Prevalence and Trajectories of Post-COVID-19 Neurological Manifestations: A Systematic Review and Meta-Analysis.

INTRODUCTION: The aim of this systematic review and meta-analysis was to evaluate the prevalence of thirteen neurological manifestations in people affected by COVID-19 during the acute phase and at 3, 6, 9 and 12-month follow-up time points. METHODS: The study protocol was registered with PROSPERO (CRD42022325505). MEDLINE (PubMed), Embase, and the Cochrane Library were used as information sources. Eligible studies included original articles of cohort studies, case-control studies, cross-sectional studies, and case series with ≥5 subjects that reported the prevalence and type of neurological manifestations, with a minimum follow-up of 3 months after the acute phase of COVID-19 disease. Two independent reviewers screened studies from January 1, 2020, to June 16, 2022. The following manifestations were assessed: neuromuscular disorders, encephalopathy/altered mental status/delirium, movement disorders, dysautonomia, cerebrovascular disorders, cognitive impairment/dementia, sleep disorders, seizures, syncope/transient loss of consciousness, fatigue, gait disturbances, anosmia/hyposmia, and headache. The pooled prevalence and their 95% confidence intervals were calculated at the six pre-specified times. RESULTS: 126 of 6,565 screened studies fulfilled the eligibility criteria, accounting for 1,542,300 subjects with COVID-19 disease. Of these, four studies only reported data on neurological conditions other than the 13 selected. The neurological disorders with the highest pooled prevalence estimates (per 100 subjects) during the acute phase of COVID-19 were anosmia/hyposmia, fatigue, headache, encephalopathy, cognitive impairment, and cerebrovascular disease. At 3-month follow-up, the pooled prevalence of fatigue, cognitive impairment, and sleep disorders was still 20% and higher. At six- and 9-month follow-up, there was a tendency for fatigue, cognitive impairment, sleep disorders, anosmia/hyposmia, and headache to further increase in prevalence. At 12-month follow-up, prevalence estimates decreased but remained high for some disorders, such as fatigue and anosmia/hyposmia. Other neurological disorders had a more fluctuating occurrence. DISCUSSION: Neurological manifestations were prevalent during the acute phase of COVID-19 and over the 1-year follow-up period, with the highest overall prevalence estimates for fatigue, cognitive impairment, sleep disorders, anosmia/hyposmia, and headache. There was a downward trend over time, suggesting that neurological manifestations in the early post-COVID-19 phase may be long-lasting but not permanent. However, especially for the 12-month follow-up time point, more robust data are needed to confirm this trend.

Autoimmune and inflammatory neurological disorders in the intensive care unit.

PURPOSE OF REVIEW: The present review summarizes the diagnostic approach to autoimmune encephalitis (AE) in the intensive care unit (ICU) and provides practical guidance on therapeutic management. RECENT FINDINGS: Autoimmune encephalitis represents a group of immune-mediated brain diseases associated with antibodies that are pathogenic against central nervous system proteins. Recent findings suggests that the diagnosis of AE requires a multidisciplinary approach including appropriate recognition of common clinical syndromes, brain imaging and electroencephalography to confirm focal pathology, and cerebrospinal fluid and serum tests to rule out common brain infections, and to detect autoantibodies. ICU admission may be necessary at AE onset because of altered mental status, refractory seizures, and/or dysautonomia. Early management in ICU includes prompt initiation of immunotherapy, detection and treatment of seizures, and supportive care with neuromonitoring. In parallel, screening for neoplasm should be systematically performed. Despite severe presentation, epidemiological studies suggest that functional recovery is likely under appropriate therapy, even after prolonged ICU stays. CONCLUSION: AE and related disorders are increasingly recognized in the ICU population. Critical care physicians should be aware of these conditions and consider them early in the differential diagnosis of patients presenting with unexplained encephalopathy. A multidisciplinary approach is mandatory for diagnosis, ICU management, specific therapy, and prognostication.

Building Equitable Neuroscience Research Collaborations in Resource-limited Settings.

The burden of noncommunicable neurological disorders, such as stroke, dementia, and headache disorders, are on the rise in low- to middle-income countries (LMICs), while neuroinfectious diseases remain a major concern. The development of neuroscience research aimed at defining the burden of neurological diseases across the lifespan, as well as optimizing diagnosis and treatment strategies, is fundamental to improving neurological health in resource-limited settings. One of the key factors to advancing neuroscience research in LMICs is the establishment of effective collaborations based on responsible and trustworthy partnerships between local scientists in LMICs and international collaborators. LMIC researchers face many logistical, institutional, and individual level challenges as they embark on their neuroscience research journey. Despite these challenges, there are opportunities for improving LMIC investigator-led research that should focus on human and institutional infrastructure development. With regard to human capacity building, potential areas for offering support include enhancing research methodology training, offering instruction in manuscript and grant-writing, institutionalizing mentorship programs, and providing opportunities to conduct funded, mentored research to disseminate in high-impact journals. The foundational elements required for implementing and optimizing neuroscience research within an institution include an institutional review board, mentorship programs, data management, research administration, and laboratory facilities. This institutional capacity varies significantly across and within countries, and many rely on collaborations with better-resourced institutions to initiate research. Successful equitable collaborations ensure the engagement of all local and international stakeholders, as well as implementation of a self-sustaining long-term program. Building research capacity in LMICs is an essential endeavor that requires ongoing commitment to training independent scientists. As research capacity increases, LMIC institutions and governments should consider developing competitive research grant programs to support innovative studies led by local researchers, foster regional collaborations, and hence create a sustainable and independent neuroscience research environment.

Threat of resurgence or hope for global eradication of poliovirus?

PURPOSE OF REVIEW: Recent outbreaks of poliomyelitis in countries that have been free of cases for decades highlight the challenges of eradicating polio in a globalized interconnected world beset with a novel viral pandemic. We provide an epidemiological update, advancements in vaccines, and amendments in public health strategy of poliomyelitis in this review. RECENT FINDINGS: Last year, new cases of wild poliovirus type 1 (WPV1) were documented in regions previously documented to have eradicated WPV1 and reports of circulating vaccine-derived poliovirus type 2 (cVDPV2) and 3 (cVDPV3) in New York and Jerusalem made international headlines. Sequencing of wastewater samples from environmental surveillance revealed that the WPV1 strains were related to WPV1 lineages from endemic countries and the cVDPV2 strains from New York and Jerusalem were not only related to each other but also to environmental isolates found in London. The evidence of importation of WPV1 cases from endemic countries, and global transmission of cVDPVs justifies renewed efforts in routine vaccination programs and outbreak control measures that were interrupted by the COVID-19 pandemic. After the novel oral poliovirus vaccine type 2 (nOPV2) received emergency authorization for containment of cVDPV2 outbreaks in 2021, subsequent reduced incidence, transmission rates, and vaccine adverse events, alongside increased genetic stability of viral isolates substantiates the safety and efficacy of nOPV2. The nOPV1 and nOPV3 vaccines, against type 1 and 3 cVDPVs, and measures to increase accessibility and efficacy of inactivated poliovirus vaccine (IPV) are in development. SUMMARY: A revised strategy utilizing more genetically stable vaccine formulations, with uninterrupted vaccination programs and continued active surveillance optimizes the prospect of global poliomyelitis eradication.

Addressing vaccine-preventable encephalitis in vulnerable populations.

PURPOSE OF REVIEW: Vaccinations have been pivotal in lowering the global disease burden of vaccine-preventable encephalitides, including Japanese encephalitis, tick-borne encephalitis, measles encephalitis, and rabies encephalitis, among others. RECENT FINDINGS: Populations vulnerable to vaccine-preventable infections that may lead to encephalitis include those living in endemic and rural areas, military members, migrants, refugees, international travelers, younger and older persons, pregnant women, the immunocompromised, outdoor, healthcare and laboratory workers, and the homeless. There is scope for improving the availability and distribution of vaccinations, vaccine equity, surveillance of vaccine-preventable encephalitides, and public education and information. SUMMARY: Addressing these gaps in vaccination strategies will allow for improved vaccination coverage and lead to better health outcomes for those most at risk for vaccine-preventable encephalitis.

Challenges in the Clinical Recognition of Acute Flaccid Myelitis and its Implications.

OBJECTIVES: To explore the challenges in diagnosing acute flaccid myelitis (AFM) and evaluate clinical features and treatment paradigms associated with under recognition. STUDY DESIGN: This was a retrospective multicenter study of pediatric patients (≤18 years) who were diagnosed with AFM from 2014 to 2018 using the Centers for Disease Control and Prevention's case definition. RESULTS: In 72% of the cases (126 of 175), AFM was not considered in the initial differential diagnosis (n = 108; 61.7%) and/or the patient was not referred for acute care (n = 90; 51.4%) at the initial clinical encounter, and this did not improve over time. Although many features of the presentation were similar in those initially diagnosed with AFM and those who were not; preceding illness, constipation, and reflexes differed significantly between the 2 groups. Patients with a non-AFM initial diagnosis more often required ventilatory support (26.2% vs 12.2%; OR, 0.4; 95% CI, 0.2-1.0; P = .05). These patients received immunomodulatory treatment later (3 days vs 2 days after neurologic symptom onset; 95% CI, -2 to 0; P = .05), particularly intravenous immunoglobulin (5 days vs 2 days; 95% CI, -4 to -2; P < .001). CONCLUSIONS: Delayed recognition of AFM is concerning because of the risk for respiratory decompensation and need for intensive care monitoring. A non-AFM initial diagnosis was associated with delayed treatment that could have a clinical impact, particularly as new treatment options emerge.

Application of VirCapSeq-VERT and BacCapSeq in the diagnosis of presumed and definitive neuroinfectious diseases.

Unbiased high-throughput sequencing (HTS) has enabled new insights into the diversity of agents implicated in central nervous system (CNS) infections. The addition of positive selection capture methods to HTS has enhanced the sensitivity while reducing sequencing costs and the complexity of bioinformatic analysis. Here we report the use of virus capture-based sequencing for vertebrate viruses (VirCapSeq-VERT) and bacterial capture sequencing (BacCapSeq) in investigating CNS infections. Thirty-four samples were categorized: (1) patients with definitive CNS infection by routine testing; (2) patients meeting clinically the Brighton criteria (BC) for meningoencephalitis; (3) patients with presumptive infectious etiology highest on the differential. RNA extracts from cerebrospinal fluid (CSF) were used for VirCapSeq-VERT, and DNA extracts were used for BacCapSeq analysis. Among 8 samples from known CNS infections in group 1, VirCapSeq and BacCapSeq confirmed 3 expected diagnoses (42.8%), were negative in 2 (25%), yielded an alternative result in 1 (11.1%), and did not detect 2 expected negative pathogens. The confirmed cases identified HHV-6, HSV-2, and VZV while the negative samples included JCV and HSV-2. In groups 2 and 3, 11/26 samples (42%) were positive for at least one pathogen; however, 27% of the total samples (7/26) were positive for commensal organisms. No microbial nucleic acids were detected in negative control samples. HTS showed limited promise for pathogen identification in presumed CNS infectious diseases in our small sample. Before conducting larger-scale prospective studies to assess the clinical value of this novel technique, clinicians should understand the benefits and limitations of using this modality.

Re-Emergence of Poliovirus in the United States: Considerations and Implications.

The first case of paralytic poliomyelitis in nearly a decade in the US was discovered in a 20-year-old unvaccinated man from Rockland County, New York, in July 2022, who developed acute flaccid myelitis. The isolated virus from stool sampling was found to be a circulating vaccine-derived poliovirus type 2, derived from the oral polio vaccine. Since the discovery of this case, local wastewater surveillance has revealed evidence of circulating vaccine-derived poliovirus type 2 in local counties, as well as in New York City, representing community transmission. In the wake of the coronavirus disease 2019 pandemic, routine vaccination administration has declined globally, with increasing numbers of communities not vaccinated for poliovirus. Now, with evidence of local community transmission, the clinical implication for at-risk unvaccinated individuals is significant. Here, we review the epidemiological origin of this discovered strain of poliovirus, national and international methods of surveillance for poliovirus, and neurological features of poliovirus. We also highlight the opportunities and challenges involved in monitoring suspected cases, as well as the unique role neurologists might play in national and global poliomyelitis surveillance. ANN NEUROL 2022;92:725-728.

Neurological Events Reported after COVID-19 Vaccines: An Analysis of VAERS.

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.

Evolutionary research trend of Polygonatum species: a comprehensive account of their transformation from traditional medicines to functional foods.

With the advances in Polygonatum research, there is a huge interest in harnessing the valuable functional ingredients of this genus with the potential for functional foods. This review emphasizes the different aspects of Ploygonatum based research starting from its bioactive compounds, their structural characterization, various extraction methods, as well as biological activities. In view of its integral use as an essential medicinal plant, our review emphasizes on its promising food applications both as an ingredient and as a whole food, and its improved health benefits with potential for agricultural and environmental relevance are also discussed. As we collated the recent research information, we present the main challenges and limitations of the current research trend in this area which can upgrade the further expansion of Polygonatum-related research that will strengthen its economic and accessible nutritional value in the food and health industries. By highlighting the need for the unattended species, this review not only fills existing research gaps, but also encourages the researchers to find new avenues for the natural production of bio-based functional materials and the development of highly functional and health-promoting foods for disease prevention and treatment.

Asparagus saponins: effective natural beneficial ingredient in functional foods, from preparation to applications.

Asparagus species is recognized as a perennial herb with several valuable functional ingredients, and has been widely used as medicine and food since ancient times. Among its main chemical constituents, saponins play a vital role in the health benefits and biological activities including anti-cancer, antioxidant, immunomodulatory, anti-microbial, anti-inflammatory, and hypoglycemic. This review summarizes the preparation methods, structure and classification, biological functions, as well as the food and non-food applications of asparagus saponins, with a special emphasis on its anti-cancer effects in vitro and in vivo. Further, the main challenges and limitations of the current research trends in asparagus saponins are highlighted after a detailed analysis of the recent research information. This review bridges the gap between bioactive components and human health and aids current research on functional and health-promoting foods and medicinal application of Asparagus saponins.

Lycium barbarum (Goji) as functional food: a review of its nutrition, phytochemical structure, biological features, and food industry prospects.

Lycium genus (Goji berry) is recognized as a good source of homology of medicine and food, with various nutrients and phytochemicals. Lately, numerous studies have focused on the chemical constituents and biological functions of the L. barbarum L., covering phytochemical and pharmacological aspects. We aim to provide exclusive data on the nutrients of L. barbarum L. fruits and phytochemicals, including their structural characterization, the evolution of extraction, and purification processes of different phytochemicals of L. barbarum L. fruit while placing greater emphasis on their wide-ranging health effects. This review also profitably offers innovative approaches for the food industry and industrial applications of L. barbarum L. and addresses some current situations and problems in the development of L. barbarum L. in deep processing products, which can provide clues for the sustainable development of L. barbarum L. industry.

Neurological Considerations with COVID-19 Vaccinations.

The benefits of coronavirus disease 2019 (COVID-19) vaccination significantly outweigh its risks on a public health scale, and vaccination has been crucial in controlling the spread of SARS-CoV-2. Nonetheless, several reports of adverse events following vaccination have been published.To summarize reports to date and assess the extent and quality of evidence regarding possible serious adverse neurological events following COVID-19 vaccination, focusing on Food and Drug Administration (FDA)-approved vaccines in the United States (BNT162b2, mRNA-1273, and Ad26.COV2.S).A review of literature from five major electronic databases (PubMed, Medline, Embase, Cochrane Library, and Google Scholar) was conducted between December 1, 2020 and June 5, 2022. Articles included in the review were systematic reviews and meta-analysis, cohort studies, retrospective studies, case-control studies, case series, and reports. Editorials, letters, and animal studies were excluded, since these studies did not include quantitative data regarding adverse side effects of vaccination in human subjects.Of 149 total articles and 97 (65%) were case reports or case series. Three phase 3 trials initially conducted for BNT162b2, MRNA-1273, and Ad26.COV2.S were included in the analysis.The amount and quality of evidence for possible neurological adverse events in the context of FDA-approved COVID-19 vaccinations is overall low tier. The current body of evidence continues to suggest that COVID-19 vaccinations have a high neurological safety profile; however, the risks and benefits of vaccination must continue to be closely monitored.

Consensus Clinical Guidance for Diagnosis and Management of Adult COVID-19 Encephalopathy Patients.

Encephalopathy, a common condition among patients hospitalized with COVID-19, can be a challenge to manage and negatively affect prognosis. While encephalopathy may present clinically as delirium, subsyndromal delirium, or coma and may be a result of systemic causes such as hypoxia, COVID-19 has also been associated with more prolonged encephalopathy due to less common but nevertheless severe complications, such as inflammation of the brain parenchyma (with or without cerebrovascular involvement), demyelination, or seizures, which may be disproportionate to COVID-19 severity and require specific management. Given the large number of patients hospitalized with severe acute respiratory syndrome coronavirus-2 infection, even these relatively unlikely complications are increasingly recognized and are particularly important because they require specific management. Therefore, the aim of this review is to provide pragmatic guidance on the management of COVID-19 encephalopathy through consensus agreement of the Global COVID-19 Neuro Research Coalition. A systematic literature search of MEDLINE, medRxiv, and bioRxiv was conducted between January 1, 2020, and June 21, 2021, with additional review of references cited within the identified bibliographies. A modified Delphi approach was then undertaken to develop recommendations, along with a parallel approach to score the strength of both the recommendations and the supporting evidence. This review presents analysis of contemporaneous evidence for the definition, epidemiology, and pathophysiology of COVID-19 encephalopathy and practical guidance for clinical assessment, investigation, and both acute and long-term management.

Arthropod-borne encephalitis: an overview for the clinician and emerging considerations.

The rapid spread of arboviral infections in recent years has continually established arthropod-borne encephalitis to be a pressing global health concern. Causing a wide range of clinical presentations ranging from asymptomatic infection to fulminant neurological disease, the hallmark features of arboviral infection are important to clinically recognise. Arboviral infections may cause severe neurological presentations such as meningoencephalitis, epilepsy, acute flaccid paralysis and stroke. While the pathogenesis of arboviral infections is still being investigated, shared neuroanatomical pathways among these viruses may give insight into future therapeutic targets. The shifting infection transmission patterns and evolving distribution of arboviral vectors are heavily influenced by global climate change and human environmental disruption, therefore it is of utmost importance to consider this potential aetiology when assessing patients with encephalitic presentations.

Preparation and Characterization of Eugenol Incorporated Pullulan-Gelatin Based Edible Film of Pickering Emulsion and Its Application in Chilled Beef Preservation.

The purpose of this study was to develop a composite film composed of eugenol Pickering emulsion and pullulan-gelatin, and to evaluate its preservation effect on chilled beef. The prepared composite film was comprehensively evaluated in terms of the stability of emulsion, the physical properties of the film, and an analysis of freshness preservation for chilled beef. The emulsion size (296.0 ± 10.2 nm), polydispersity index (0.457 ± 0.039), and potential (20.1 ± 0.9 mV) proved the success of emulsion. At the same time, the films displayed good mechanical and barrier properties. The index of beef preservation also indicated that eugenol was a better active ingredient than clove essence oil, which led to the rise of potential of hydrogen, chroma and water content, and effectively inhibited microbial propagation, protein degradation and lipid oxidation. These results suggest that the prepared composites can be used as promising materials for chilled beef preservation.

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial.

BACKGROUND: Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. METHODS: TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). RESULTS: Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). CONCLUSIONS: In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. CLINICAL TRIALS REGISTRATION: NCT02958709.

Acute flaccid myelitis: cause, diagnosis, and management.

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.

Compassionate-use pocapavir and immunoglobulin therapy for treatment of rituximab-associated enterovirus meningoencephalitis.

A 71-year-old woman previously on rituximab treatment for rheumatoid arthritis presented with 2 years of progressive neurologic symptoms. She was found to have persistent hypogammaglobulinemia and B cell depletion despite rituximab discontinuation a year prior. MRI revealed diffuse meningeal enhancement along the entire neuroaxis. LP showed a CSF lymphocytic pleocytosis, elevated protein, and presence of enterovirus by PCR. The patient was hospitalized several times for progressive clinical and radiologic decline, though she had transient improvements following treatment with immunoglobulin therapy. Her CSF remained positive for enterovirus PCR for at least 12 months. Though two brain biopsies were non-diagnostic, pan-Enterovirus was ultimately identified using a high-throughput next-generation sequencing technique. She was treated with compassionate-use pocapavir with clinical stabilization at 4-month follow-up; however, she expired 8 months later from a bacterial pneumonia.

Timing of headache after COVID-19 vaccines and its association with cerebrovascular events: An analysis of 41,700 VAERS reports.

BACKGROUND: Delayed-onset of headache seems a specific feature of cerebrovascular events after COVID-19 vaccines. METHODS: All consecutive events reported to the United States Vaccine Adverse Reporting System following COVID-19 vaccines (1 January to 24 June 2021), were assessed. The timing of headache onset post-vaccination in subjects with and without concomitant cerebrovascular events, including cerebral venous thrombosis, ischemic stroke, and intracranial haemorrhage was analysed. The diagnostic accuracy in predicting concurrent cerebrovascular events of the guideline- proposed threshold of three-days from vaccination to headache onset was evaluated. RESULTS: There were 314,610 events following 306,907,697 COVID-19 vaccine doses, including 41,700 headaches, and 178/41,700 (0.4%) cerebrovascular events. The median time between the vaccination and the headache onset was shorter in isolated headache (1 day vs. 4 (in cerebral venous thrombosis), 3 (in ischemic stroke), or 10 (in intracranial hemorrhage) days, all P < 0.001). Delayed onset of headache had an area under the curve of 0.83 (95% CI: 0.75-0.97) for cerebral venous thrombosis, 0.70 (95% CI: 0.63-76) for ischemic stroke and 0.76 (95% CI: 0.67-84) for intracranial hemorrhage, and >99% negative predictive value. CONCLUSION: Headache following COVID-19 vaccination occurs within 1 day and is rarely associated with cerebrovascular events. Delayed onset of headache 3 days post-vaccination was an accurate diagnostic biomarker for the occurrence of a concomitant cerebrovascular events.