Epstein–Barr virus encephalitis presenting as cerebellar hemorrhage

Abstract

Epstein–Barr virus (EBV) belongs to the human herpesvirus family and is ubiquitously found in the adult human population. The most common clinical manifestation of EBV is the syndrome of infectious mononucleosis. Central nervous system involvement by EBV is rare, with very few cases of EBV encephalitis reported in the literature. The majority of these cases report cerebral cortical changes on magnetic resonance imaging. We present a rare case of EBV encephalitis in a young patient with meningitis-like symptoms and cerebellar hemorrhage on magnetic resonance imaging.

Introduction

Epstein–Barr virus (EBV) is a member of the human herpesvirus family. It is ubiquitously found in the adult human population, colonizing about 90% of adults, and residing in B lymphocytes. The most common clinical manifestation of EBV is the syndrome of infectious mononucleosis. EBV is implicated in neoplastic pathologies including Burkitt’s and Hodgkin’s lymphoma.¹ Central nervous system (CNS) involvement by EBV is rare and may be in the form of acute disseminated encephalomyelitis or demyelination.² In fact, patients with infectious mononucleosis have a 20-fold increased risk for developing multiple sclerosis.³ However, very few cases of EBV encephalitis have been reported in the literature, with the vast majority showing cerebral cortical changes on magnetic resonance imaging (MRI).^2,3 We present a rare case of EBV encephalitis in a young patient with meningitis-like symptoms and cerebellar hemorrhage on MRI, with the diagnosis confirmed by positive polymerase chain reaction (PCR) on cerebrospinal fluid (CSF) analysis. Due to the ubiquitous colonization of EBV, the diagnosis is made clinically and supplemented by assessing for EBV-specific antibodies, or by assessing viral load in CSF using PCR.^4,5 Isolated cerebellar and brainstem involvement can be seen in viral encephalitis as is depicted by this case.

Case report

A 24-year-old woman with a past medical history of inflammatory bowel disease presented to an outside hospital with severe headache, nausea and photophobia. She was found to have nuchal rigidity and was initially admitted for presumed meningitis. Lumbar puncture was performed, which revealed normal glucose (57 mg/100 mL), elevated protein levels (341 mg/100 mL) along with an elevated white blood cell count of 295 suggesting an underlying viral process. Blood and CSF bacterial cultures were negative. Herpes simplex virus (HSV) PCR was negative. She was diagnosed with aseptic meningitis in the setting of immunosuppression (she was on methotrexate and prednisone at home for her bowel disease). She was started on broad spectrum antibiotics and acyclovir. She was sent to our university hospital where MRI of the brain was performed. MRI showed cerebellar hemorrhage with intrinsic T1 hyperintensity and low signal on T2-weighted image (Figure 1(a) and (b)). Axial fluid-attenuated inversion recovery images through the posterior fossa show increased signal in the peri-aqueductal region of the midbrain and the cerebellum (Figure 1(c)) (orange arrows). Signal dropout and blooming was noted on susceptibility-weighted images (yellow arrows) confirming hemorrhagic changes (Figure(d)). Repeat lumbar puncture after 2 days showed decreasing protein levels (190 mg/100 ml) with a white blood cell count of 70. The PCR test for EBV was, however, positive. Subsequently, acyclovir was discontinued and the patient was kept on supportive treatment. The patient’s symptoms such as headache, photophobia and nuchal rigidity improved throughout admission and she was discharged after 7 days. Follow-up MRI performed after two months showed complete resolution of hemorrhage and signal changes in the posterior fossa.

Figure 1.

Axial T-1 (a) and T2-weighted (b) images reveal cerebellar hemorrhage with intrinsic T1 hyperintensity and low signal on T2-weighted image (arrows). Axial fluid-attenuated inversion recovery images through the posterior fossa show increased signal in the periaqueductal region of the midbrain and the cerebellum (c) (orange arrows). Corresponding susceptibility-weighted images (d) show signal dropout and blooming in those regions (yellow arrows) confirming hemorrhagic changes.

Discussion

EBV is a double-stranded DNA human herpes virus best known for producing the syndrome of infectious mononucleosis.⁶ This is a benign, self-limited infection classically presenting with fever, pharyngitis, posterior cervical lymphadenopathy and hepatosplenomegaly. In approximately 1% of cases, a variety of CNS complications including CNS lymphoma, multiple sclerosis, meningitis, encephalitis and acute disseminated encephalomyelitis may occur with EBV infection.⁷

Encephalitis is an inflammation of the brain parenchyma, which occurs as a rare complication of common viral infections. This may occur as a result of direct viral invasion into the CNS (viral encephalitis), or it may occur after a viral illness due to an immune reaction (post-infectious encephalitis or acute disseminated encephalomyelitis).^7,8 Encephalitis usually presents with fever, change in level of consciousness, seizures, focal neurologic deficits, photophobia, nuchal rigidity, nausea, vomiting and sometimes increased intracranial pressure evidenced by papilledema.⁸ However, the presentation varies depending on the site of inflammation within the CNS, the inciting pathogen and the immune response of the host. When encephalitis is suspected, it is essential to consider HSV infection, as this has a high mortality rate and requires prompt treatment with acyclovir. In fact, empiric therapy for HSV with acyclovir is indicated in suspected encephalitis until a definitive diagnosis can be made.⁹ However, the differential diagnosis is broad and includes other CNS infections, primary or metastatic tumors, delirium and a variety of others.

This case is an example of EBV viral encephalitis, a rare cause of this condition. This occurs most commonly in children and adolescents, but can occur at any age and tends to be more severe at the extremes of age. The diagnosis of EBV encephalitis is made presumptively based on the described clinical features and supported with findings on imaging and laboratory testing. In cases in which increased intracranial pressure is suspected, computed tomography and MRI should be performed prior to sampling of the CSF. While computed tomography scan is unlikely to show EBV encephalitis, it is valuable in ruling out space-occupying lesions or hemorrhage prior to performing a lumbar puncture.¹⁰ Diffusion-weighted imaging identifies diffusion gradients of water within tissue and is sensitive enough to distinguish intracellular from extracellular water. Restriction of these diffusion gradients, as seen in this case, may indicate cytotoxic edema secondary to viral infection.^6,11 However, this finding is also seen in a variety of conditions including ischemia, hypoglycemia and trauma. MRI studies in EBV encephalitis range from entirely normal to displaying diffuse edema and inflammation. Most of the cases in the literature report signal changes in the cerebral cortex and deep gray matter nuclei with few involving the brainstem. However, we could not find any reported case of isolated cerebellar and brainstem involvement in EBV encephalitis. Electroencephalography is also frequently abnormal.

After imaging is performed to rule out a space-occupying lesion, CSF sampling can be carried out. Examination of the fluid will show a lymphocytic pleocytosis, elevated protein concentration and normal glucose concentration.¹² PCR can be performed to assess directly for the presence of EBV DNA within the CSF, as was done in this case. PCR for other viruses, including HSV, West Nile, varicella zoster, cytomegalovirus and HIV can also be performed. The recovery of EBV DNA suggests an acute viral encephalitis rather than a post-infectious encephalitis. In cases in which PCR is negative, serology may be helpful. Frequently, no cause is identified and brain biopsy may be used as a last resort in cases when patients do not show improvement.¹²

The prognosis of EBV encephalitis is variable, with many patients recovering fully without intervention. However, some studies have shown a variety of neurologic effects including cognitive impairment, focal deficits, or death in a substantial number of patients. Due to the relatively small number of documented cases, a standard method of management has not been developed. However, due to the severity of possible effects, treatment with ganciclovir or acyclovir with or without corticosteroids is recommended.¹³

Conclusion

Viral encephalitis is a common condition in adults as well as the pediatric age group, with the majority being HSV infection. Encephalitis can be a rare complication of EBV disease. However, imaging findings are non-specific ranging from entirely normal to displaying diffuse edema and inflammation. Isolated cerebellar and/or brainstem involvement can be a rare imaging presentation of viral encephalitis.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.