Ischemic Stroke after COVID-19 Vaccination: Case Presentation, Pathophysiology, and Narrative Review

1. Introduction

Coronavirus disease 2019 (COVID-19) began as an outbreak of pneumonia of presumed viral origin in Wuhan, Hubei, China, in December 2019, likely originating from a bat-borne virus reservoir [1,2]. The disease was initially characterized by pulmonary symptoms, fever, cough, and myalgia, and was later attributed to SARS-CoV-2 [3]. On 11 March 2020, the World Health Organization declared COVID-19 a pandemic [2,4]. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an RNA virus of the Betacoronavirus family. Its genome encodes four main structural proteins: the spike surface glycoprotein, membrane protein, envelope protein, and nucleocapsid protein. The receptor-binding domain of the spike protein binds to angiotensin-converting enzyme 2 (ACE2) on the plasma membrane, initiating receptor-mediated endocytosis and viral entry [3,4].

The rapid spread of the virus and the lack of curative drugs prompted the urgent development of vaccines [4,5,6,7,8]. By August 2020, many vaccine platforms and candidate drugs were under investigation [3,4]. COVID-19 vaccine development was scientifically rapid and included attenuated or inactivated-virus vaccines, viral-vector vaccines such as ChAdOx1 nCoV-19/AZD1222 (COVID-19 Vaccine AstraZeneca; later Vaxzevria; hereafter ChAdOx1/AZD1222), Ad26.COV2.S, and Sputnik, and mRNA vaccines such as mRNA-1273 and BNT162b2 [4,5,6,7,8,9].

The ChAdOx1/AZD1222 vaccine demonstrated efficacy in phase III clinical trials [9], as did other marketed vaccines [10,11,12]. However, very rare adverse events may become apparent only after large-scale population rollout; therefore, real-world serious vaccine adverse events (SVAEs) were primarily characterized in phase IV population-based studies and pharmacovigilance systems. For viral-vector vaccines, a newly described syndrome termed vaccine-induced immune thrombotic thrombocytopenia (VITT), or immune-induced thrombosis, was identified [13,14]. VITT may present with venous thrombosis, secondary hemorrhage, and arterial thrombosis, including myocardial infarction and stroke [13,14]. The mechanism is incompletely understood but involves platelet factor 4 antibodies [15].

These unexpected events led to temporary regulatory actions in Europe [16]; European regulators later emphasized their rarity and the positive benefit-risk balance [17], although ChAdOx1/AZD1222 was not authorized in the United States [18]. Subsequent pharmacovigilance studies, particularly the European study by Cari et al. [19], showed that stroke as an SVAE is very infrequent after COVID-19 vaccination, although more frequent than after influenza vaccination in some analyses [20]. A large Mexican SVAE series reported that most strokes occurred after viral-vector vaccines, especially ChAdOx1/AZD1222, and after the first dose, but events were also reported with other vaccines [21].

In summary, ischemic strokes associated with COVID-19 vaccination are rare in the general population, including events unrelated to VITT. This article presents a case of ischemic stroke after ChAdOx1/AZD1222 vaccination and reviews incidence, clinical features, pathological data, and pathophysiological mechanisms, particularly in relation to Western vaccines linked to the spike protein antigen [22,23]. We also reviewed whether post-COVID-19 syndrome (PCS), neurologic PCS/Neuro-COVID, and post-COVID-19 vaccination syndrome (PCVS) may be associated with increased stroke risk or cerebral microvascular injury, recognizing that post-acute SARS-CoV-2-related syndromes may involve overlapping inflammatory, coagulation, endothelial, and systemic vascular pathways [24,25,26,27,28,29,30,31].

2. Methods

In addition to the case presentation and discussion, we conducted a traditional narrative review focusing on the clinical, epidemiological, pathological, and pathophysiological aspects of ischemic stroke after SARS-CoV-2 infection, COVID-19 vaccination, PCS, and PCVS. The search was primarily in MEDLINE, with a selective approach to the large COVID-19 literature, prioritizing best-match articles, systematic reviews, and recent publications. Google Scholar was also used for its broader coverage of journals and sources.

This was not designed as a systematic review or meta-analysis. The objective was to contextualize a rare clinical presentation and to synthesize relevant evidence without adding unsupported causal claims.

The literature search was updated through 15 May 2026 using combinations of the terms ‘COVID-19’, ‘SARS-CoV-2’, ‘stroke’, ‘ischemic stroke’, ‘vaccination’, ‘post-COVID syndrome’, ‘long COVID’, and ‘post-vaccination syndrome’. Priority was given to systematic reviews, large observational studies, clinically informative case reports, and pathology-based studies relevant to the aims of this narrative review.

3. Case Presentation and Review Findings

3.1. Case Illustration

A 63-year-old male physician with a medical history of well-controlled arterial hypertension, Gilbert syndrome, and remote tobacco use, which had ceased approximately 12 years earlier, received the first dose of the adenoviral-vector COVID-19 vaccine ChAdOx1 nCoV-19/AZD1222 (COVID-19 Vaccine AstraZeneca; later Vaxzevria). There was no known history of previous thrombosis, autoimmune disease, or recent heparin exposure. The relevant family history included cerebrovascular disease.

Within the first 24 h after vaccination, the patient developed fever, headache, malaise, marked fatigue, and nocturnal chills. Approximately 36–48 h after vaccination, abrupt severe hypertension, with a reported peak blood pressure of approximately 220/115 mmHg, was followed by nausea and vomiting and prominent vestibulocerebellar symptoms, including vertigo, gait ataxia, dysarthria, and diplopia. These symptoms prompted presentation to the emergency department on 21 April 2021.

The main neurological findings were gaze-evoked nystagmus, impaired abduction of the left eye with binocular diplopia, mild facial weakness, and dysmetria of the left upper limb, accompanied by mild dysarthria and gait instability. The National Institutes of Health Stroke Scale score at presentation was 5.

Non-contrast head computed tomography demonstrated a hypodense lesion in the left cerebellar hemisphere compatible with acute ischemia, together with chronic lacunar infarcts in the bilateral caudate nuclei, right thalamus, and left corona radiata, and mild periventricular leukoaraiosis. Computed tomography angiography showed approximately 50% stenosis of the intradural segment of the left vertebral artery, without large-vessel occlusion. The dural venous sinuses were patent. Routine laboratory testing did not reveal clinically significant biochemical abnormalities; platelet count was within the reference range, and SARS-CoV-2 PCR from a nasopharyngeal swab was negative.

Brain magnetic resonance imaging (MRI) at admission confirmed an acute ischemic lesion in the left cerebellar hemisphere, extending into the middle cerebellar peduncle (Figure 1). Three additional small acute ischemic lesions were identified in the supratentorial compartment. Radiologists did not agree on whether these lesions represented old lacunar infarcts or recent ischemic lesions.

Chest radiography, electrocardiography, and transthoracic echocardiography did not identify a clear cardioembolic source. Because thrombolysis and thrombectomy were not indicated, the patient received medical treatment, including antihypertensive therapy and dual antiplatelet therapy. After 12 days, he was transferred to inpatient rehabilitation with partial improvement. Platelet counts remained within the reference range, anti-PF4 antibody testing and quantitative D-dimer levels were normal, and the clinical picture did not support a diagnosis of VITT.

During the following months, the patient reported persistent cognitive and affective symptoms, including impaired concentration, recent-memory difficulties, marked mental fatigue, sleep disturbance, and depressive symptoms, with substantial occupational impairment. Retrospectively, these symptoms were compatible with a brain-fog-like post-stroke/post-vaccination neurocognitive syndrome, although they were nonspecific and cannot by themselves establish PCVS. At 5-year follow-up, the focal neurological deficit and post-stroke depression had largely improved, but memory difficulties, apathy/fatigue, and gait disturbance persisted.

The case timeline is summarized in Table 1.

3.2. Case Commentary

Although causality cannot be established definitively from a single case, the temporal relationship, systemic post-vaccination symptoms, absence of SARS-CoV-2 infection, absence of VITT, and lack of a clear alternative cardioembolic source make the clinical presentation compatible with a serious vaccine adverse event (SVAE). The case differs from typical VITT-related stroke because platelet counts remained normal, cerebral venous sinus thrombosis was not present, anti-PF4 antibody testing and quantitative D-dimer levels were normal, and no VITT syndrome was identified.

The temporal sequence does not allow determination of whether severe hypertension acted as a trigger for the posterior-circulation stroke or represented an early physiological response to evolving ischemia; this uncertainty is considered in the interpretation of the case.

Previously reported vaccine-associated arterial strokes include cases with VITT after ChAdOx1/AZD1222 or Ad26.COV2.S vaccination and cases without VITT after several vaccine platforms [32,33,34,35,36,37,38,39,40,41,42,43]. Table 2 summarizes examples from the literature together with the present case. The table is descriptive and does not imply that each reported stroke was causally related to vaccination.

3.3. Svae Assessment, Pharmacovigilance, and Epidemiological Context

Assessment of a suspected SVAE requires distinguishing a temporal association from a causal interpretation. Black et al. [44], on behalf of the Brighton Collaboration, emphasized that even large phase III vaccine trials have limited power to detect very rare adverse events and that post-introduction vaccine-safety assessment should combine standardized case evaluation, adverse events of special interest, background rates, and surveillance studies. They describe four principal routes that may support causal inference after vaccination: (i) mechanistic laboratory evidence; (ii) the occurrence of a unique or relatively unique clinical syndrome in vaccine recipients; (iii) recurrence of the event after re-exposure; and (iv) epidemiological evidence showing that the observed event rate exceeds the expected background rate [44]. They also note that Brighton/SPEAC adverse events of special interest lists and case-evaluation tools have been used in international vaccine-safety initiatives, including endorsement by the WHO Global Advisory Committee on Vaccine Safety and adaptation by EMA-funded ACCESS activities [44].

In the present case, the first and third routes are not applicable because no specific laboratory marker establishes vaccine causality, and no vaccine re-challenge occurred. However, the case has several clinical features that make an SVAE interpretation plausible rather than merely chronological: systemic post-vaccination symptoms within 24 h, abrupt severe hypertension followed by posterior-circulation ischemic stroke within 36–48 h, absence of SARS-CoV-2 infection, absence of VITT, no cerebral venous sinus thrombosis, and no clear cardioembolic source. This clinical pattern overlaps with reported non-VITT vaccine-associated arterial stroke cases and with proposed vascular mechanisms following SARS-CoV-2 antigen exposure [32,33,34,35,36,37,38,39,40,41,42,43,45]. The fourth route, epidemiological support, is addressed below by considering pharmacovigilance data, background-rate comparisons, self-controlled designs, and case-crossover studies. Accordingly, the case should be described as clinically compatible with a very rare SVAE, not as definitive proof of individual causality.

At the population level, a major methodological challenge is the study of rare SVAEs in large administrative or pharmacovigilance databases. Studies promoted by health authorities typically compare SVAEs recorded in surveillance databases, including passive and electronic systems, with background rates observed in the general population [19,46,47,48]. These analyses also occur in a context where the overall efficacy and public health value of COVID-19 vaccination have been emphasized [11,49,50,51].

Several limitations affect these comparisons. First, SVAE reporting in large databases is often nonspecific and depends on patient reporting, clinician judgment, and comorbidities [46,47,48,52,53]. Second, results may be affected by healthy-vaccinee bias [54], and other more complex vaccination bias [53,54,55,56,57,58,59], all of which have been discussed in the COVID-19 vaccination literature [19,44,54,55,56,57,58,59]. Third, many surveys do not adequately stratify results by age, sex, and comorbidity, despite the importance of these factors [53,54,55,56,57,58,59,60,61,62,63]. These limitations contribute to variability across countries and demographic groups and may affect estimates of SAE incidence [19,46,62,63,64].

Despite these limitations, background-rate studies in Europe [19,46,63] and the United States [60,62,64] provided important comparators for assessing vaccine safety. Cohort analyses comparing vaccinated and unvaccinated populations have challenges in validating stroke as an SVAE [65,66]. Faghir-Ganji et al. [65] concluded that the absolute incidence of stroke in cohort surveys after vaccination remains extremely low. More complex epidemiological designs, including self-controlled case series and case-crossover studies [67,68,69], have been used to evaluate post-vaccination stroke risk [70,71,72,73,74,75,76,77].

The survey by Torabi et al. [75], which included more than 2 million individuals in Wales who received ChAdOx1/AZD1222 or BNT162b2, reported stronger associations of ChAdOx1/AZD1222 with ischemic stroke and of BNT162b2 with myocardial infarction. McKeigue et al. [76], using case-crossover methodology and neuroimaging ascertainment in Scotland, estimated cerebral venous thrombosis rates in a low-incidence setting. Similar findings have been discussed in surveys from Denmark, Norway, and the United States [78,79]. These examples emphasize both the large populations required to study such events and the very low incidence of SVAEs and strokes, particularly outside viral-vector vaccines [65,66,70,78,79].

Analyses comparing adverse-event profiles across vaccine types have also been informative. The EudraVigilance analysis by Cari et al. [19] suggested that recipients of viral-vector vaccines, including ChAdOx1/AZD1222 and Ad26.COV2.S, had higher rates of several SVAEs, including venous thrombosis, hemorrhage, thromboembolism, myocardial infarction, and stroke, than recipients of mRNA vaccines. Moreover, many thrombotic events associated with viral-vector vaccines occurred without thrombocytopenia, indicating that VITT accounts for only a minority of observed thrombotic complications [19,21].

In the EudraVigilance survey [19], recipients of Ad26.COV2.S or ChAdOx1/AZD1222 vaccines had higher average reporting rates of cerebral arterial events than recipients of BNT162b2. Stroke reporting rates were 12.2, 53.8, and 65.3 cases per one million administered doses for BNT162b2, ChAdOx1 nCoV-19/AZD1222, and Ad26.COV2.S, respectively, in Supplementary Table S12 [19]. In the Mexican vaccination survey, stroke was a very rare SVAE, reported as 0.71 cases per one million administered doses [21]. Underreporting and differences in reporting systems may help explain the difference between these estimates [80,81,82].

The EudraVigilance findings are broadly consistent with those of Whiteley et al. [83], who reported higher rates of venous and arterial thrombosis after ChAdOx1/AZD1222 vaccination, particularly in individuals younger than 75 years, than after BNT162b2 vaccination. Data from the United States [60,66,79] are less directly comparable because ChAdOx1/AZD1222 was not used there. Other studies reported broadly similar SVAE profiles across Ad26.COV2.S, BNT162b2, and mRNA-1273 vaccines [60,66,79], although ischemic stroke incidence was somewhat higher with viral-vector vaccines in some datasets [19,21,62,79,83].

Population-based data should be interpreted together with pathological and pathophysiological data. Pathology-proven cases and short series with biopsy or necropsy findings have been reported after vaccination [84,85,86,87,88,89]. Although pathological data remain limited [90], these observations support biological plausibility for vascular SVAEs, including myocarditis [85,91,92] and selected fatal cases [93]. Negative necropsy series are also part of the evidence base [94,95].

PCS studies also merit discussion, as tens of millions of people may have experienced long-term consequences following COVID-19 [96]. Stroke risk has been reported as increased in many surveys of PCS or cardiovascular disorders after SARS-CoV-2 infection [97,98,99,100,101,102,103,104], although some surveys and reviews report conflicting data or do not analyze stroke [31,101,105,106,107]. PCVS has also been invoked in relation to neurologic and cardiovascular manifestations, but stroke appears extremely uncommon in this setting [24,27,28,29,30,89,108].

The mechanisms underlying stroke and other vascular SAEs after SARS-CoV-2 infection, vaccination, PCS, and PCVS are probably multiple and incompletely understood. Proposed mechanisms include viral or spike-protein persistence [22,23,24,25,26,27,28,29,30,109,110,111,112], complex immune-inflammatory pathways [13,14,15,16,26,28,76,77,78,79,86,113,114,115,116,117,118], and vascular endothelial dysfunction [22,26,28,116,119,120,121,122,123,124,125,126]. Endothelial injury may be one of the most coherent explanations across these entities.

Taken together, within both the Black/Brighton framework and the broader causality postulates used in vaccine-injury pathology, the presented case is clinically compatible with a very uncommon SVAE associated with the ChAdOx1/AZD1222 vaccine. The case meets several key criteria supporting an SVAE-compatible interpretation: temporality; consistency with previously reported vaccine-associated arterial stroke cases; biological plausibility; and coherence with known immune, hypertensive, endothelial, and prothrombotic mechanisms. It also shows a degree of clinical specificity, given the early systemic post-vaccination symptoms followed by vertebrobasilar ischemic stroke in the absence of SARS-CoV-2 infection, VITT, cerebral venous sinus thrombosis, or a clear cardioembolic source, and by analogy with COVID-19-related and VITT-related arterial thrombosis [32,33,34,35,36,37,38,39,40,41,42,43,45,91,115,116,118,127]. This interpretation is further supported by the epidemiological context [19,21,70,74,76], pathology-based observations [84,91,92,128], and pathophysiological plausibility [13,14,15,16,22,23,24,25,26,27,28,29,30,115,116,117,118,119,120,121,122,123,124,125,126]. The strength of association is necessarily limited by the rarity of the event and the single-case nature of the observation; experimental evidence remains indirect, and the statement should not be read as definitive proof of causation in an individual patient. Rather, the case should be regarded as clinically compatible with a very rare SVAE in a biologically plausible context [19,21,44,91,127,128], consistent with the WHO causality-assessment framework for adverse events following immunization [129].

4. Discussion

4.1. Stroke in Acute Sars-Cov-2 Infection

Stroke is a leading cause of disease burden worldwide. The 21st-century definition of stroke is an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction [130]. Stroke epidemiology varies substantially by country, sex, race, and age, with higher prevalence in less developed countries [131]. In Western countries, ischemic stroke accounts for the majority (80–90%) of cases and hemorrhagic stroke for 10–15% [132,133,134], whereas hemorrhagic stroke is more frequent in some Eastern populations, including China [135]. In broad terms, the prevalence of stroke in the general population is 1–4.9% in people older than 20 years [132]. The estimated global lifetime risk of stroke from age 25 onward is high (approximately 25%) and varies according to cardiovascular risk factors, sex, and age [133,136].

COVID-19 infection has been associated with increased stroke risk compared with some other viral infections, including influenza, after adjustment for relevant variables [137]. The incidence estimates vary [138]. A systematic review reported rates of around 1.4% among infected persons [139], whereas some hospital-based reviews reported rates approaching 5% [138,140]. Other studies reported lower rates [141]. The literature includes conflicting short reports [142,143,144,145,146,147,148,149,150,151,152,153,154], systematic reviews with different aims [155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177], and an umbrella review [178].

Clinically, a large collaborative investigation of acute ischemic stroke in COVID-19 reported that affected patients were younger, had more severe strokes, worse disability and mortality, more frequent large-artery involvement, and a high proportion of vertebrobasilar events compared with the general stroke population [179]. The literature also describes heterogeneous clinical pictures, including diffuse encephalopathic stroke [180,181], small-vessel disease [172], and complex findings [182]. Pathological and histopathological data have also documented brain vascular lesions in selected COVID-19 patients [143,182].

Most systematic reviews, meta-analyses [155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177], and the umbrella review [178] agree that stroke increased in patients with COVID-19, especially severe COVID-19, with high associated mortality. Ischemic strokes, cryptogenic mechanisms, and male sex were frequent features. Children and young people also experienced increased ischemic stroke in some studies [147,148,170]. During the pandemic, hospital admissions for mild stroke and transient ischemic attack decreased in some settings, while severe presentations increased [173,175]. A recent survey also reported an increased risk of adverse events among hospitalized COVID-19 patients after discharge [183]. These real-world data differ from the low absolute incidence reported in clinical trials [184].

In summary, COVID-19 infection is associated with increased stroke risk, mainly ischemic stroke, often with cryptogenic etiology and unfavorable prognosis.

The causal association between SARS-CoV-2 infection and stroke is incompletely understood. Proposed mechanisms include systemic inflammation [24,25,117,163], immune-inflammatory mechanisms [28,117,118,185], a procoagulant state [24,186,187], thrombotic microangiopathy [172,180,181], viral persistence and immune-induced derangements [109,110,111,112], spike protein-related mechanisms [22,23,24,25,188], and endothelial injury [22,26,28,116,119,120,121,122,123,124,125,126]. Experimental and pathology-based studies support endothelial injury as a central mechanism in COVID-19-related vascular injury [118,188]. Systemic endotheliitis may also be an important feature of SARS-CoV-2 infection [189,190,191]. These overlapping inflammatory, thrombotic, endothelial, and vascular pathways provide a mechanistic framework for SARS-CoV-2-associated cerebrovascular injury, as summarized in Figure 2.

4.2. Stroke After the Acute Phase: Pcs and Neuro-Covid

A review of stroke after the acute phase of SARS-CoV-2 infection requires consideration of a long time frame, ranging from four weeks to several years. Several terms have been used, including long COVID, post-acute COVID-19, and post-COVID-19 syndrome (PCS) [27,28,29,30,31,193,194]. Definitions have also been proposed by major organizations and Delphi panels [195,196]. Because terminology and content remain heterogeneous, this review uses PCS descriptively to refer to the period beginning after the acute infection, generally after four weeks.

PCS symptoms and signs can be diverse. Many definitions require symptoms lasting approximately three months and beginning after the acute infection [27,28]. Presentations may be predominantly neurological, including brain fog [197,198], or may involve gastrointestinal, respiratory, musculoskeletal, or multisystem symptoms [27,195]. Fatigue is a common accompanying symptom. PCS can affect multiple organ systems and may cause severe and prolonged impairment. It appears particularly frequent after severe SARS-CoV-2 infection and has been described as a multisystem post-viral disease rather than a group of pathologically independent subsyndromes [28,105,199,200].

The main neurological and neurovascular manifestations relevant to PCS and Neuro-COVID, including brain fog, cognitive dysfunction, microvascular clot formation, endothelial dysfunction, and stroke, are summarized in Figure 3.

To evaluate whether patients who have experienced SARS-CoV-2 infection have increased stroke risk after the acute period, two scenarios should be distinguished: stroke risk during a long follow-up period after infection, and stroke risk in the context of other PCS manifestations, including general health or neurological disorders. This distinction is partly academic because many clinical series do not separate these categories.

Long-term investigations after SARS-CoV-2 infection [97,100,201,202,203,204,205,206,207], reviews [208], and systematic reviews [209] generally resemble PCS surveys [97,98,100], reviews [28,96,99,210,211], and systematic reviews [104,107] in reporting an increased risk of stroke. Specific topics include cardiovascular disease and stroke in PCS [103,212], SARS-CoV-2 persistence [213], microcirculatory impairment in pediatric PCS [214], and long Neuro-COVID-19 [30,113,215]. Other surveys and reviews that included cardiac or general health information did not provide sufficient information on stroke [102,216,217,218,219,220,221,222,223,224,225,226,227,228,229].

Examples of reported risk estimates include a cohort of 236,379 recovered patients in which, at six months, intracranial hemorrhage occurred in 0.56% and ischemic stroke in 2.10%; among severe patients who required intensive therapy, estimates increased to 2.66% for intracranial hemorrhage and 6.92% for ischemic stroke [100]. In a review of more than 23 million survivors of COVID-19, ischemic stroke at nine months occurred in 4.40 per 1000 compared with 3.25 per 1000 controls [209]. In PCS, a systematic review reported a pooled stroke risk 1.71 times higher than in non-COVID-19 patients [104]. In more than four million participants, ischemic stroke risk remained increased beyond two years [204]. By contrast, individuals with community-managed SARS-CoV-2 infection did not show increased long-term stroke risk in one study [207].

Age, cardiovascular risk factors, and severity of SARS-CoV-2 infection appear to modify stroke risk after COVID-19 [192,207]. Mild or community-managed SARS-CoV-2 infection may be associated with a lower or no increase in long-term stroke risk in some studies [207]. The modifying effects of vaccination status, early antiviral treatment, and genetic predisposition require further study.

Before turning to vaccination-related syndromes, it is important to distinguish Neuro-COVID from post-vaccination long-COVID-like illness and complex chronic adverse events following immunization, which are discussed separately below [230,231].

Neuro-COVID-19 is a clinically important entity characterized primarily by cognitive sequelae, including memory loss, anxiety, brain fog, microvascular effects, and fatigue [29,30,217,219,220,232,233,234]. Some authors consider it a manifestation of PCS with brain vascular pathology and immune-mediating molecules contributing to its pathogenesis [234]. Reliable data on stroke incidence specifically within Neuro-COVID-19 are lacking.

4.3. Vaccination, Pcvs, and Stroke Risk

The epidemiological data reviewed above indicate that stroke occurring within 30 days of COVID-19 vaccination is a very uncommon SVAE across all vaccine platforms. However, available pharmacovigilance data suggest that reported stroke events are more frequent after viral-vector vaccines than after mRNA vaccines. In the EudraVigilance analysis by Cari et al. [19], the reporting rates of stroke were 12.2, 53.8, and 65.3 cases per one million administered doses for BNT162b2, ChAdOx1 nCoV-19/AZD1222, and Ad26.COV2.S, respectively. These findings should be interpreted with caution because spontaneous reporting systems are subject to underreporting and reporting bias and cannot establish causality. These findings are broadly consistent with other surveys [83], although estimates differ markedly from those of the Mexican study [21]. A VAERS-based disproportionality analysis also reported thromboembolic, hemorrhagic, thrombocytopenic, cardiac arrhythmia, hypertension, and other SVAE after BNT162b2, mRNA-1273, and Ad26.COV2.S vaccination; however, this design is based on spontaneous reports and cannot estimate population incidence or establish causality [60].

PCVS [27,28,29,30,89,108,113,231,235,236,237,238,239] is not codified in formal diagnostic nosology [231,238], but the term is increasingly used in case reports, observational studies, and preliminary mechanistic research [231]. In this review, PCVS is used descriptively and cautiously rather than as an established diagnostic category. Reported symptoms are heterogeneous and include fatigue, nerve pain, dizziness, cardiac dysfunction or rhythm disturbances, and brain fog. Reported frequency estimates vary by source and vaccine type [113,237]. Because symptom clusters are complex [236,237], Table 3 summarizes the relationship between SARS-CoV-2-related syndromic entities and stroke or cerebrovascular manifestations.

PCVS and Neuro-COVID-19 have pathophysiological mechanisms related to vascular endothelial injury [29,30,89,114,239,240], but no clearly demonstrated increase in clinical stroke manifestations has been described.

4.4. Shared Pathophysiological Mechanisms

The syndromic entities described in this review have several possible pathophysiological explanations related to SARS-CoV-2 infection and COVID-19 vaccination, with important overlap. The consequences of SARS-CoV-2 infection and the response to vaccines that expose the immune system to viral or viral-derived antigens, especially the spike protein, may share some mechanistic features [23,89,138,240,241]. The main mechanisms linking SARS-CoV-2 infection and vaccination to cardiovascular disease and stroke include inflammation, immune dysregulation, coagulation abnormalities, endothelial injury, and microvascular damage [23,24,25,26,70,78,84,85,86,106,110,113,138,154,155,156,157,158,192,236,241].

A pan-vascular model of SARS-CoV-2-related endothelial dysfunction and multi-organ injury is shown in Figure 4.

After reviewing the mechanisms summarized in Table 4, the most frequently discussed mechanisms are spike protein toxicity or persistence, procoagulation effects, endothelial injury, and microvascular dysfunction. The vascular endothelium has an extensive surface area and may account for important pathological [22,189,266], experimental [118,188,244,255,256,257,267], and pathophysiological findings. Careful characterization of rare adverse events is compatible with a pro-vaccination and vaccine-safety framework [268]. Figure 5 highlights endotheliopathy in relation to infection and vaccination.

4.5. Limitations

This review has several limitations. First, it is a narrative synthesis of a very large literature on COVID-19 and stroke and is therefore subject to selection bias, although it draws on peer-reviewed literature. Second, the focus on stroke may underrepresent other important disorders associated with SARS-CoV-2 infection and COVID-19 vaccination, including immunological complications such as Guillain–Barré syndrome and cardiac complications such as myocarditis or cardiomyopathy. Third, many available studies rely on pharmacovigilance or administrative data. They are affected by underreporting, misclassification, assumptions about background rates, healthy-vaccinee bias, differential reporting, and incomplete adjustment for age, sex, comorbidities, and infection severity [53,54,55,56,57,58,61,80,81,82,192].

Finally, the authors emphasize the overall public-health success of COVID-19 vaccination [49,50,51]. This review places substantial emphasis on biological plausibility and mechanistic hypotheses, but these should be interpreted alongside negative, neutral, or non-confirmatory epidemiological findings and the limitations of spontaneous-reporting systems. Critical appraisal of vaccine platforms, excipients, and adverse-event mechanisms [52,53,157,160,215] remains compatible with a pro-vaccination framework. Careful description and study of SVAEs can support vaccination science by clarifying rare mechanisms of harm and improving pharmacovigilance [157,215,268].

5. Conclusions

The presented ischemic stroke case is clinically compatible with an SVAE given its temporal profile, clinical characteristics, and biological plausibility, although causality cannot be definitively established from a single case [19,21,44,45,91,127,128,129]. This review summarizes the relationships among SARS-CoV-2 infection, COVID-19 vaccination, PCS, PCVS, and stroke, and analyzes the clinical, epidemiological, pathological, and pathophysiological aspects of these entities.

Increased stroke risk is notable after SARS-CoV-2 infection, vaccination in rare cases, and long COVID-19, while possible cerebral microvascular involvement has been proposed in PCVS and Neuro-COVID. Endotheliopathy and microvascular injury may represent central mechanisms affecting cerebrovascular health in these syndromes.