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BRIEF RESEARCH REPORT
published: 23 June 2022
doi: 10.3389/fneur.2022.904796
Frontiers in Neurology | www.frontiersin.org 1June 2022 | Volume 13 | Article 904796
Edited by:
Erwin Chiquete,
Instituto Nacional de Ciencias
Médicas y Nutrición Salvador Zubirán
(INCMNSZ), Mexico
Reviewed by:
Martin Rakuša,
Maribor University Medical
Centre, Slovenia
Marialuisa Zedde,
IRCCS Local Health Authority of
Reggio Emilia, Italy
*Correspondence:
Michael E. Benros
Michael.eriksen.benros@regionh.dk
Daniel Kondziella
daniel.kondziella@regionh.dk
Specialty section:
This article was submitted to
Neuroepidemiology,
a section of the journal
Frontiers in Neurology
Received: 25 March 2022
Accepted: 26 May 2022
Published: 23 June 2022
Citation:
Zarifkar P, Peinkhofer C, Benros ME
and Kondziella D (2022) Frequency of
Neurological Diseases After
COVID-19, Influenza A/B and Bacterial
Pneumonia.
Front. Neurol. 13:904796.
doi: 10.3389/fneur.2022.904796
Frequency of Neurological Diseases
After COVID-19, Influenza A/B and
Bacterial Pneumonia
Pardis Zarifkar 1, Costanza Peinkhofer 1, Michael E. Benros 2,3
*and Daniel Kondziella 1,4
*
1Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, 2Copenhagen
Research Center for Mental Health–CORE, Mental Health Center Copenhagen, Copenhagen University Hospital,
Copenhagen, Denmark, 3Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark,
4Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Introduction: COVID-19 might affect the incidence of specific neurological diseases, but
it is unknown if this differs from the risk following other infections. Here, we 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.
Methods: This population-based cohort study utilized electronic health records covering
∼50% of Denmark’s population (n=2,972,192). Between 02/2020 and 11/2021,
we included individuals tested for COVID-19 or diagnosed with community-acquired
bacterial pneumonia in hospital-based facilities. Additionally, we included individuals
tested for influenza in the corresponding pre-pandemic period between 02/ 2018 and
11/2019. We stratified cohorts for in- and outpatient status, age, sex, and comorbidities.
Results: In total, 919,731 individuals were tested for COVID-19, of whom 43,375
tested positive (35,362 outpatients, 8,013 inpatients). Compared to COVID-negative
outpatients, COVID-19 positive outpatients had an increased RR of Alzheimer’s disease
(RR =3.5; 95%CI: 2.2–5.5) and Parkinson’s disease (RR =2.6; 95%CI: 1.7–4.0),
ischemic stroke (RR =2.7; 95%CI: 2.3–3.2) and intracerebral hemorrhage (RR =4.8;
95%CI: 1.8–12.9). However, when comparing to other respiratory tract infections, only
the RR for ischemic stroke was increased among inpatients with COVID-19 when
comparing to inpatients with influenza (RR =1.7; 95%CI: 1.2–2.4) and only for those >80
years of age when comparing to inpatients with bacterial pneumonia (RR =2.7; 95%CI:
1.2–6.2). Frequencies of multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome
and narcolepsy did not differ after COVID-19, influenza and bacterial pneumonia.
Conclusion: The risk of neurodegenerative and cerebrovascular, but not neuroimmune,
disorders was increased among COVID-19 positive outpatients compared to
COVID-negative outpatients. However, except for ischemic stroke, most neurological
disorders were not more frequent after COVID-19 than after other respiratory infections.
Keywords: COVID-19, SARS-CoV-2, bacterial pneumonia, Alzheimer’s disease (AD), Parkinson’s disease (PD),
ischemic stroke (IS), auto-immune
Zarifkar et al. Neurological Diseases After COVID-19
INTRODUCTION
Neurological symptoms, including headache and anosmia,
are present in more than 80% of hospitalized COVID-19
patients (1,2). There is also evidence of an inflammatory
hypercoagulable state with subsequent cerebrovascular incidents,
(3–8) and case descriptions exist of Guillain-Barré syndrome
(GBS) and Parkinson’s disease following COVID-19 (9,10).
To our knowledge, however, epidemiologic studies investigating
the incidence of specific neurodegenerative diseases such as
Alzheimer’s disease and Parkinson’s disease or auto-immune
disorders (e.g., multiple sclerosis, narcolepsy, and myasthenia
gravis) after COVID-19 are still missing.
The aim of this study was to provide the first broad
investigation into the influence of COVID-19 on neurological
diseases, providing a rapid glimpse based on the electronic
health record data currently available while awaiting more
detailed longitudinal nationwide registry studies. Specifically, we
aimed to (1) characterize the frequency and relative risk (RR)
of neurodegenerative, cerebrovascular, and immune-mediated
diseases in patients with COVID-19, and (2) to compare the risk
of being diagnosed with a neurological disease after COVID-
19 to the risk after influenza A/B and community-acquired
bacterial pneumonia.
METHODS
Study Population
Using previously published methods, (5) we extracted patient
data from electronic health records covering 2,972,192
individuals, equating to ∼50% of the Danish population
from two (of five in total) well-defined administrative regions
in Denmark, i.e., the Capital Region (Greater Copenhagen and
Bornholm) and Region Zealand. The electronic health records
(EPIC, version 2021, Wisconsin, USA) Slicer-Dicer function,
were searched from implementation in 2016 to November 27,
2021. All individuals ≥18 years who were tested in a hospital
setting for COVID-19, influenza A/B (referred to as influenza)
or diagnosed with community-acquired bacterial pneumonia
(referred to as bacterial pneumonia) were followed for new-onset
neurological diseases up to 12 months later. Included individuals
were (1) hospitalized patients tested for COVID-19, influenza,
or diagnosed with bacterial pneumonia during admission
(referred to as “inpatients”), and (2) non-hospitalized patients
tested during ambulatory visits, or healthy individuals tested
in hospital-based facilities that serve the general population
(referred to as “outpatients”). Individuals tested for COVID-19
in the community setting (e.g., over-the-counter antigen tests or
PCR tests from private providers and primary care settings) were
not captured. We also collected anonymized aggregated data on
age, sex, smoking, pre-existing comorbidities, laboratory data,
medical prescriptions, and history of neurological disorders.
Data extraction and analysis were conducted in consultation
with EPIC data experts from our institution (Rigshospitalet,
Copenhagen University Hospital) according to previous
publications by our group (5).
Slicer Dicer search strategies are detailed in
Supplementary Table 1.
Study Period
The study period spanned from February 27, 2018 to November
27, 2021. COVID-19 and bacterial pneumonia patients were
included from February 27, 2020 (the first reported case of
COVID-19 in Denmark) (11) to November 27, 2021 (the day
before the first reported case of the omicron variant in Denmark)
(12), and influenza patients from February 27, 2018, to November
27, 2019 (the corresponding 2-year pre-pandemic period).
Assessment of Infection Exposure
COVID-19 or influenza positive cases were determined by
positive reverse-transcriptase polymerase chain reaction assays
of nasal, pharyngeal, or tracheal samples. We defined COVID-
19 or influenza negative cases as having negative laboratory test
results and (for those tested more than once) no previous history
of positive laboratory tests.
Assessment of Neurological Outcomes
Using ICD-10 diagnoses, we identified individuals with
neurodegenerative (Alzheimer’s disease, Parkinson’s disease),
cerebrovascular (ischemic stroke, intracerebral hemorrhage,
subarachnoid hemorrhage), and immune-mediated (multiple
sclerosis, GBS, myasthenia gravis, and narcolepsy) disorders.
ICD-10 diagnosis codes are detailed in Supplementary Table 1.
Statistical Analyses
We calculated the risk of new-onset neurological diagnoses in
the acute (1 month), subacute (3 and 6 months), and chronic
(12 months) phases after a diagnosis of COVID-19, influenza,
or bacterial pneumonia. Specifically, we calculated the relative
risk (RR) of diagnosis rates with 95% confidence intervals (CI)
and stratified the study population across admittance status
(inpatients and outpatients), age (18–39, 40–59, 60–79, and
≥80 years), and sex (male and female), using R studio (2021
Vienna, Austria). To reduce the risk of type II errors, statistical
analyses were only conducted for diseases with ≥4 cases in each
group. Hospitalization and delirium [which occurs at higher
rates in COVID-19 patients (Table 1)] can lead to cognitive
decline and aggravate neurodegenerative diseases (13–16). Thus,
to best balance recovery from hospitalization and allow for
reliable diagnoses, Alzheimer’s disease and Parkinson’s disease
patients diagnosed within the first 3 months after admission were
excluded from 6 and 12-month assessments (14–16).
Sensitivity Analyses
To search for possible bias related to restricted access to
diagnostic work-up during the pandemic, the prevalence
of disease-specific diagnostic procedures (including cerebral
fluorodeoxyglucose (FDG)- positron emission tomography
(PET)-18 for Alzheimer’s disease and single-photon emission
computerized tomography (SPECT) for Parkinson’s disease),
medical prescriptions and common risk factors, including
smoking status, and pre-existing comorbidities were compared
across groups using chi-squared statistics with a Yates correction.
Where there was a significant difference in risk factors
Frontiers in Neurology | www.frontiersin.org 2June 2022 | Volume 13 | Article 904796
Zarifkar et al. Neurological Diseases After COVID-19
TABLE 1 | Clinical characteristics and demographics at baseline.
Inpatient status at baseline Outpatient status at baseline
COVID-19
positive
(n=8,013)
COVID-19
negative
(n=230,686)
Influenza
positive
(n=4,142)
Pneumonia
(n=1,474)
COVID-19
positive
(n=35,362)
COVID-19
negative
(n=645,670)
Influenza
positive
(n=3,960)
Age, n(%)
Mean, years 66y 58y 68y 75y 48y 47y 52y
18–39 1,023
(12.8%)
65,333
(28%)
508
(12.3%)
44
(3%)
14,309
(40.1%)
258,412
(40%)
1,352
(34.1%)
40–59 1,841
(23%)
38,108
(20.9%)
854
(20.6%)
140
(9.5%)
12,526
(35.4%)
234,480
(36.3%)
1,482
(37.4%)
60–79 3,128
(39%)
76,865
(33.3%)
1,743
(42.08%)
671
(45.5%)
5,731
(16.2%)
128,382
(19.9%)
929
(23.4%)
≥80 2,021
(25.2%)
40,380
(17.5%)
1,037
(25%)
619
(42%)
2,796
(7.9%)
24,396
(3.8%)
197
(5%)
Sex, n(%)
Females 3,567
(44.5%)
131,399
(57%)
2,257
(54%)
625
(42.4%)
20,913
(59.1%)
368,142
(57%)
2,374
(59.9%)
Smoking status, n(%)
Current or history of
smoking (%)
3,141
(39.2%)
93,283
(40.4%)
2,053
(49.6%)
829
(56.2%)
6,180
(17.5%)
117,505
(18.2%)
931
(23.5%)
Pre-existing comorbidities, n(%)
Celiac disease 11
(0.1%)
370
(0.2%)
1
(0.02%)
1
(0.07%)
51
(0.1%)
1,071
(0.2%)
3
(0.08%)
Delirium 149
(1.9%)
1,335
(1%)
19
(0.5%)
33
(2.2%)
127
(0.4%)
429
(0.1%)
1
(0.03%)
Diabetes mellitus, type 1 30
(0.4%)
719
(0.3%)
16
(0.4%)
7
(0.5%)
66
(0.2%)
974
(0.2%)
9
(0.2%)
Diabetes mellitus, type 2 501
(6.2%)
7,880
(3.4%)
142
(3.4%)
102
(6.9%)
4,397
(1.4%)
5,335
(0.8%)
30
(0.8%)
Hashimoto’s
auto-immune thyroiditis
11
(0.14%)
417
(0.2%)
5
(0.1%)
0
(0%)
67
(0.2%)
1,103
(0.2%)
3
(0.08%)
Hypercholesterolemia 431
(5.4%)
9,571
(4.2%)
118
(2.9%)
83
(5.6 %)
560
(1.6%)
8,303
(1.3%)
39
(1%)
Hypertension 1,681
(21%)
36,754
(15.9%)
519
(12.5%)
411
(27.9%)
2,155
(6.1%)
29,935
(4.6%)
155
(4%)
Ischemic stroke 340
(4.2%)
10,030
(4.4%)
53
(1.3%)
96
(6.5%)
442
(1.3%)
3,829
(0.6%)
26
(0.7%)
Obesity 356
(4.4%)
10,962
(4.8%)
60
(1.5%)
36
(2.4%)
959
(2.7%)
15,465
(2.4%)
56
(1.4%)
Rheumatoid arthritis 46
(0.6%)
982
(0.4%)
22
(0.5%)
13
(0.9%)
66
(0.2%)
995
(0.2%)
10
(0.2%)
Transitory cerebral
ischemia
130
(1.6%)
4,197
(1.8%)
24
(0.6%)
37
(2.5%)
220
(0.6%)
2,505
(0.4%)
7
(0.2%)
between groups, the populations at risk were excluded from
comparative analyses.
Ethics and Data Availability Statement
The Scientific Ethics Committee of the Capital Region of
Denmark waives approval for register-based studies on
aggregated anonymized data (Section 14.2, Committee Act 2).
The datasets included in this study are freely available to medical
and administrative staff in Denmark with access to electronic
health records in EPIC.
RESULTS
Between February 27, 2020 and November 27, 2021, a total of
919,731 individuals were tested for COVID-19 in a hospital-
based facility. Of these, 43,375 individuals had a positive COVID-
19 test (equating to 20% of the COVID-19 positive population
in the surveyed areas) (17) and 876,356 had a negative COVID-
19 test (40% of the COVID-negative population in these areas)
(18). A total of 1,474 individuals were diagnosed with bacterial
pneumonia in a hospital-based facility during the same period.
Between February 27, 2018 and November 27, 2019, a total of
Frontiers in Neurology | www.frontiersin.org 3June 2022 | Volume 13 | Article 904796
Zarifkar et al. Neurological Diseases After COVID-19
FIGURE 1 | Flowchart of individuals tested for COVID-19 or Influenza A/B, and diagnosed with community-acquired bacterial pneumonia.
8,102 individuals were tested positive for influenza. A flowchart
of the study population is depicted in Figure 1, and demographic
and clinical characteristics are detailed in Table 1.
Risk Factors at Baseline
The prevalence and comparative analyses of clinical
baseline characteristics are detailed in Table 1 and
Supplementary Table 2. Compared to COVID-negative
individuals (in- and outpatients separately and combined) and
influenza inpatients, COVID-19 positive individuals carried
higher rates of some pre-existing cerebrovascular risk factors,
(19) including hypercholesterolemia, diabetes mellitus type 2
and hypertension. Compared to COVID-negative outpatients
and influenza inpatients, COVID-19 positive individuals
also had higher rates of obesity, and a history of transitory
ischemic attack. By contrast, smoking rates were higher among
COVID-negative individuals, and influenza and pneumonia
inpatients. Pneumonia inpatients also had higher rates of past
transitory ischemic attacks. There were no other differences
in cerebrovascular risk factors, nor in the rates of pre-existing
auto-immune disorders.
The Incidence of New-Onset
Neurodegenerative, Cerebrovascular and
Auto-Immune Disorders
The incidence, absolute risk, and RR of all neurological diseases
in COVID-19 positive and COVID-negative individuals are
depicted in Figure 2 and Table 2. Stratifications by age and sex
are detailed in Supplementary Table 3, and stratifications by in-
and outpatient status are detailed in Supplementary Table 4.
The incidences, absolute risks, and RR’s of all neurological
diseases in COVID-19 positive, influenza positive, and
bacterial pneumonia patients are depicted in Table 3 and
Supplementary Table 5.
Alzheimer’s Disease and Parkinson’s
Disease
The RR of Alzheimer’s disease was increased 6 and 12
months after a positive test in COVID-19 positive compared
to COVID-negative individuals (in- and outpatients combined),
and separately among in- and outpatients (in- and outpatients:
RR =3.5; 95%CI: 2.5–5.6 at 6 months and RR =3.4; 95%CI: 2.3–
5.1 at 12 months; inpatients: six (RR =3.3; 95%CI: 1.7–9.3 at 6
months and RR =3.7; 95%CI: 1.7–8.0 at 12 months; outpatients;
RR =3.6; 95%CI: 2.1–6.1 at 6 months and RR =3.5, 95%CI:
2.2–5.5 at 12 months).
Notably, COVID-19 positive individuals had a higher
frequency of delirium, an independent risk factor for
dementia (20) (0.6 vs. 0.3%, χ2=128.2, p<0.00001),
compared to COVID-negative individuals. After exclusion
of those with a history of delirium, the RR for Alzheimer’s
disease remained elevated in COVID-19 individuals (in-
and outpatients combined) (Supplementary Table 6), and
separately in both in- and outpatients. COVID-19 positive
individuals also had a higher frequency of cerebrovascular
Frontiers in Neurology | www.frontiersin.org 4June 2022 | Volume 13 | Article 904796
Zarifkar et al. Neurological Diseases After COVID-19
FIGURE 2 | Relative risk of neurodegenerative, cerebrovascular and neuroimmune neurological disorders after COVID-19 (A). Bar chart of the relative risks (RR) of
new-onset neurodegenerative disorders and cerebrovascular events after 12 months in COVID-19 positive versus COVID-negative individuals, inpatients, and
outpatients. Barcharts depict RR with 95% confidence intervals. (B) Forest plot of the RR of new-onset neurodegenerative, cerebrovascular and neuroimmune
disorders six (black) and twelve (blue) after COVID-19 in COVID-19 positive outpatients compared to negative outpatients.
risk factors (Table 1 and Supplementary Table 2). After
exclusion of those with cerebrovascular risk factors, the RR for
Alzheimer’s disease remained elevated in COVID-19 individuals
(Supplementary Table 6). In the inpatient group, there were too
few cases for statistical analyses.
The RR of Parkinson’s disease was increased 6 and 12
months after a positive test in COVID-19 positive compared
to COVID-negative individuals (in- and outpatients combined)
and specifically in COVID-19 outpatients (in- and outpatients
combined: RR =2.4; 95%CI: 1.5–3.8 at 6 months and RR
=2.2; 95%CI: 1.5–3.4 at 12 months; outpatients: RR =2.7;
95%CI: 1.7–4.4 at 6 months and RR =2.6; 95% CI: 1.7–
4.0. Among inpatients, there were not enough Parkinson’s
disease cases to conduct meaningful statistics. Finally, there
was no excess risk of Alzheimer’s disease or Parkinson’s
disease compared to influenza or bacterial pneumonia inpatients
(Table 3).
From February 27, 2020 to November 27, 2021, 1,137
cerebral PET-FDG-18 scans were conducted in COVID-19
positive individuals and 23,889 in COVID-negative individuals,
corresponding to a 3% scanning rate in each group (χ2=1.7, p=
0.19). Similarly, there was no difference in the number of SPECT
scans among COVID-19 positive and negative individuals (0.04
vs. 0.03%, χ2=2.1, p=0.14), indicating equal access to these
diagnostic tools.
Ischemic Stroke
The frequency of new-onset ischemic stroke did not differ
significantly between COVID-19 positive and COVID-negative
individuals (in- and outpatients combined), nor between
COVID-19 positive and COVID-negative inpatients (Table 2
and Supplementary Table 4). Compared to COVID-negative
outpatients, the RR of ischemic stroke was increased three,
six, and 12 months after a positive test in COVID-19 positive
outpatients but was insignificant within the first month (RR =
1.4, 95%CI: 1.0–2.0, p=0.08 after 1 month, RR =2.3; 95%
CI: 1.8–3.0 after 3 months, RR =2.8; 95%CI: 2.2–3.4 after
6 months and RR =2.7; 95%CI: 2.3–3.2 after 12 months).
Notably, age-specific stratifications showed that the relative risk
was highest among younger patients between 40 and 59 years
(Supplementary Table 3). After exclusion of cerebrovascular risk
factors, the RR for ischemic stroke remained elevated in COVID-
19 positive outpatients (RR =1.8; 95%CI: 1.5–2.8 after 3 months,
RR =2.2; 95% CI:1.5–3.1 after 6 months, and RR =2.1; 95%
CI:1.5–2.8 after 12 months).
Compared to influenza positive inpatients, COVID-19
inpatients had an increased RR of ischemic stroke one, three, and
6 months after a positive test (RR =1.7; 95%CI: 1.1–2.6 after
1 month; RR =1.7; 95%CI: 1.2–2.5 after 3 months; RR =1.7;
95%CI: 1.2–2.4 after 6 months). After 12 months, the RR between
the two groups was decreased (RR =1.3; 95%CI: 1.0–1.8, p=
0.09). After removal of cerebrovascular risk factors, the RR of
ischemic stroke remained increased in COVID-19 inpatients (RR
=3.4; 95%CI: 1.4–8.2 after 1 month; RR =3.0; 95%CI: 1.5–6.3
after 3 months; RR =3.5; 95%CI: 1.7–7.2 after 6 months; RR =
2.8; 95%CI: 1.5–5.0 after 12 months; Supplementary Table 6).
The frequency of ischemic stroke did not differ significantly
between COVID-19 positive and bacterial pneumonia inpatients
(Table 3). After removal of individuals with significant
cerebrovascular risk factors, there remained no significant
difference between groups (Supplementary Table 6). After
stratification for age, the incidence of ischemic stroke was
increased in COVID-19 positive inpatients aged ≥80 (RR =2.7;
95%CI: =1.2–6.2), but not in other age groups.
Intracerebral and Subarachnoid
Hemorrhage
The RR of intracerebral hemorrhage was increased 12 months
after a positive test in COVID-19 positive compared to COVID-
negative outpatients (RR =4.8; 95%CI: 1.8–12.9). There
were no other differences in the rates of intracerebral and
subarachnoid hemorrhage between groups (Tables 2,3and
Supplementary Tables 4, 5). Notably, COVID-19 outpatients
received higher rates of intravenous thrombolysis, a risk factor
for medically induced intracerebral hemorrhage (21) (0.14% in
COVID-19 positive vs. 0.02% in COVID-negative outpatients,
Frontiers in Neurology | www.frontiersin.org 5June 2022 | Volume 13 | Article 904796
Zarifkar et al. Neurological Diseases After COVID-19
TABLE 2 | Relative risk of neurodegenerative, cerebrovascular and neuroimmune disorders in COVID-19 positive compared to COVID-negative individuals.
COVID-19
positive
(n=43,375)
COVID-19
negative
(n=876,356)
RR
(95%CI)
COVID-19
positive
(n=43,375)
COVID-19
negative
(n=876,356)
RR
(95%CI)
COVID-19
positive
(n=43,375)
COVID-19
negative
(n=876,356)
RR
(95%CI)
COVID-19
positive
(n=43,375)
COVID-19
negative
(n=876,356)
RR
(95%CI)
1 month, n(%) 3 months, n(%) 6 months, n(%) 12 months, n(%)
Alzheimer’s
disease
- - - - - - 21
(0.05%)
121
(0.01%)
3.5
(2.2–5.6)*
29
(0.07%)
171
(0.02%)
3.4
(2.3–5.1)*
Parkinson’s
disease
- - - - - - 20
(0.05%)
169
(0.02%)
2.4
(1.5–3.8)*
26
(0.06%)
234
(0.03%)
2.2
(1.5–3.4)*
Ischemic stroke 117
(0.3%)
6,251
(0.7%)
0.4
(0.3–0.5)*
180
(0.4%)
6,908
(0.8%)
0.6
(0.5–0.7)*
227
(0.5%)
7,365
(0.8%)
0.6
(0.5–0.7)*
281
(0.6%)
7,910
(0.9%)
0.7
(0.6–0.8)
Intracerebral
hemorrhage
7
(0.02%)
250
(0.03%)
0.6
(0.3–1.2)
10
(0.02%)
280
(0.03%)
0.7
(0.4–1.4)
13
(0.03%)
306
(0.03%)
0.9
(0.5–1.5)
16
(0.04%)
330
(0.04%)
1.0
(0.6–1.6)
Subarachnoid
hemorrhage
4
(0.01%)
201
(0.02%)
0.4
(0.1–1.1)
5
(0.01%)
233
(0.03%)
0.4
(0.2–1.1)
6
(0.01%)
254
(0.03%)
0.5
(0.2–1.1)
ll10
(0.02%)
289
(0.03%)
0.7
(0.4–1.3)
Guillain-Barré
syndrome
1
(0.002%)
52
(0.006%)
N/A 2
(0.005%)
58
(0.007)
N/A 2
(0.005)
61
(0.007%)
N/A 2
(0.005)
64
(0.007%)
N/A
Multiple sclerosis 4
(0.01%)
185
(0.02%)
0.4
(0.2–1.2)
6
(0.01%)
246
(0.03%)
0.5
(0.2–1.1)
11
(0.03%)
293
(0.03%)
0.8
(0.4–1.4)
14
(0.03%)
332
(0.04%)
0.9
(0.5–1.5)
Myasthenia gravis 1
(0.002%)
44
(0.005%)
N/A 1
(0.002%)
59
(0.007%)
N/A 1
(0.002%)
61
(0.007%)
N/A 1
(0,002%)
71
(0.008%)
N/A
Narcolepsy 0
(0.0%)
19
(0.002%)
N/A 0
(0.0%)
30
(0.003%)
N/A 0
(0.0%)
37
(0.004%)
N/A 0
(0.0%)
41
(0.005%)
N/A
Statistical analyses were only conducted for diseases with ≥4 cases in each group.
*Statistically significant RR (p <0.05) are highlighted in bold.
Excluding inpatient cases of Alzheimer’s disease and Parkinson’s disease the first three months after hospitalization with COVID-19.
Frontiers in Neurology | www.frontiersin.org 6June 2022 | Volume 13 | Article 904796
Zarifkar et al. Neurological Diseases After COVID-19
TABLE 3 | Relative risk of neurodegenerative, cerebrovascular and neuroimmune disorders in inpatients with COVID-19 compared to influenza inpatients and community-acquired bacterial pneumonia inpatients.
COVID- 19
positive
(n=7,964)
Influenza
positive
(n=4,142)
RR
(95%CI)
COVID-19
positive
(n=7,964)
Influenza
positive
(n=4,142)
RR
(95%CI)
COVID-19
positive
(n=7,891)
Pneumonia
(n=1,474)
RR
(95%CI)
COVID-19
positive
(n=7,891)
Pneumonia
(n=1,474)
RR
(95%CI)
1 month, n(%) 3 months, n(%) 1 month, n(%) 3 months, n(%)
Ischemic stroke 85
(1.07%)
26
(0.63%)
1.7
(1.1–2.6)*
113
(1.4%)
34
(0.8%)
1.7
(1.2–2.5)*
79
(1.0%)
14
(0.9%)
1.1
(0.6–1.9)
107
(1.4%)
19
(1.3%)
1.18
(0.6–1.7)
Intracerebral
hemorrhage
6
(0.08%)
0
(0.0%)
N/A 8
(0.1%)
0
(0.0%)
N/A 9
(0.1%)
0
(0.0%)
N/A 8
(0.1%)
0
(0.0%)
N/A
Subarachnoid
hemorrhage
4
(0.05%)
0
(0.0%)
N/A 5
(0.06%)
0
(0.0%)
N/A 6
(0.08%)
0
(0.0%)
N/A 5
(0.06%)
0
(0.0%)
N/A
Guillain-Barré
syndrome
1
(0.01%)
2
(0.05%)
N/A 1
(0.01%)
2
(0.05%)
N/A 1
(0.01%)
1
(0.07%)
N/A 1
(0.01%)
1
(0.07%)
N/A
Multiple sclerosis 1
(0.01%)
0
(0.0%)
N/A 1
(0.01%)
1
(0.02%)
N/A 1
(0.01%)
2
(0.1%)
N/A 1
(0.01%)
2
(0.1%)
N/A
Myasthenia gravis 1
(0.01%)
0
(0.0%)
N/A 1
(0.01%)
0
(0.0%)
N/A 1
(0.01%)
0
(0.0%)
N/A 1
(0.01%)
0
(0.0%)
N/A
Narcolepsy 0
(0.0%)
0
(0.0%)
N/A 0
(0.0%)
0
(0.0%)
N/A 0
(0.0%)
0
(0.0%)
N/A 0
(0.0%)
0
(0.0%)
N/A
6 months, n(%) 12 months, n(%) 6 months, n(%) 12 months, n(%)
Alzheimer’s
disease
4
(0.05%)
1
(0.02%)
N/A 7
(0.09%)
3
(0.07%)
N/A 4
(0.05%)
0 N/A 7
(0.09%)
0
(0.0%)
N/A
Parkinson’s
disease
0
(0.0%)
0
(0.0%)
N/A 2
(0.03%)
4
(0.1%)
N/A 1
(0.01%)
0 N/A 3
(0.04%)
3
(0.2%)
N/A
Ischemic stroke 128
(1.6%)
39
(0.9%)
1.7
(1.2–2.4)*
145
(1.8%)
58
(1.4%)
1.3
(1.0–1.8)
121
(1.5%)
23
(1.6%)
1.0
(0.6–1.5)
139
(1.8%)
28
(1.9%)
0.9
(0.6–1.4)
Intracerebral
hemorrhage
10
(0.1%)
0
(0.0%)
N/A 11
(0.14%)
1
(0.02%)
N/A 10
(0.1%)
0
(0.0%)
N/A 11
(0.1%)
0
(0.0%)
N/A
Subarachnoid
hemorrhage
5
(0.06%)
0
(0.0%)
N/A 7
(0.09%)
0 N/A 5
(0.1%)
0
(0.0%)
N/A 7
(0.1%)
0
(0.0%)
N/A
Guillain-Barré
syndrome
1
(0.01%)
2
(0.05%)
N/A 1
(0.01%)
2
(0.05%)
N/A 1
(0.01%)
1
(0.07%)
N/A 1
(0.01%)
1
(0.07%)
N/A
Multiple sclerosis 1
(0.01%)
2
(0.05%)
N/A 1
(0.01%)
2
(0.05%)
N/A 1
(0.01%)
2
(0.1%)
N/A 1
(0.01%)
2
(0.1%)
N/A
Myasthenia gravis 1
(0.01%)
0
(0.0%)
N/A 1
(0.01%)
0
(0.0%)
N/A 1
(0.01%)
0
(0.0%)
N/A 1
(0.01%)
0
(0.0%)
N/A
Narcolepsy 0
(0.0%)
0
(0.0%)
N/A 0
(0.0%)
0
(0.0%)
N/A 0
(0.0%)
0
(0.0%)
N/A 0
(0.0%)
0
(0.0%)
N/A
Statistical analyses were only conducted for diseases with ≥4 cases in each group.
*Statistically significant RR (p <0.05) are highlighted in bold.
Frontiers in Neurology | www.frontiersin.org 7June 2022 | Volume 13 | Article 904796
Zarifkar et al. Neurological Diseases After COVID-19
χ2=177.6, p<0.0001). After exclusion of those treated with
intravenous thrombolysis, the RR of intracerebral hemorrhage
remained elevated after 12 months (RR =4.4, 95%CI 1.6–11.5).
There were too few cases to carry out meaningful statistics after
1–6 months.
Multiple Sclerosis and Other Auto-Immune
Disorders
The frequency of new-onset multiple sclerosis did not differ
significantly between COVID-19 positive and COVID-negative
individuals (in- and outpatients combined), nor separately
across in- and outpatients (Table 2 and Supplementary Table 3).
There was also no significant difference in multiple sclerosis
rates between COVID-19 positive inpatients and influenza
inpatients (Table 3), and there were not enough cases to conduct
meaningful statistics in pneumonia inpatients.
Among 43,375 COVID-19 individuals, one developed
Guillain-Barré syndrome within 1 month (0.002%) and two
(0.005%) within 3 months. One individual (0.002%) developed
myasthenia gravis one through 12 months, and none (0.0%)
developed narcolepsy (Tables 2,3). There were not enough cases
to conduct meaningful comparisons between groups.
DISCUSSION
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.
Neurodegenerative Diseases
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.
Cerebrovascular Disorders
Ischemic Stroke
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
Frontiers in Neurology | www.frontiersin.org 8June 2022 | Volume 13 | Article 904796
Zarifkar et al. Neurological Diseases After COVID-19
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
Guillain-Barré Syndrome
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).
Multiple Sclerosis
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.
Strengths and Limitations
The strengths of this study include the large population and
wide catchment area, constituting half of the Danish population.
We were able to include all individuals irrespective of age, sex,
ethnicity, lifestyle, and socioeconomic background without loss-
to-follow-up. Sensitivity analyses showed no differences in rates
of clinical work-ups utilizing cerebral PET-FDG-18 and SPECT
for diagnoses of neurodegenerative disorders, nor in the rates of
risk factors for auto-immune disorders.
Given the nature of aggregated data, several caveats need to be
considered. First, we could not adjust for potential confounders
such as socioeconomic, lifestyle, pre-existing comorbidities, and
length of hospitalization. Instead, we stratified analyses by age,
sex, smoking status and pre-existing comorbidities.
Second, we only captured a subset of the Danish population’s
absolute number of tested individuals, because only COVID-
19 tests performed in hospital facilities are registered in the
Danish electronic health record system, and not those performed
in the community setting (including over-the-counter antigen
tests or PCR tests from private providers and the primary care
sector). Altogether, we captured ∼20% of the COVID-19 positive
(17) and 40% of the COVID-negative (18) population in the
Capital Region and Region Zealand (which together correspond
to roughly half the population in Denmark).
To assess the representativeness of our study population,
we compared the frequencies of neurological diseases in
our COVID-negative population with those of the general
Danish population. We found that the prevalence or incidences
of Alzheimer’s disease, Parkinson’s disease, narcolepsy, and
intracerebral hemorrhage were representative of the Danish
and other Western populations (Supplementary Table 7) (63).
However, the prevalence of ischemic stroke, subarachnoid
hemorrhage, and GBS were higher than previous reports from
Denmark (64–66). While these results may be surprising, they
are in line with a recent Danish study of 23,688 individuals
that showed an increase in ischemic stroke in the pandemic
period from March 13, 2020 – February 28, 2021, (67) and
another showing increasing rates of GBS from 2019 to 2020
(68). The incidence of multiple sclerosis was also higher than
the reported yearly incidence in the Danish population, (69)
and may be accounted for by the younger population in the
Greater Copenhagen area (18) and, possibly, by greater air
pollution in urban areas (70–72). Altogether, however, these
figures suggest that our study cohorts are representative of the
general Danish population.
Given the attention on COVID-19 in the medical community,
the frequency of neurological diagnoses may have been increased
during the pandemic, thereby artificially increasing the numbers
in our study. Conversely, we may have missed the diagnosis of
some neurologic cases given the nature of aggregated data from
electronic health records and the one-year follow-up duration
which arguably is too short to detect longer-term changes, as
might be the case for multiple sclerosis after Ebstein-Barr virus
infection (73).
CONCLUSION
In this population-based study covering ∼50% of the Danish
population, we found support for an increased risk of
neurodegenerative disorders (i.e., Alzheimer’s disease and
Parkinson’s disease) and cerebrovascular disorders (i.e., ischemic
stroke and intracerebral hemorrhage), in COVID-19 patients
compared to individuals tested negative for COVID-19. While
the risk of ischemic stroke was increased with COVID-19
compared to influenza, reassuringly, most neurological disorders
do not appear to be more frequent after COVID-19 than after
Frontiers in Neurology | www.frontiersin.org 9June 2022 | Volume 13 | Article 904796
Zarifkar et al. Neurological Diseases After COVID-19
influenza or community-acquired bacterial pneumonia. Future
nationwide registry-based studies of pre-and post-pandemic
disease rates with full nationwide follow-up are required to
confirm these observations.
DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included
in the article/Supplementary Material, further inquiries can be
directed to the corresponding authors.
AUTHOR CONTRIBUTIONS
PZ, CP, MB, and DK contributed to the conception and design
of the study. PZ and CP extracted data, performed statistical
analyses, and drafted the first version of the manuscript. All
authors contributed to manuscript revision and approved the
submitted version.
FUNDING
This research was supported by grants from Novo Nordisk
(Grant Number NNF21OC0067769) and the Lundbeck
Foundation (Grant Number R349-2020-658).
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fneur.
2022.904796/full#supplementary-material
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