypoxic injury. Brain stem involvement may explain persistent autonomic abnormalities and anxiety.

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Neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives


  1. Jonathan P Rogers1,2, Cameron J Watson3,


There is accumulating evidence of the neurological and neuropsychiatric features of infection with SARS-CoV-2. In this systematic review and meta-analysis, we aimed to describe the characteristics of the early literature and estimate point prevalences for neurological and neuropsychiatric manifestations.

We searched MEDLINE, Embase, PsycINFO and CINAHL up to 18 July 2020 for randomised controlled trials, cohort studies, case-control studies, cross-sectional studies and case series. Studies reporting prevalences of neurological or neuropsychiatric symptoms were synthesised into meta-analyses to estimate pooled prevalence.

13 292 records were screened by at least two authors to identify 215 included studies, of which there were 37 cohort studies, 15 case-control studies, 80 cross-sectional studies and 83 case series from 30 countries. 147 studies were included in the meta-analysis. The symptoms with the highest prevalence were anosmia (43.1% (95% CI 35.2% to 51.3%), n=15 975, 63 studies), weakness (40.0% (95% CI 27.9% to 53.5%), n=221, 3 studies), fatigue (37.8% (95% CI 31.6% to 44.4%), n=21 101, 67 studies), dysgeusia (37.2% (95% CI 29.8% to 45.3%), n=13 686, 52 studies), myalgia (25.1% (95% CI 19.8% to 31.3%), n=66 268, 76 studies), depression (23.0% (95% CI 11.8% to 40.2%), n=43 128, 10 studies), headache (20.7% (95% CI 16.1% to 26.1%), n=64 613, 84 studies), anxiety (15.9% (5.6% to 37.7%), n=42 566, 9 studies) and altered mental status (8.2% (95% CI 4.4% to 14.8%), n=49 326, 19 studies). Heterogeneity for most clinical manifestations was high.

Neurological and neuropsychiatric symptoms of COVID-19 in the pandemic’s early phase are varied and common. The neurological and psychiatric academic communities should develop systems to facilitate high-quality methodologies, including more rapid examination of the longitudinal course of neuropsychiatric complications of newly emerging diseases and their relationship to neuroimaging and inflammatory biomarkers.

This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

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