Epstein-Barr Virus: An Imaging Perspective Unpacking the CNS Manifestations of

SUMMARY: Epstein-Barr virus is a ubiquitous herpesvirus that may cause both infective (encephalitis, meningitis, and so forth) and postinfection in ﬂ ammatory (such as Guillain-Barré syndrome, acute disseminated encephalomyelitis) manifestations in the CNS. Diagnosis of Epstein-Barr virus – related CNS pathologies is often complicated due to a nonspeci ﬁ c clinical presentation and overlap with other infectious and noninfectious causes, both clinically and on imaging. The Epstein-Barr virus is also implicated in several lymphoproliferative disorders in both immunocompromised and immunocompetent hosts. MR imaging is preferred for evaluating the extent of involvement and monitoring therapy response, given its high sensitivity and speci ﬁ city, though imaging ﬁ ndings may be nonspeci ﬁ c. Herein, we review the imaging spectrum of Epstein-Barr virus – associated CNS disorders. ABBREVIATIONS:

T he Epstein-Barr virus (EBV), also known as herpesvirus 4 human, belongs to the herpesvirus family.It is highly prevalent and affects .90% of individuals worldwide. 1Primary EBV infection in childhood is usually asymptomatic.It causes infectious mononucleosis in young adults and presents with fever, lymphadenopathy, and tonsillopharyngitis. 2 Depending on age and immune status, CNS manifestations may occur in about 18% of patients.These include encephalitis, meningitis, cerebellitis, cranial nerve palsy, Guillain-Barré syndrome, acute disseminated encephalomyelitis (ADEM), and infectious or acute transverse myelitis (ATM). 3Cheng et al 4 reported a cohort of 89 children with EBV-related neurologic involvement.Encephalitis and meningoencephalitis (72%) were the most common presentations, followed by Guillain-Barré syndrome (17%), ADEM (3.4%), acute myelitis (2.2%), and posttrantplant lymphoproliferative disorders (PTLDs) (1.1%).6][7] Given the varied and nonspecific clinical manifestations, EBV antibodies and polymerase chain reaction (PCR) analysis in blood or CSF are often used for confirmation. 8][11][12] Herein, we present an illustrative review of neuroimaging manifestations of EBV-associated disorders.Understanding the clinical context and awareness of the varied imaging characteristics can facilitate management of these potentially life-threatening conditions.

Pathogenesis
EBV is a double-stranded DNA human herpesvirus discovered in 1964.EBV is mainly transmitted through saliva; however, transmission through blood transfusions and organ transplants has been reported.EBV infects B lymphocytes, causing lytic and latent infections, and establishes life-long carrier status by residing in peripheral blood lymphocytes. 13EBV can invade the CNS through a hematogeneous route or retrograde along nerve fibers. 14he pathogenesis of EBV-associated neurologic disease is complex, resulting from direct infection, immunologic response, and reactivation of latent infection. 4BV infection can potentially induce demyelination, neuroinflammation, and ADEM, leading to multifocal demyelination in the white matter of the brain.6][17] The pathogenesis remains complex and poorly understood, but in many children with ADEM, elevated serum MOG levels are observed.Yet, no correlation has been observed between anti-EBNA-1 and anti-MOG immunoglobulin antibody titers in EBV-seropositive children. 15EBVtransformed B-cells may also secrete antineuronal or anti-EBV protein antibodies that cross-react with neuronal antigens. 18This likelihood is further compounded by a complex dysregulated immune response exacerbating CNS injury. 14,19EBV-specific B cells may enter the brain and form a site of antigen recognition with the help of other immune cells.A recent study found that EBNA-1 mimics the glial-cell adhesion molecule, a CNS protein expressed by myelin-forming cells.Antibodies targeting EBNA-1 cross-react with the glial-cell adhesion molecule in patients with MS, potentially causing autoimmune attacks on the CNS myelin. 20BV is an oncogenic virus associated with various epithelial, mesenchymal, and hematologic malignancies.EBV-latent membrane protein (LMP1) genetic deletion and high EBNA-2 expression are important for EBV-positive primary CNS lymphomas (PCNSLs). 21In immunocompetent hosts, cytotoxic Tcells suppress EBV-infected lymphocytes, whereas immunosuppression leads to uncontrolled B-cell proliferation.The complex pathogenesis involves oncogenic transformation and tumor immune evasion and drives tumor cell proliferation, differentiation, invasion, metastasis, and resistance to apoptosis. 17The pathogenesis of EBV-related smooth-muscle cell tumors (EBV-SMTs) remains unclear.It is suggested that EBV infects SMTs through interaction with the CD21 receptor, similar to B lymphocytes.Other potential mechanisms include overactivation of the MTOR/Akt pathway and overexpression of the MYC protooncogene. 22The process of EBV infection and the pathogenesis of EBV-related diseases are briefly illustrated in the Online Supplemental Data.

Diagnosis of EBV CNS Infections
Given the nonspecific clinical symptomatology, the differential considerations include infectious, noninfectious inflammatory, metabolic, autoimmune, and neoplastic etiologies. 23Lesion distribution on MR imaging, duration of illness, immune status, and CSF analysis help narrow the differential considerations.Positive serum viral capsid antigen immunoglobulin (Ig) M or detection of EBV DNA through a PCR in CSF or serum or both are generally confirmatory. 24

EBV Cerebellitis
0][31] A positive CSF PCR suggests direct infiltration of the cerebellum by EBV, supported by evidence of EBV-encoded RNA expression in infiltrating inflammatory cells from cerebellar biopsies. 32Children are commonly affected; the condition often occurs following infectious mononucleosis.Studies have shown no MR imaging abnormalities 32 to cerebellum swelling causing obstructive hydrocephalus. 34EBVlinked unilateral cerebellitis has been reported in immunocompromised adults with HIV. 33EBV cerebellitis is generally selflimiting, but IV immunoglobulin may reduce the severity and duration. 31BV-associated cranial neuropathies are rare and generally manifest as facial nerve mononeuritis, though multiple cranial nerves may rarely be affected. 35Occasionally, oculomotor nerve palsy may manifest as the presenting symptom of primary EBV infection, with imaging demonstrating focal edema and enhancement at the root exit zone of the affected nerve (shooting star sign). 36inal Cord Involvement ATM is generally idiopathic or postinfectious immune-mediated demyelination, with EBV being a rare culprit. 4,37,38EBV myelitis is characterized by T2 hyperintensity in the spinal cord that extends over $2 segments covering equal or more than two-thirds of the cord, with the thoracic cord being the most affected (Figs 2 and 3).Enhancement patterns range from none to diffuse, with leptomeningeal and nerve root enhancement reported. 37,39,40EBV serologies can aid in diagnosing postinfectious EBV myelitis/ATM because MR imaging findings resemble those of other ATM etiologies.Spinal cord ischemia, MS, neuromyelitis optica, and autoimmune-related myelitis are imaging differential diagnoses for ATM.MS plaques usually affect less than one-half of the cord area and may have concomitant brain lesions.Spinal cord infarction shows bilateral anterior horn cell T2 hyperintensity symmetrically. 38Although rare in immunocompetent individuals, EBV ATM should be considered in cases of high CSF cell count atypical for idiopathic ATM. 40

EBV-Associated Demyelinating Disorders
ADEM primarily affects children, with an incidence of 0.3-0.6/100,000,][43] MR imaging typically shows asymmetric, multifocal white matter T2-hyperintense lesions.One-third of patients show ringlike or patchy peripheral contrast enhancement and restricted diffusion.Spinal cord involvement also occurs in about one-third of patients, manifesting as large lesions extending over multiple segments accompanied by cord edema. 44ifferential considerations include MS, neuromyelitis optica, and acute hemorrhagic leukoencephalitis.Evidence of recent EBV infection, a monophasic course, and specific imaging features like periventricular sparing and the absence of Dawson fingers can help to differentiate the entity from MS. 45 Patients usually respond to systemic steroids, and follow-up MR imaging typically shows resolution. 46

Lymphoproliferative Disorders
Age-related impaired cell-mediated immunity or iatrogenic immune suppression increases the risk of several B-cell LPDs.
These include lymphomatoid granulomatosis (LG), posttransplant and other immunodeficiency-associated LPDs, and B-and T-cell lymphomas. 6,47,48mphomatoid Granulomatosis Under the World Health Organization Classification of Hematolymphoid Tumors (2022), LG is an LPD occurring exclusively in immunocompetent patients.Brain involvement is reported in up to 30% of patients with LG and is often secondary, with sporadic primary CNS involvement. 49Brain lesions may be diffusely infiltrating or masslike and show nodular, perivascular, or ringlike enhancement.Subependymal extension or leptomeningeal involvement may be present (Fig 4).LG typically exhibits an angiocentric and angiodestructive infiltrate consisting of lymphocytes, histiocytes, and sporadic plasma cells, with rare neutrophils and eosinophils.Necrosis may be observed in higher-grade lesions, while well-formed granulomas are not seen.The differential diagnosis for LG includes CNS lymphoma and vasculitis. 50,511][52][53][54] Treatment options include observation, resection, chemoradiation, corticosteroids, interferon, immunoglobulin, and rituximab. 54

EBV-Positive CNS Lymphoma
PCNSL is rare and, by definition, is confined to the brain, spinal cord, eyes, and CSF without systemic involvement.It is generally EBV-negative in immunocompetent patients and has a worse prognosis when EBV-positive. 55mmunodeficiency-associated PCNSLs account for 8%-10% of cases and corresponds explicitly to EBV-positive diffuse large B-cell lymphoma. 6,56,57CNSL in immunocompetent patients may present as solitary or multifocal lesions that restrict diffusion and enhance homogeneously, often involving  the white matter, corpus callosum, or basal ganglia (Fig 5). 58ompared with glioblastoma multiforme and metastases, PCNSLs show a lower CBV, peak height on the perfusion curve, and increased diffusion restriction due to cellular density. 59tereotactic biopsy with histopathologic examination remains the criterion standard for diagnosis. 60Lee et al 61 compared MR imaging features in 10 EBV-positive PCNSLs with 45 EBV-negative PCNSLs (neither group with HIV/AIDS).Tumor necrosis, hemorrhage, and irregular or ring enhancement were common in EBV-positive PCNSLs (P , .001each).However, ADC, maximum relative CBV, relative CBV, and Cho/NAA ratios were similar between the groups.
PCNSLs in immunosuppressed patients are usually deep, periventricular, and often multiple, with necrosis, hemorrhage, and rim enhancement. 6,55[64][65] PTLD PTLD is a rare EBV-driven polyclonal B-cell proliferation occurring in patients posttransplantation.CNS involvement is seen in 5%-20% of PTLDs after solid organ transplantation and portends a poor prognosis.Biopsy may be essential because in some cases, there is no EBV DNA in the plasma/CSF. 49Balaguer-Rosello et al identified 25 cases of EBV PTLDs in 1009 adult patients with allogeneic stem cell transplants and noted isolated CNS involvement in 36% of cases.Detection of plasma EBV DNA was significantly lower with isolated CNS PTLDs (33%) compared with extra-CNS disease (100%).MR imaging findings are nonspecific and overlap with other tumoral and nontumoral pathologies.These include solitary or multiple necrotic lesions with rim enhancement; perivascular, cranial nerve, or dural enhancement; and, rarely, choroid plexus involvement.The treatment involves reducing immunosuppression, chemoradiation, immunotherapy, and surgery. 66

EBV-Related SMTs
][69][70][71][72][73] Lee et al 67 were the first to link EBV with SMTs in immunocompromised patients.Symptoms depend on location, with some patients being asymptomatic.Diagnosis often requires a biopsy.Intracranial posttransplant SMT is typically along the dural sinuses, cerebral veins, and dura mater. 68Paez-Nova et al 69 analyzed 47 cases of intracranial EBV-SMTs, with 40% being leiomyosarcomas and 60% being leiomyomas.EBV-SMTs resemble meningiomas on imaging and should be considered in HIV-positive and posttransplant patients of any age. 70Cavernous sinus involvement may occur and may present clinically as Tolosa-Hunt syndrome, but a negative response to steroids should suggest an alternate etiology, including EBV-associated neoplasia in immunosuppressed patients. 68EBV-SMTs appear as dural-based extra-axial lesions with iso-to hyperdensity and substantial enhancement on CT scans.On MR imaging, lesions are often hypo-to isointense on T1-weighted images, with T2 prolongation and variable enhancement (Fig 6).Unlike PCNSL, diffusion restriction is typically absent in EBV-SMTs. 71Spinal EBV-SMTs appear as intradural-extramedullary lesions and may resemble neurofibromas and schwannomas, with dumbbell-shaped tumors at the neural foramina. 71,72Schwannomas stain strongly for S100 protein, while EBV-associated SMTs show minor expression.In patients with HIV, immunohistochemistry can help to differentiate EBV-SMTs from Kaposi sarcoma, schwannoma, follicular dendritic cell sarcomas, and mycobacterial pseudotumor.In a study with 61 SMTs, desmin, smooth-muscle actin, muscle-specific actin, and CD21 were positive.Negative staining included S100 (27 cases), CD34 (17 cases), epithelial membrane antigen (15 cases), and cytokeratin (5 cases). 73EBV-SMTs exhibit short interlacing fascicles of atypical spindle cells with abundant eosinophilic cytoplasm. 71,73The optimal treatment for EBV-SMTs is unclear and may involve excision, radiation therapy, and/or chemotherapy.Although complete resection is the most effective treatment, 40% of patients undergo partial resection due to high risk. 69ecent studies have shown promise in alternative therapies such as mTOR/AKT inhibitors (sirolimus), EBV-specific immunotherapy, and demethylating agents. 69,70NCLUSIONS EBV in the CNS may be associated with a spectrum of infectious, noninfectious inflammatory, and lymphoproliferative disorders.MR imaging is preferred for evaluating and monitoring EBVrelated CNS complications.Increased awareness of these uncommon but clinically relevant entities and their imaging spectrum may help with early diagnosis and therapy.
Disclosure forms provided by the authors are available with the full text and PDF of this article at www.ajnr.org.

FIG 1 .
FIG 1. EBV meningoencephalitis in a patient with infectious mononucleosis.CSF was positive for EBV.Axial T2 FLAIR (A and B) images show multifocal areas of hyperintensity mainly within the subcortical white matter of the bilateral cerebral hemispheres (arrows) without diffusion abnormalities on axial DWI (C).Postcontrast axial T1-weighted image (D) shows diffuse leptomeningeal enhancement.The patient was fully recovered on follow-up.

FIG 2 .
FIG 2. EBV-related transverse myelitis, EBV IgM-positive.T2-weighted sagittal image of the thoracic spine (A) and axial images (B and C) reveal diffuse long-segmental hyperintense signal (arrows) in the spinal cord more in the central gray matter region along with mild cervical cord swelling.No abnormal enhancement on the sagittal T1-weighted postcontrast image (D) was seen.

FIG 5 .
FIG 5. EBV-positive PCNSL in a 65-year-old male patient.T2-weighted (A) and FLAIR (B) images demonstrate the left parietal lobe necrotic T2-hyperintense lesion with a peripheral iso-to hypointense rim and surrounding white matter edema (arrows).The lesion demonstrates a hypointense rim (hemorrhage) (arrows) on the susceptibility-weighted (C) image, increased restriction on DWI (D, arrow), and a peripheral rim-enhancement pattern (arrows) on the postcontrast axial T1-weighted image (E).

FIG 4 .
FIG 4. EBV lymphomatoid granulomatosis.A 40-year-old man with a history of HIV.EBV lymphomatoid granulomatosis was the finding of a prior right thalamus biopsy.Lymphohistiocytic infiltrate was the finding of a biopsy, consistent with EBV-associated lymphoproliferative disorder.Coronal T1-weighted postcontrast images show linear and punctate enhancement foci in the left parieto-occipital lobes (arrow).