Much has been said about the long-term effects of coronavirus disease 2019 (COVID-19), including neurological side effects. A new study compares the rates of onset of several types of neurological illness, whether degenerative, stroke-related or immunological, after COVID-19 or other respiratory infections.

Introduction

Over 80% of COVID-19 patients hospitalized with the diagnosis have reported neurological symptoms, the most common being headache and anosmia. An increased clotting tendency also exists, and strokes have been described to happen as a complication. Some patients have developed neuropathies such as Guillain-Barre syndrome (GBS) or Parkinson’s disease (PD).

This led to the question as to whether COVID-19 actually increased the risk of neurodegenerative or post-infectious neurological disease.

The current paper, published online in the journal Frontiers in Neurology, examined electronic health records (EHR) for approximately half the population of Denmark, looking for people with a diagnosis of COVID-19 or hospitalized with community-acquired pneumonia, in the period from February 2020 to November 2021. The researchers also included people tested for the flu between February 2018 and November 2019.

Findings

Of over 900,000 people with a history of COVID-19 testing, over 43,000 tested positive. During the same period, approximately 1,500 people had bacterial pneumonia. Thirdly, during the study period, over 8,000 had influenza.

The group of individuals with COVID-19, whether hospitalized or not, had higher rates of COVID-19 risk factors, such as high cholesterol levels, type 2 diabetes mellitus and hypertension, than those hospitalized with the flu. Obesity was more common in COVID-19-positive individuals, or those hospitalized with influenza, and have a history of transient ischemic attacks (TIA).

The latter was more likely among pneumonia inpatients as well, as was smoking, which was also more common among influenza inpatients. Delirium, which is known to be a risk factor for dementia, was more common among COVID-19 patients, at double the frequency among non-COVID-19 patients.

The risk of hemorrhage into the brain was 5 times higher for outpatients with a history of COVID-19. Against this, it must be remembered that intravenous thrombolysis was seven times more common in this group, at 0.14%. Even after accounting for this risk factor, the risk continued to be over four-fold higher.

Alzheimer’s disease (AD) risk increased by 3.5 times, up to a year later. This was the case even after excluding cases with delirium and those who were at risk for stroke, both of which are independent risk factors for AD.

The risk of Parkinson’s disease and ischemic stroke were almost 3-fold higher at up to 12 months in those with a diagnosis of COVID-19.  

However, this was brought into perspective when compared with the rates of the same conditions among individuals who had been hospitalized with influenza or bacterial pneumonia, who showed equivalent rates of both AD and PD.

In this situation, the risk of stroke was almost twice as high among COVID-19 outpatients (but not combined in- and out-patients, or inpatients alone), compared to those without COVID-19, once stroke risk factors were compensated for. This risk was not seen at one month, but began to become obvious from 3 months post-COVID-19. The increase in risk was highest among patients aged 40-59 years, younger than the typical at-risk group for ischemic strokes.

Compared to those with influenza, COVID-19 inpatients also showed a 70% increase in the stroke risk up to 6 months later, diminishing to 30% at one year. When stroke risk factors were accounted for, the risk was found to be tripled or higher in COVID-19 inpatients, even at one year.

Moreover, when compared to inpatients with bacterial pneumonia who were over 80 years of age, the risk was almost 3 times higher among COVID-19 inpatients, but no overall increase in risk was found after accounting for the stroke risk factors.

There was no observable difference in the rates of post-infectious neuropathies or neurodegenerative disease among those with or without a history of any of these infectious conditions.

Implications

The results of this study indicate a causative role of neuroinflammation, tiredness and negative emotions in COVID-19 patients that may have contributed to the higher incidence of AD and PD at one year from the initial diagnosis. Young patients who died of COVID-19 have been found to have abnormally elevated concentrations of the pathological protein β-amyloid in their brains.

Against this must be set the higher attention paid to patients with a history of COVID-19, which may have led to an earlier and more frequent diagnosis of these conditions in their later history, compared to COVID-19-negative patients. However, AD and PD rates were comparable to those found after hospitalization with influenza or bacterial pneumonia.

In contrast, there was an increased incidence of ischemic stroke among COVID-19 patients compared to those with a history of influenza or bacterial pneumonia. The explanations may include the inflammatory state, the cardiac involvement leading to cardiac embolism, immobilization during the hospital stay, or some unique characteristic of this infection.   

The incidence of intracerebral bleeds was more common at one month among COVID-19 outpatients, compared to individuals without COVID-19, but comparable to that found after prior influenza or bacterial pneumonia. Risk factors include anticoagulant therapy, mechanical ventilation, and the use of extracorporeal membrane oxygenation (ECMO).

Even after compensating for thrombolysis, the risk of hemorrhage remained elevated, showing that COVID-19 itself posed a risk factor. The findings here suggest that patients with a history of respiratory infections should be monitored for neurodegenerative disorders, and that ischemic stroke appears to be a risk peculiar to COVID-19. Further studies will be required to validate this hypothesis.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.