A new study by researchers from Copenhagen University Hospital- Denmark and the University of Copenhagen-Denmark has shown that compared to influenza or bacterial pneumonia, COVID-19 infections lead to higher risk of ischemic strokes.
The COVID-19-Ischemic Strokes study team characterized the frequency of neurodegenerative, cerebrovascular, and immune-mediated neurological diseases after COVID-19 compared to individuals without COVID-19 and those with other respiratory tract infections.
The study findings were published in the peer reviewed journal: Frontiers in Neurology. https://www.frontiersin.org/articles/10.3389/fneur.2022.904796/full
Key findings from this population-based cohort study covering roughly half of Denmark’s population include an increased frequency of new-onset neurodegenerative and cerebrovascular (but not neuroimmune) disorders in COVID-19 positive compared to COVID-negative individuals.
However, when comparing the frequencies of these disorders after COVID-19 with those after influenza and community-acquired pneumonia, we found no significant differences, except for ischemic stroke.
Alzheimer’s disease was 3.4 times more frequent and Parkinson’s disease was 2.2 times more frequent in COVID-19 positive than COVID-negative individuals, 12 months after a COVID-19 test. These findings should be considered in light of the prolonged temporal course and the complex pathophysiology of these disorders, including a possible role for neuroinflammation: it is hypothesized that the body’s innate response and subsequent inflammatory processes can induce a toxic cycle of accumulating β-amyloid and alpha-synuclein peptides (the pathologic hallmarks of Alzheimer’s and Parkinson’s diseases) (22–26).
In support of this, unexpectedly high amounts of β-amyloid peptides have been discovered in brain autopsies of young deceased patients with COVID-19 (27). Other factors such as fatigue, depression, and anxiety after COVID-19 may also contribute to the development of neurodegenerative disorders (20, 28–34).
Moreover, it is uncertain if the risk of Alzheimer’s disease and Parkinson’s disease differs after COVID-19 compared to after influenza and bacterial pneumonia. Finally, the scientific focus on long-term sequelae after COVID-19 may have led to increased recognition by clinicians and hence earlier diagnosis, perhaps explaining some of the observed increase in neurodegenerative diagnoses.
New-onset ischemic stroke was 2.3 times more frequent in COVID-19 positive than COVID-negative outpatients after 3 months. Ischemic stroke was also 1.7 times more frequent in COVID-19 inpatients compared to influenza inpatients in the early and subacute phases after a positive test, as supported by previous retrospective studies (albeit with shorter observation periods) (5, 35).
Ischemic stroke was also 2.7 times more frequent in COVID-19 inpatients compared to bacterial pneumonia among the elderly. In our study, the overall incidence of ischemic stroke in COVID-19 positive inpatients (1.8%) is well in line with previously reported data (0.4-2.7%) (36–39).
Of note, age-specific stratifications showed that the relative risk for ischemic stroke was highest amongst patients between 40 and 59 years. A recent study of 37,379 Medicare fee-for-service beneficiaries aged ≥65 years diagnosed with COVID-19 (36) and a multi-center study involving a further 423 patients (40) similarly found an increase in ischemic stroke among younger patients when compared to population studies before the pandemic.
Increased rates of ischemic stroke in COVID-19 patients may occur for several reasons. In line with an inflammatory etiology, there were minimal differences in cerebrovascular events between COVID-19 positive and community-acquired pneumonia inpatients in our study, except for elderly patients, who generally have a weaker inflammatory response (41).
It is unknown if the increased risk of thromboembolic events in COVID-19 patients can be directly attributed to unique properties of the virus, or if it is a consequence of a more pronounced inflammatory state (41). Moreover, given the association of COVID-19 with cardiac disorders, including myocarditis, arrhythmias, heart failure, and myocardial infarction, cardiac embolism is also a potential mechanism (42–44).
It should be noted that COVID-19 patients had a slightly higher rate of certain pre-existing risk factors for ischemic stroke, including hypercholesterolemia, diabetes mellitus, and hypertension, as have previously been reported (3, 45). However, even when these cerebrovascular risk factors were excluded from analysis, the COVID-19 population maintained a higher risk of ischemic stroke. Finally, factors such as immobilization during hospital admission may increase stroke risk as well (44).
Intracerebral and Subarachnoid Hemorrhage
The 1-month incidence of intracerebral hemorrhage among COVID-19 inpatients was 0.1%, similar to previously published studies (46). The frequency was 4.8 times higher in COVID-19 positive compared to negative outpatients. There was, however, no excess risk compared to patients with influenza or community-acquired bacterial pneumonia.
Some authors have argued that a subset of intracerebral hemorrhages may be due to hemorrhagic conversion of ischemic events, particularly after anticoagulation therapy (47–49). In two recent studies, 76% (25 of 33) and 60% (6 out 10) of patients developed intracerebral hemorrhage after low- or high-dose anticoagulation therapy (47, 48).
Besides anticoagulation, a systematic review of 94 studies found that older age, mechanical ventilation and extracorporeal membrane oxygenation also increased the risk of intracranial hemorrhage in COVID-19 patients (46). In our study, the risk of intracerebral hemorrhage remained elevated after removal of patients who received intravenous thrombolysis, indicating an independent COVID-19 related risk.
In our study of over 43,000 COVID-19 patients, only four individuals developed subarachnoid hemorrhage within the first month, and 10 within 12 months. This does not represent an excess risk compared to COVID-negative individuals and patients with influenza or bacterial pneumonia. Our results confirm findings from another large study with 85,645 COVID-19 patients, in which 86 developed SAH, without an excess risk compared to COVID-negative patients (50).
Auto-Immune Neurological Diseases
In our study, only two patients developed GBS. In a study of 1,200 COVID-19 patients from Italy (51) and a study of 3,927 COVID-19 patients from India, there were five cases of GBS each, (52) which appears to be an order of magnitude higher than our data. Another epidemiologic study showed that the incidence of GBS was lower during the pandemic than the corresponding months in the four preceding pre-pandemic years (53). However, precautionary measures intended to reduce the risk of COVID-19 transmission might also have reduced the rate of other infectious diseases associated with GBS (54).
In the COVID-19 positive population, 14 of 43,375 individuals developed MS 12 months after a positive test, which did not represent an excess risk. Cases of multiple sclerosis after COVID-19 infection or vaccination have been reported, (55–59) but to our knowledge, no study has yet investigated the incidence of multiple sclerosis after COVID-19.
Myasthenia Gravis and Narcolepsy
In the COVID-19 cohort, only one individual developed myasthenia gravis, and none were diagnosed with narcolepsy, 12 months after a positive test. Only a few cases of new-onset myasthenia gravis following COVID-19 have been reported, (60, 61) and to our knowledge, none of narcolepsy. Based on our findings, it appears that COVID-19 does not increase the 1-year risk of myasthenia gravis or narcolepsy.
It must, however, be kept in mind that the median age of new-diagnosed narcolepsy patients is 12 years (62). Given the inclusion criteria of adults ≥18 years, we may have missed a possible association between COVID-19 and narcolepsy. Longer follow-up studies in larger and younger COVID-19 populations are needed to exclude subsequent risks of myasthenia gravis and narcolepsy.