Stroke as a rare complication of scorpion stings: A systematic review and analysis

Approximately 1 million scorpion stings are recorded annually worldwide, resulting in 3000 deaths. Scorpion venom has various effects on the human body, with neurological complications occurring in about 2% of cases. Among these complications, stroke—whether ischemic or hemorrhagic—is particularly significant. A systematic literature review was conducted through a bibliographic search using key terms in the PubMed, Scopus, Scielo, Latin American and Caribbean Literature in Health Sciences (LILACS) and Google Schoolar databases without date restrictions. Articles related to stroke due to scorpion stings in Spanish, English, and Portuguese were included. Our protocol was registered in PROSPERO. A total of 24 articles met the inclusion criteria for this review. The primary neurological symptoms caused by scorpion stings include hemiplegia, hemiparesis, seizures, and limb weakness. Stroke should be suspected in the presence of these symptoms, as scorpion stings can lead to both hemorrhagic and ischemic strokes in both adults and pediatric populations. While stroke is a rare complication of scorpion stings, it is crucial to consider this diagnosis in patients presenting with neurological symptoms, necessitating the use of computed tomography or magnetic resonance imaging if stroke is suspected.


Introduction
There are at least 2500 species of scorpions on the planet, and they are part of most ecosystems worldwide (Lira et al., 2023).Scorpions are venomous arthropods, members of the class Arachnida in the order Scorpiones (Cloudsley-Thompson, 1993).Based on geographic distribution, at least 50 species are clinically significant for humans (Naranjo et al., 2021a;Santos et al., 2016).As humans inhabit these regions, coexistence with scorpions is common, leading to frequent interactions and an increased risk of sting-related injuries and fatalities (Petricevich, 2010).Annually, scorpion stings affect over 1 million people, resulting in numerous injuries and hospitalizations, with at least 3000 cases resulting in death worldwide (Gopalakrishnakone et al., 2015;Naranjo et al., 2021a).
Due to their widespread distribution, scorpion stings represent an often forgotten public health issue (Baleela et al., 2024).These species are found in tropical and subtropical regions, including Central and South America, North Africa, the Middle East, and India (Nejati et al., 2018).Notably, in Morocco, scorpion stings are the leading cause of high morbidity and mortality, representing the most common form of poisoning (Imad et al., 2023).Similarly, in India, scorpion stings have a reported mortality rate of 1.5% (Gadwalkar et al., 2006).In South America, approximately 16.36 cases per 100,000 inhabitants are reported annually, with a mortality rate of 0.05 per 100,000 inhabitants.In Mexico, the incidence is 233.64 per 100,000 inhabitants, while in the Amazon River Basin, there are 22.15 cases per 100,000 inhabitants per year, with a mortality rate of 0.03% (Ochoa-Andrade et al., 2022;Trinidad-Porfirio et al., 2023).
Among severe cases, scorpion toxins can not only affect the nervous system but also target specific organs such as the heart and brain (Godoy et al., 2021.).In rare instances, ischemic or hemorrhagic strokes have been reported as consequences of scorpion stings, leading to neurological complications in 2-5% of cases (Naranjo et al., 2021a).Although infrequent, stroke due to scorpion envenomation is mentioned in various prevention guides and first aid manuals (Kalkonde et al., 2018).
The public health significance of scorpion stings and their consequences has been well-documented (Lacerda et al., 2022).However, the previously anecdotal link between scorpion stings and stroke is now recognized as a more relevant global health issue due to the potential for ischemic or hemorrhagic complications in the brain.These can lead to severe neurological sequelae and even death (Naranjo et al., 2021b).
To address this, we have comprehensively collected data on strokes caused by scorpion stings.Our goal is to provide global readers and the medical community with a detailed guide to understanding these rare but serious cases.This review aims to enhance our understanding and management of this severe consequence of scorpion envenomation, ensuring better preparedness and response in medical practices worldwide.

Research question
Can scorpion stings cause ischemic or hemorrhagic strokes?

Study design
We conducted a systematic review that included cross-sectional studies, case-control studies, descriptive observational studies, case reports, and case series.Excluded from this review were systematic reviews, meta-analyses, narrative reviews, letters to the editor, editorials, and opinion articles.The methodology followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, which are recommended for conducting systematic reviews and metaanalyses.Our review protocol is registered in PROSPERO under the registration ID: CRD42024555500.

Search strategies
Bibliographic searches were conducted in Spanish, English, and Portuguese to encompass the widest range of available information.We reviewed the PubMed, Scopus, Scielo, Latin American and Caribbean Literature in Health Sciences (LILACS) and Google Schoolar databases without time restrictions to cover extensive literature.Additionally, reference lists of identified articles were reviewed to access potentially relevant studies.

Studies selection 2.4.1. Inclusion criteria
-All manuscripts involving human subjects.
-Manuscripts with "scorpion sting" or "scorpion envenomation" or "scorpionism" in the title or abstract and including "stroke" or "cerebrovascular disease" or "ischemic stroke" in the title or abstract.

Exclusion criterion
-Animal studies.
-Studies evaluating bites or stings of other arachnids or insects.
-Studies examining neurological complications other than stroke.
-Studies analyzing cardiovascular complications other than stroke.
The initial bibliographic search yielded 68 papers.In the first screening phase, 51 studies were excluded.Of the remaining 17 papers, 5 were excluded due to retrieval issues.Finally, 12 papers underwent a full review and were included.Additionally, 12 manuscripts from other sources (websites) were included after a full review, totaling 24 studies in this investigation.Fig. 1 illustrates the selection process based on the PRISMA flow chart for the studies analyzed in this manuscript.

Bias assessment
To minimize bias, data extraction was independently performed by JEV, KD, and EGR at different times.Discrepancies in data collection from primary studies were resolved through discussion and consensus.

Data synthesis
We conducted a comprehensive review of all manuscripts meeting the inclusion criteria.Quantitative analysis was performed using the Newcastle-Ottawa Quality Assessment Scale for cohort and case-control studies, the Joana Briggs Institute (JBI) critical appraisal checklist for analytical cross-sectional studies, and the JBI critical appraisal checklist for case reports and case series.The studies evaluated with these scales were of moderate to high quality.Information from the manuscripts was then organized and synthesized into tables for better clarity and analysis.
This process ensured a thorough evaluation of the quality and relevance of the included studies, providing a robust foundation for our conclusions and recommendations.

Results
A total of 24 articles met the inclusion criteria for this systematic review.Table 1 presents the main characteristics of the included studies.Quality assessment revealed that 2 cohort studies were of good quality (see Table S1), while 19 case reports were included, with 16 rated as high quality and 3 as moderate quality (see Fig. 2A and Table S2).Additionally, 3 case series were included, with 2 classified as high quality and 1 as moderate quality (see Table S3).All identified records were published between 1991 and 2024 (Fig. 2B).
To provide a comprehensive overview of the relationship between scorpion stings and cerebrovascular incidents, we reviewed 24 studies that met our inclusion criteria.These studies encompass various designs, including case reports, cohort studies, and case series, illustrating the diverse clinical presentations and outcomes associated with scorpion envenomation.The following table summarizes the key characteristics and findings of each study, highlighting the types of scorpions involved, the study populations, and the specific cerebrovascular effects observed.This compilation aims to underscore the significant yet often overlooked impact of scorpion stings on human health, particularly regarding their potential to induce ischemic and hemorrhagic strokes (Table 1).

Overall description and characteristics of included studies
We identified cases from 9 countries across different continents (Asia, Africa, and South America).The majority of articles originated from India (n = 11), followed by Turkey (n = 3).Most cases occurred in males, with a total of 14 articles reporting male patients, while 7 articles focused on females.Two articles included both genders, and 1 did not specify the sex of the cases (see Table 2).The overall mean age of the cases was 29.92 years (SD: 24.46).The most common site of scorpion stings was the lower extremities, particularly the feet (Annobil et al., 1991;Aslanyavrusu et al., 2024;Bucaretchi et al., 2016;Majumdar et al., 2020;Naranjo et al., 2021a;Nataraja et al., 2016;Sousa et al., 1995;Uysal et al., 2023) (Table 2).
Among the Buthidae family, Tityus is known for its potent venom, which can cause severe symptoms and even death in humans.Leiurus, often referred to as the "deathstalker," is similarly notorious for its highly toxic sting, which can lead to intense pain, respiratory issues, and cardiovascular complications (Ghoneim et al., 2020).Hottentotta, though less well-known, also poses significant health risks with its venom, potentially causing neurotoxic and cardiotoxic effects.
The Diplocentridae family, represented by the genus Nebo, is less commonly reported in medical literature but still poses serious health risks (Hendrixson, 2006).The venom of Nebo species can cause severe local pain, systemic symptoms, and, in rare cases, more severe complications such as stroke.

Imaging findings
The primary imaging modalities that are used to confirm a stroke after scorpion envenomation are computed tomography (CT) and magnetic resonance imaging (MRI).In the pediatric population, CT findings revealed hyperdense areas in the parieto-occipital lobes and both cerebellar lobes, along with areas of white matter in the frontal lobe, centrum semiovale, and caudate nucleus.Hypodense regions were also observed in the frontoparietal and front-parietal-temporal lobes (Annobil et al., 1991;Imad et al., 2023;Naranjo et al., 2021a;Prasad et al., 2014;Sousa et al., 1995).An identical case of bilateral frontal opercular infarction was also documented (Groswasser et al., 1991).
Regarding MRI findings, extensive cortical and subcortical lesions were observed from the Sylvian region to the right occipital lobe, characterized by low intensity on T1 and high intensity on T2.Additionally, lesions in the pons extended into the cerebral peduncle, showing low signal on T1 and high signal on T2, with focal intensities in the cerebellum and cortical and subcortical areas extending to the corpus callosum (Sıgırcı et al., 2014).
In the adult population, CT scans revealed hypodensities in the occipital lobes and thalamus, as well as infarctions involving the cerebellum, parieto-occipital and parietal regions, corona radiata, lentiform nucleus, basal ganglia, and thalamic regions.Hyperdense areas were noted in the parietal lobes, and hemorrhages were observed in the left frontal region and left basal ganglia, extending into the left temporoparietal lobe with intraventricular extension.Asymmetry was noted in the bilateral occipital lobes, right medulla and pons, right temporal lobe, right thalamus, left parietal lobe, and cerebellar hemispheres (Bucaretchi et al., 2016;Jain et al., 2006;Majumdar et al., 2020;Nagar et al., 2018;Nataraja et al., 2016;Ravi and Kandan, 2023;Uysal et al., 2023).MRI findings in adults included ischemic strokes involving the middle cerebral artery territory, affecting cortical and subcortical areas, and subarachnoid hemorrhages (Bhattacharya et al., 2008;Reddy et al., 2017;Uysal et al., 2023).

Discussion
This systematic review shows that the most common manifestations after a scorpion sting include local discomfort such as pain, edema, and erythema.However, systemic complications such as allergic reactions, pancreatitis, renal failure, acute respiratory failure, and systemic inflammatory response syndrome can also occur.Approximately 2% of complications involve the central nervous system, and an additional 8% are related to cerebrovascular problems (Eze et al., 2014;Nataraja et al., 2016;Uysal et al., 2023).Damage to the nervous system may occur through several mechanisms, including systemic arterial hypertension, reduced carotid arterial blood flow (Karnad, 1998;Naranjo et al., 2021a), direct effects of toxins causing encephalopathies, or direct damage to the endothelium causing vasculitis (Gowtham et al., 2022).
Several mechanisms have been identified through which a scorpion sting can cause stroke (Fig. 3).In hemorrhagic cases, sympathetic overstimulation can lead to a sudden increase in blood pressure, potentially rupturing perforating arteries (Del Brutto and Del Brutto, 2013).Cerebral hypoperfusion-related cases highlight disseminated intravascular coagulation, which increases platelet aggregation, excess catecholamines inducing endothelin increase and subsequent vasospasm, and cardiogenic cerebral embolism resulting from myocarditis (Bhattacharya et al., 2008;Del Brutto, 2013;Reddy et al., 2017).The venom's vasculotoxicity damages endothelial cells and causes vasculitis.Moreover, increased acetylcholine levels due to scorpion venom effects lead to excessive sweating and vomiting, contributing to hypotension.This, combined with carotid vasospasm, can exacerbate cerebral ischemia (Eze et al., 2014;Prasad et al., 2014).Finally, depressed left ventricular function is another potential mechanism for stroke development (Fernández-Bouzas et al., 2000).
Living in rural areas is the main risk factor for scorpion stings.In countries like India, scorpion stings pose a significant public health challenge in rural settings (Nataraja et al., 2016).Rural environments often require storing firewood, leaves, tools, or construction materials near homes, creating ideal habitats for scorpions.A study in Mexico showed that handling firewood increases sting risk due to prolonged field exposure and ground interaction (Trinidad-Porfirio et al., 2023).Poultry farming in rural areas also creates ideal scorpion habitats, with straw from nests providing shelter and increasing human contact risks (Trinidad-Porfirio et al., 2023).The lack of secure housing and proximity to scorpion habitats in rural areas facilitate their entry into homes and increase human interaction opportunities (Ebrahimi et al., 2017).
Symptomatic management, life support, and venom neutralization are key to managing scorpion stings.Antivenom administration within the first few hours' post-sting is recommended.Clinical conditions often rapidly improve with timely antivenom administration, with plasma venom levels typically becoming undetectable within an hour of treatment initiation (Boyer Leslie V. et al., 2009;Ochoa-Andrade et al., 2022).The use of prazosin, an alpha-1 adrenergic receptor antagonist, has been shown to reduce mortality, and early administration can prevent cerebrovascular complications from scorpion envenomation (Biswal et al., 2006;Ochoa-Andrade et al., 2022;Prasad et al., 2014).
From a public and global health perspective, rural and marginalized remote areas are disproportionately affected by scorpion stings.It is our responsibility to generate calls to action to train local doctors and healthcare providers to manage these stings effectively.Enhanced training and resources in these areas can significantly reduce the burden of scorpion stings, improve patient outcomes, and prevent severe complications like stroke.Efforts must be made to ensure that medical professionals in these regions are equipped with the necessary knowledge and tools to respond promptly and effectively to scorpion envenomation cases, ultimately reducing morbidity and mortality rates associated with these incidents.

Limitations
One of the main limitations of this study is the reliance on case reports, which do not establish causal relationships.Additionally, the   nature of these studies does not allow for identifying risk factors predisposing individuals to stroke following a scorpion sting.Focusing exclusively on stroke may have caused us to overlook other neurological complications related to scorpion stings.A significant limitation was the frequent lack of identification of the responsible scorpion species in the articles reviewed, hindering conclusions about which species are more likely to cause strokes.Furthermore, restricting the literature search to English and Spanish may have resulted in the omission of relevant studies published in other languages.

Conclusion
This systematic review underscores the importance of recognizing the potential for severe neurological complications, including strokes, following scorpion stings.Early diagnosis and intervention are crucial in improving patient outcomes.Healthcare providers, especially in regions where scorpions are prevalent, should be trained to recognize and manage these symptoms promptly.Enhanced awareness and training can lead to better preparedness and response, ultimately reducing the morbidity and mortality associated with scorpion stings.
Furthermore, efforts should be made to identify the specific scorpion species responsible for stings to understand better the risks associated with different species and to develop targeted prevention and treatment strategies.Expanding research to include studies in multiple languages and broadening the scope to encompass all neurological complications can provide a more comprehensive understanding of the health impacts of scorpion envenomation.

Acknowledgements
None.   1. Were patient demographics clearly described?2. Was the patient's history clearly described and presented as a timeline?3. Was the patient's current clinical condition clearly described at the time of presentation?4. Were diagnostic tests or evaluation methods and results clearly described?5. Were interventions or treatment procedures clearly described?

Supplementary material
6. Was the post-intervention clinical condition clearly described?7. Were adverse (harm) or unforeseen events identified and described?8. Does the case report provide lessons to take away?Quality scores were categorized into three groups: Low: 1-4, Moderate: 5-7, and High: >8

Fig. 2 .
Fig.2.Distribution of the publications of stroke due scorpion sting.A. Publication types, in English or in Spanish; B. Period of publication of the papers, divided into periods of 5 years.

Fig. 3 .
Fig.3.Main mechanisms by which stroke occurs due to the scorpion sting.

Comparability 5 .
Cohort comparability based on design or analysis.Results 6. Evaluation of the result.7. Was the follow-up long enough for the results to occur? 8. Adequacy of cohort follow-up.Interpretation Good quality: 3 or 4 stars in the selection domain and 1 or 2 stars in the comparability domain and 2 or 3 stars in the outcome/exposure domain.Acceptable quality: 2 stars in the selection domain and 1 or 2 stars in the comparability domain and 2 or 3 stars in the outcome/exposure domain.Poor quality: 0 or 1 star in the selection domain or 0 stars in the comparability domain or 0 or 1 stars in the outcome/exposure domain.

Table 1
Main Characteristics of Included Studies: This table presents a detailed overview of the 24 studies included in the systematic review, highlighting key characteristics such as author, year, study design, population, scorpion type, and major findings related to scorpion stings and their clinical impact.

Table 2
Main Characteristics and Clinical Findings of Patients from Analyzed Studies: This table summarizes the primary data from individual case reports and series, including patient age, sex, country of incident, sting location, main symptoms, and imaging findings.The data provides insights into the demographic and clinical profiles of scorpion sting cases associated with ischemic and hemorrhagic strokes.
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Table 2
(continued ) Note:A study can receive a maximum of one star for each item numbered within the Selection and Result categories.A maximum of two stars can be awarded for comparability.Demonstration that the current outcome of interest was not present at baseline.

Table S3
JBI Critical Appraisal Checklist for Case Series