Epstein–Barr virus-associated focal cerebral arteriopathy in a child with stroke: a case report

1. Introduction

Although infrequent, pediatric stroke is associated with significant morbidity and mortality, with mortality rates ranging from 10% to 25% and a high recurrence rate of 25% [1, 2]. Notably, approximately 70% of strokes result in persistent neurological deficits, seizure disorders or developmental challenges. Diagnosis is often challenging, as 61–64% of pediatric stroke patients present with non-localizing symptoms such as headache, vomiting and altered mental status, whereas 15–31% exhibit focal or generalized seizures [3]. Among the various causes of arterial ischemic stroke (AIS) in children, focal cerebral arteriopathy (FCA) is one of the most common etiology [4]. FCA is characterized by inflammatory changes in the cerebral arterial wall, leading to transient vasculitis triggered by antecedent viral infections, followed by progressive vasculopathy [5]. While varicella zoster virus (VZV) has been identified as a causative agent of FCA [6], few reports have specifically linked FCA with other herpes viruses, including Epstein–Barr virus (EBV).

2. Case report

A previously healthy 10-year-old girl presented to our emergency department (ED) with acute left-sided weakness and headache. Upon arrival, she was fully conscious, and her vital signs were stable without fever. Neurological examination revealed left hemiplegia, dysesthesia, absence of the left nasolabial fold and a positive Babinski sign on the left side. The family medical history was unremarkable, and there were no known preexisting medical conditions.

A brain computerized tomography scan revealed non-specific findings. Brain magnetic resonance imaging revealed an area of restricted diffusion over the right globus pallidus caused by ischemic infarction in the vascular territory of the right middle cerebral artery (Fig. 1). Magnetic resonance angiography (MRA) revealed narrowing of the supraclinoid portion of the right internal carotid artery (Fig. 2), suggesting arteriopathy. Complete blood count, differential count, and biochemical laboratory test results revealed nonspecific findings. In addition, viral tests using nasopharyngeal swabs (including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus, influenza virus, parainfluenza virus and respiratory syncytial virus) and serum samples (Epstein-Barr virus (EBV) and herpes simplex virus (HSV)) were performed; the results of these tests were negative except for positive serum EBV Immunoglobulin G (IgG). The patient received a loading dose of 300 mg of aspirin in the emergency department and was subsequently admitted to the intensive care unit for supportive treatment, including the maintenance of normotension and normoglycemia, as well as dehydration prevention with the administration of maintenance isotonic intravenous fluids. Routine investigations, including tests for coagulopathies (D-dimer, factor V Leiden mutation, factor VII assay, homocysteine, protein S and C, antithrombin III levels, antiphospholipid antibodies, and lactic acid), metabolic disorders (lipid profile, plasma amino acids, ketone body, zinc and copper blood levels, folic acid and thyroid function), congenital heart disease (echocardiogram and 24-h Holter electrocardiogram), immune system abnormalities (anti-dsDNA, IgG, Immunoglobulin A (IgA), Immunoglobulin M (IgM), Anti-Sjögren’s Syndrome A/Anti-Sjögren’s Syndrome B antibody (SSA/SSB Ab) and C3/C4) and electroencephalography, were conducted to explore potential underlying causes of childhood ischemic stroke; all the results were negative. The patient began a rehabilitation program on the fifth day of hospitalization and was discharged without neurological deficits on the 24th day. Brain MRA performed 4 months after discharge revealed patent intracranial vessels (Fig. 3).

Fig. 1.Brain magnetic resonance imaging revealed an area of restricted diffusion over the right globus pallidus.

Fig. 2.Magnetic resonance angiography revealed narrowing of the supraclinoid portion of the right internal carotid artery (yellow arrow).

Fig. 3.Brain MRA 4 months after discharge from the hospital revealed that cerebral arteriopathy had resolved.

3. Discussion

Pediatric stroke is often diagnosed after a significant delay and is increasingly acknowledged as a risk factor for childhood disability, with an annual incidence ranging from 1.2 to 13 per 100,000 children [7]. The most relevant risk factors for the occurrence of stroke in children are vasculopathies, infections, cardiac causes, and coagulopathies [1]. FCA in childhood with unilateral stenosis of the anterior circulation is reported to account for up to one-quarter of childhood AIS cases. In the early stages, FCA can rapidly progress over days to weeks. Patients with progressive arteriopathies have a greater risk of recurrence [8]. The majority of FCA cases regress or stabilize over time; therefore, FCA is retrospectively defined as transient cerebral arteriopathy [9]. Most cases are presumed to be inflammatory. Among AIS patients, up to 40% had previous medical conditions, such as fever, cough or flu-like symptoms, and had a medical visit one month before stroke [10]. In addition, in a vaccinated population, VZV may play a modest role in childhood stroke pathogenesis [11].

Like VZV, EBV is a herpesvirus in the herpes family and is known to be a trigger for systemic vasculitis, including Kawasaki disease [12], systemic lupus erythematosus [13], and rheumatoid arthritis [14]. In a recent study, Gatto et al. [15] observed significant increases in interleukin-6 (IL-6) and interleukin-1β (IL-1β) levels in the cerebrospinal fluid of a 2-year-old female with EBV-induced ischemic stroke. The possible cause for this increase is that EBV infection triggers the activation of host macrophages and lymphocytes, leading to the release of pro-inflammatory cytokines (IL-6 and IL-1β). These cytokines have been implicated in initiating the coagulation cascade and promoting thrombus formation [16], which contributes to the subsequent development of ischemic stroke. This could suggest another pathogenesis of EBV-associated arteriopathy distinct from the inflammatory pathway.

Currently, there are no standard treatment guidelines for AIS because of its various etiologies. Generally, treatment begins with supportive care, focusing on the maintenance of normotension, euglycemia, and euvolemia, followed by emergent MRI to determine the subsequent treatment strategy [7]. The most comprehensive multicenter trial on intravenous tissue plasminogen activator (tPA) use in pediatric stroke patients is the Thrombolysis in Pediatric Stroke (TIPS) study, which was published in 2015 [17]. Unfortunately, the study was terminated because of poor recruitment. Therefore, no specific inclusion criteria for the use of intravenous thrombolytics in children have been created to date. The use of heparin [18], low-molecular weight heparin (LMWH) [19] or warfarin [2] as anticoagulants is determined by the physician on the basis of the patient’s clinical condition, which is particularly necessary in children with congenital heart disease [20]. For patients with human herpesvirus infection-related FCA, aspirin (3–5 mg/kg/day) [21], corticosteroids (methylprednisolone, 10–20 mg/kg per dose, up to 1 g per day for 3–5 days) [22] and acyclovir (10–15 mg/kg daily for 10–14 days) are acceptable treatments [22] (Table 1 (Ref. [21, 22])). Aspirin may reduce recurrence in children [23], and a previous retrospective study suggested that administering corticosteroids may improve functional outcomes due to the underlying acute inflammation process [21]. Recently, a randomized controlled trial was conducted with the aim of providing stronger evidence in support of corticosteroid treatment [24].

One limitation of our report is the inability to confirm Epstein–Barr virus (EBV) reactivation. At our institution, EBV serology is assessed using enzyme-linked immunosorbent assay (ELISA), which yields only qualitative results based on predefined thresholds: values >11 Net Tulare Units (NTU) are considered positive, <9 NTU negative and 9–11 NTU equivocal. However, the exact NTU values are not available for clinical interpretation. Therefore, we do not perform repeated testing of EBV IgM and IgG to confirm reactivation. In this case, the patient was negative for EBV IgM and positive for EBV IgG. This pattern may reflect a very early stage of acute infection, where the EBV IgM level had not yet reached the 9 NTU threshold, along with prior exposure to EBV, which could explain the presence of EBV IgG antibodies.

Only one previous case report reported chronic EBV infection leading to diffuse central nervous system (CNS) vasculopathy in an 18-year-old male with X-linked lymphoproliferative disease [25]. In our case report, we present the case of a previously healthy 10-year-old girl who developed FCA due to EBV infection. The establishment of a relationship between FCA and EBV infection is supported by the detection of seroconversion against EBV, with all other stroke-related examinations yielding normal results. Although corticosteroids and acyclovir were not used in this patient’s treatment, we achieved a satisfactory outcome through the use of aspirin, adequate intravenous hydration to maintain euvolemia, and the implementation of early aggressive rehabilitation. More education on pediatric strokes is needed because of their subtle signs and rarity. This case reminds ED doctors to consider EBV infection as a potential differential diagnosis for pediatric stroke patients; EBV infection should be treated as soon as possible to potentially improve patient prognosis.

Availability of data and materials

Not applicable.

Author contributions

ZYL—Investigation, Writing–Original Draft. CCH—Investigation, Writing–Review & Editing. WLC—Validation. CHC—Writing–Review & Editing. CCC—Methodology, Project Administration. YRL—Conceptualization, Supervision; ZYL and CCH—mainly written manuscript. CCC and YRL—helped with the revision of the manuscript. WLC and CHC—contributed invaluable assistance to the revision process. All authors read and approved the final manuscript.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board (IRB) of Changhua Christian Hospital (IRB No. 240707). Written informed consent was obtained from the patient and the patient’s legal representative prior to publication.

Acknowledgment

Not applicable.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.