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Pitfalls and biases in neuroepidemiological studies of COVID-19 and the nervous system: a critical appraisal of the current evidence and future directions

Beghi E, Ivashynka A, Logroscino G, de Oliveira FF, Fleisher JE, Dumitrascu OM, et al.

J Neurol, 2023 Nov;270(11):5162-5170.
PMID: 37682315 DOI: 10.1007/s00415-023-11981-y

BACKGROUND: Neurological manifestations frequently occur in individuals with COVID-19, manifesting during the acute phase, persisting beyond the resolution of acute symptoms, and appearing days or weeks after the initial onset of COVID-19 symptoms. However, predicting the incidence, course, and outcome of these neurological manifestations at the individual patient level remains challenging. Biases in study design and limitations in data collection may contribute to the inconsistency and limited validity of the reported findings. Herein, we focused on critically appraising pitfalls and biases of prior reports and provide guidance for improving the quality and standardization of future research. Patients with COVID-19 exhibit diverse demographic features, sociocultural backgrounds, lifestyle habits, and comorbidities, all of which can influence the severity and progression of the infection and its impact on other organ systems. Overlooked or undocumented comorbidities and related treatments may contribute to neurological sequelae, which may not solely be attributable to COVID-19. It is crucial to consider the potential side effects of vaccines in relation to neurological manifestations.
CONCLUSION: To investigate neurological manifestations of COVID-19, it is essential to employ valid and reliable diagnostic criteria and standard definitions of the factors of interest. Although population-based studies are lacking, well-defined inception cohorts, including hospitalized individuals, outpatients, and community residents, can serve as valuable compromises. These cohorts should be evaluated for the presence of common comorbidities, alongside documenting the primary non-neurological manifestations of the infectious disease. Lastly, patients with COVID-19 should be followed beyond the acute phase to assess the persistence, duration, and severity of neurological symptoms, signs, or diseases.
EpiNet study of incidence of status epilepticus in Auckland, New Zealand: Methods and preliminary results

Bergin PS, Brockington A, Jayabal J, Scott S, Litchfield R, Roberts L, et al.

Epilepsia, 2018 10;59 Suppl 2:144-149.
PMID: 30159885 DOI: 10.1111/epi.14478

The EpiNet project has been commenced to facilitate investigator-led collaborative research in epilepsy. A new Web-based data collection tool has been developed within EpiNet to record comprehensive data regarding status epilepticus and has been used for a study of status epilepticus in Auckland, New Zealand. All patients aged >4 weeks who presented to any of the five public hospitals and the major private hospital within Auckland city (population = 1.61 million) with an episode of status epilepticus between April 6, 2015 and April 5, 2016 were identified using multiple overlapping sources of information. For this study, status epilepticus was defined as any seizure exceeding 10 minutes in duration, or repeated seizures lasting >10 minutes without recovery between seizures. Patients who had either convulsive or nonconvulsive status epilepticus were included. Episodes of status epilepticus were classified according to the 2015 International League Against Epilepsy ILAE status epilepticus classification. A total of 477 episodes in 367 patients were considered as definite or probable status epilepticus; 285 episodes (62%) lasted >30 minutes, which is the duration that has previously been used for epidemiological studies of status epilepticus.
Status epilepticus in Auckland, New Zealand: Incidence, etiology, and outcomes

Bergin PS, Brockington A, Jayabal J, Scott S, Litchfield R, Roberts L, et al.

Epilepsia, 2019 08;60(8):1552-1564.
PMID: 31260104 DOI: 10.1111/epi.16277

OBJECTIVE: To determine the incidence, etiology, and outcome of status epilepticus (SE) in Auckland, New Zealand, using the latest International League Against Epilepsy (ILAE) SE semiological classification.
METHODS: We prospectively identified patients presenting to the public or major private hospitals in Auckland (population = 1.61 million) between April 6, 2015 and April 5, 2016 with a seizure lasting 10 minutes or longer, with retrospective review to confirm completeness of data capture. Information was recorded in the EpiNet database.
RESULTS: A total of 477 episodes of SE occurred in 367 patients. Fifty-one percent of patients were aged <15 years. SE with prominent motor symptoms comprised 81% of episodes (387/477). Eighty-four episodes (18%) were nonconvulsive SE. Four hundred fifty episodes occurred in 345 patients who were resident in Auckland. The age-adjusted incidence of 10-minute SE episodes and patients was 29.25 (95% confidence interval [CI] = 27.34-31.27) and 22.22 (95% CI = 20.57-23.99)/100 000/year, respectively. SE lasted 30 minutes or longer in 250 (56%) episodes; age-adjusted incidence was 15.95 (95% CI = 14.56-17.45) SE episodes/100 000/year and 12.92 (95% CI = 11.67-14.27) patients/100 000/year. Age-adjusted incidence (10-minute SE) was 25.54 (95% CI = 23.06-28.24) patients/100 000/year for males and 19.07 (95% CI = 16.91-21.46) patients/100 000/year for females. The age-adjusted incidence of 10-minute SE was higher in Māori (29.31 [95% CI = 23.52-37.14]/100 000/year) and Pacific Islanders (26.55 [95% CI = 22.05-31.99]/100 000/year) than in patients of European (19.13 [95% CI = 17.09-21.37]/100 000/year) or Asian/other descent (17.76 [95% CI = 14.73-21.38]/100 000/year). Seventeen of 367 patients in the study died within 30 days of the episode of SE; 30-day mortality was 4.6%.
SIGNIFICANCE: In this population-based study, incidence and mortality of SE in Auckland lie in the lower range when compared to North America and Europe. For pragmatic reasons, we only included convulsive SE if episodes lasted 10 minutes or longer, although the 2015 ILAE SE classification was otherwise practical and easy to use.
Fulltext Neurological Events Reported after COVID-19 Vaccines: An Analysis of VAERS

Frontera JA, Tamborska AA, Doheim MF, Garcia-Azorin D, Gezegen H, Guekht A, et al.

Ann Neurol, 2022 Mar 02;91(6):756-71.
PMID: 35233819 DOI: 10.1002/ana.26339

OBJECTIVE: To identify the rates of neurological events following administration of mRNA (Pfizer, Moderna) or adenovirus vector (Janssen) vaccines in the U.S..
METHODS: We utilized publicly available data from the U.S. Vaccine Adverse Event Reporting System (VAERS) collected between January 1, 2021-June 14, 2021. All free text symptoms that were reported within 42 days of vaccine administration were manually reviewed and grouped into 36 individual neurological diagnostic categories. Post-vaccination neurological event rates were compared between vaccine types and to age-matched baseline incidence rates in the U.S. and rates of neurological events following COVID.
RESULTS: Of 306,907,697 COVID vaccine doses administered during the study timeframe, 314,610 (0.1%) people reported any adverse event and 105,214 (0.03%) reported neurological adverse events in a median of 1 day (IQR0-3) from inoculation. Guillain-Barre Syndrome (GBS), and cerebral venous thrombosis (CVT) occurred in fewer than 1 per 1,000,000 doses. Significantly more neurological adverse events were reported following Janssen (Ad26.COV2.S) vaccination compared to either Pfizer-BioNtech (BNT162b2) or Moderna (mRNA-1273; 0.15% versus 0.03% versus 0.03% of doses, respectively,P<0.0001). The observed-to-expected ratios for GBS, CVT and seizure following Janssen vaccination were ≥1.5-fold higher than background rates. However, the rate of neurological events after acute SARS-CoV-2 infection was up to 617-fold higher than after COVID vaccination.
INTERPRETATION: Reports of serious neurological events following COVID vaccination are rare. GBS, CVT and seizure may occur at higher than background rates following Janssen vaccination. Despite this, rates of neurological complications following acute SARS-CoV-2 infection are up to 617-fold higher than after COVID vaccination. This article is protected by copyright. All rights reserved.
Fulltext EpiNet as a way of involving more physicians and patients in epilepsy research: Validation study and accreditation process

Bergin PS, Beghi E, Sadleir LG, Brockington A, Tripathi M, Richardson MP, et al.

Epilepsia Open, 2017 Mar;2(1):20-31.
PMID: 29750210 DOI: 10.1002/epi4.12033

Objective: EpiNet was established to encourage epilepsy research. EpiNet is used for multicenter cohort studies and investigator-led trials. Physicians must be accredited to recruit patients into trials. Here, we describe the accreditation process for the EpiNet-First trials.

Methods: Physicians with an interest in epilepsy were invited to assess 30 case scenarios to determine the following: whether patients have epilepsy; the nature of the seizures (generalized, focal); and the etiology. Information was presented in two steps for 23 cases. The EpiNet steering committee determined that 21 cases had epilepsy. The steering committee determined by consensus which responses were acceptable for each case. We chose a subset of 18 cases to accredit investigators for the EpiNet-First trials. We initially focused on 12 cases; to be accredited, investigators could not diagnose epilepsy in any case that the steering committee determined did not have epilepsy. If investigators were not accredited after assessing 12 cases, 6 further cases were considered. When assessing the 18 cases, investigators could be accredited if they diagnosed one of six nonepilepsy patients as having possible epilepsy but could make no other false-positive errors and could make only one error regarding seizure classification.

Results: Between December 2013 and December 2014, 189 physicians assessed the 30 cases. Agreement with the steering committee regarding the diagnosis at step 1 ranged from 47% to 100%, and improved when information regarding tests was provided at step 2. One hundred five of the 189 physicians (55%) were accredited for the EpiNet-First trials. The kappa value for diagnosis of epilepsy across all 30 cases for accredited physicians was 0.70.

Significance: We have established criteria for accrediting physicians using EpiNet. New investigators can be accredited by assessing 18 case scenarios. We encourage physicians with an interest in epilepsy to become EpiNet-accredited and to participate in these investigator-led clinical trials.
Fulltext Frequency of Neurologic Manifestations in COVID-19: A Systematic Review and Meta-analysis

Misra S, Kolappa K, Prasad M, Radhakrishnan D, Thakur KT, Solomon T, et al.

Neurology, 2021 Dec 07;97(23):e2269-e2281.
PMID: 34635561 DOI: 10.1212/WNL.0000000000012930

BACKGROUND AND OBJECTIVES: One year after the onset of the coronavirus disease 2019 (COVID-19) pandemic, we aimed to summarize the frequency of neurologic manifestations reported in patients with COVID-19 and to investigate the association of these manifestations with disease severity and mortality.
METHODS: We searched PubMed, Medline, Cochrane library, ClinicalTrials.gov, and EMBASE for studies from December 31, 2019, to December 15, 2020, enrolling consecutive patients with COVID-19 presenting with neurologic manifestations. Risk of bias was examined with the Joanna Briggs Institute scale. A random-effects meta-analysis was performed, and pooled prevalence and 95% confidence intervals (CIs) were calculated for neurologic manifestations. Odds ratio (ORs) and 95% CIs were calculated to determine the association of neurologic manifestations with disease severity and mortality. Presence of heterogeneity was assessed with I 2, meta-regression, and subgroup analyses. Statistical analyses were conducted in R version 3.6.2.
RESULTS: Of 2,455 citations, 350 studies were included in this review, providing data on 145,721 patients with COVID-19, 89% of whom were hospitalized. Forty-one neurologic manifestations (24 symptoms and 17 diagnoses) were identified. Pooled prevalence of the most common neurologic symptoms included fatigue (32%), myalgia (20%), taste impairment (21%), smell impairment (19%), and headache (13%). A low risk of bias was observed in 85% of studies; studies with higher risk of bias yielded higher prevalence estimates. Stroke was the most common neurologic diagnosis (pooled prevalence 2%). In patients with COVID-19 ≥60 years of age, the pooled prevalence of acute confusion/delirium was 34%, and the presence of any neurologic manifestations in this age group was associated with mortality (OR 1.80, 95% CI 1.11-2.91).
DISCUSSION: Up to one-third of patients with COVID-19 analyzed in this review experienced at least 1 neurologic manifestation. One in 50 patients experienced stroke. In those >60 years of age, more than one-third had acute confusion/delirium; the presence of neurologic manifestations in this group was associated with nearly a doubling of mortality. Results must be interpreted with the limitations of observational studies and associated bias in mind.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020181867.
Fulltext Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Burstein R, Henry NJ, Collison ML, Marczak LB, Sligar A, Watson S, et al.

Nature, 2019 Oct;574(7778):353-358.
PMID: 31619795 DOI: 10.1038/s41586-019-1545-0

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2-to end preventable child deaths by 2030-we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000-2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations.