Discussion
The mechanism underlying EBV-associated CNS infection is not well
established. Current evidence suggests that EBV gains access to the CNS
by utilizing infected lymphocytes to traverse the blood-brain barrier.
Postmortem studies in specific cases have identified infiltrated
lymphocytes containing EBV DNA in meninges and perivascular areas, with
their absence in neurons indicating inflammatory brain damage resulting
from an immune response rather than direct viral invasion, in contrast
to herpes simplex virus (HSV) infection [5-9]. An in-vitro study
provides an intriguing alternative perspective, demonstrating EBV’s
capacity to infect various neural cells, generating progeny virus
through lytic replication and causing host cell destruction, potentially
infecting other neurons and mononuclear cells [10]. In a rat
encephalitis model, anti-neuronal antibodies have been detected
[11]. Despite these controlled laboratory findings, demonstrating
this phenomenon in vivo remains inconclusive with current knowledge.
EBV-associated CNS infection can occur in 1-3 weeks following an acute
infection [12], but can also occur in the absence of acute
infection, potentially attributed to reactivation. There is currently no
established diagnostic criteria of EBV-associated CNS infection. While a
possible diagnosis has been suggested based on positive serologic
findings alongside compatible neurological symptoms [13], the rarity
of this condition dictates the exclusion of more common viruses in
suspected cases among young immunocompetent patients [8]. Further
support for diagnosis may be provided by a positive cerebrospinal fluid
(CSF) polymerase chain reaction (PCR) for EBV DNA [6, 13], yet the
specificity and sensitivity of this test remain undetermined. In a
review of 23 cases diagnosed with EBV-associated CNS infection, 20
tested positive on the CSF PCR [11]. However, even when CSF PCR for
EBV DNA is positive, co-infection is prevalent, found in 22% of
patients with compatible symptoms. In such cases, it has been suggested
that, instead of being the primary pathogen, EBV may be reactivated
secondary to inflammatory responses from other pathogens, or even
contamination from EBV-infected lymphocytes [9]. While direct
isolation of the virus in brain biopsy or culture from the CSF could
support the diagnosis [6], such approaches are less practical in
clinical practice.
In our patient, the EBV DNA in CSF is measured at less than 200
copies/ml [3,4], which falls within the previously reported range of
51-216,000 copies/ml [9][14]. The absence of other pathogens on
PCR and bacterial panels makes contamination unlikely. In cases
involving potential co-infections with other pathogens, we concur that
utilizing reverse transcription-polymerase chain reaction (RT-PCR) for
messenger RNA (mRNA) of the lytic cycle gene BZLF in the CSF may be the
optimal approach to establishing the pathogenic role of EBV [9]. The
BZLF gene, responsible for encoding a transcription regulator protein,
is expressed by EBV only during the transition from latent to lytic
infection.
Our case also demonstrated the challenging nature of determining the
chronicity of an EBV-related CNS infection. For an acute infection, a
positive serum EBV-specific IgM and IgG to the Viral Capsid Antigen (VCA
IgG, IgM), a positive IgG to the early antigen (EA IgG), and a negative
IgG to nuclear antigen (EBNA IgG) is suggestive. If follow-up serology
were obtained, significant changes in EBV-specific antibodies such as a
rise in IgG level, the disappearance of VCA-IgM and EA IgG, and the
appearance of EBNA IgG further support an acute infection [13]. The
positive EBNA IgG in the context of positive VCA IgM and VCA IgG in our
patient may initially appear perplexing. VCA IgM is a marker of acute
infection. At the same time, EBNA IgG is usually expressed only during
latent infection, beginning from 6 weeks after the first infection, as
EBNA are proteins responsible for maintaining an episomal state of EBV
DNA as well as immortalizing B-cells in which EBV persists during latent
infection. However, this can be reconciled by the fact that VCA IgM can
be presented up to 3 months following acute infection. Our patient’s
reported symptoms of infectious mononucleosis 8 weeks prior and mild
hepatosplenomegaly on the exam are consistent with that. Another
possibility is a reactivation infection. In either case, the timing of
the infection is not likely to be clinically significant, and we suggest
serial follow-up serology in case chronicity needs to be elucidated.
Neuroimaging is normal in most of the patients with EBV-associated CNS
infection, as in our patient. However, it is essential to perform an MRI
to rule out other causes of CNS infection such as HSV encephalitis or
acute disseminated encephalomyelitis (ADEM), which typically presents
with lesions mostly in the deep and subcortical white matter [10].
The MRI findings in EBV-associated CNS infection can vary widely in
hyperintensity in the basal ganglia, thalamus, cerebral cortex,
brainstem, optic nerves, splenium, and corpus callosum [15, 16].
These manifestations may extend to brainstem hemorrhage [5],
meningeal enhancement and multi-level spinal cord involvement [13].
While most MRI abnormalities are observed in the FLAIR and T2 sequences,
restricted diffusion on the DWI sequence can also be presented.
Additionally, heterogeneous signals on ADC sequences can be observed,
ranging from hypointensity to hyperintensity [17]. However, none of
these findings is specific to EBV infection.
There is no standard treatment guideline for EBV-associated CNS
infection. There have been reports of ganciclovir or acyclovir treatment
with or without corticosteroids. This is due to ganciclovir’s ability to
suppress replication in DNA viruses and good in-vitro activity against
EBV virus [16]. However, the efficacy remains unclear [9,18].
Suppose the main pathogenetic cause of EBV-associated CNS infection is
the result of the inflammatory response by the body’s immune system
rather than direct viral invasion. In that case, systemic
corticosteroids are more likely to be efficacious. While the exact
pathogenesis of EBV-associated CNS infection is not yet entirely clear,
we believe it is reasonable, in the absence of contraindications, to
initiate treatment with both antivirals and systemic corticosteroids.
Our patient received both systemic corticosteroid and intravenous
acyclovir empirically and they were discontinued once the patient showed
continuous improvement, and we thus believe the duration of this
treatment could be guided by the patient’s clinical response.
Conclusions
EBV infection involves a very heterogeneous constellation of symptoms.
Isolated, EBV-associated CNS infection should be considered in young
adults with altered mental status when other more common CNS viral
infections have been ruled out. A positive CSF PCR for EBV DNA strongly
supports the diagnosis in the absence of other pathogens in the PCR. MRI
findings typical of other conditions, such as ADEM, also must be ruled
out. Due to the unclear pathogenesis of EBV-associated CNS infection, we
suggest the combination of antivirals and systemic corticosteroids if
not contraindicated.