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\begin{document}

\title{EBV-associated CNS Infection in an Immunocompetent Adult: A Case Report
and Literature Review}



\author[1]{Gwyn Srifuengfung}%
\author[2]{Pichatorn Suppakitjanusant}%
\author[2]{Nattanicha Chaisrimaneepan}%
\affil[1]{Texas Tech University College of Arts and Sciences}%
\affil[2]{Texas Tech University Health Sciences Center}%


\vspace{-1em}



  
  \date{March 14, 2025}


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\textbf{EBV-associated CNS Infection in an Immunocompetent Adult: A Case
Report and Literature Review}

Gwyn Srifuengfung, MD\textsuperscript{1}, Pichatorn Suppakitjanusant,
MD\textsuperscript{1}, Nattanicha Chaisrimaneepan, MD\textsuperscript{2}

\textsuperscript{1}Department of Neurology, Texas Tech University Health
Sciences Center, Lubbock, TX, USA

\textsuperscript{2}Department of Medicine, Texas Tech University Health
Sciences Center, Lubbock, TX, USA

\textbf{Corresponding author:} Nattanicha Chaisrimaneepan, MD

Department of Internal Medicine, Texas Tech University Health Sciences
Center, Lubbock, TX, USA

3601 4th St, Lubbock, TX 79430

Email: nattanicha.chaisrimaneepan@ttuhsc.edu

Disclosure: All the authors declare no conflict of interest.

Verbal and written consent was obtained from the patient to publish his
case.

Abstract

Epstein-Barr virus (EBV) infections typically manifest with respiratory
symptoms, lymphadenopathy, and, rarely, central nervous system (CNS)
involvement. We report an uncommon case of an immunocompetent
18-year-old male with altered mental status due to EBV-associated CNS
infection. The patient, with a recent history of infectious
mononucleosis, presented with fever and meningeal irritation signs.
Initial investigations revealed leukocytosis, atypical lymphocytes, and
positive heterophile antibodies, but a head CT scan was normal.
Empirical treatment for bacterial meningitis was initiated. Results of
further assessments, including a positive EBV serology, a consistent
cerebrospinal fluid analysis and positive EBV DNA in the CSF led to the
diagnosis of EBV-associated CNS infection-more specifically
meningoencephalitis. Neuroimaging, including MRI, showed no
abnormalities. The patient improved with supportive care and a four-day
course of acyclovir. We discussed the challenges in diagnosing
EBV-associated CNS infection, emphasizing the role of CSF PCR in
confirming the diagnosis. The importance of ruling out other infections
is highlighted, and the heterogeneity in the mechanism of infection is
explored. The case underscores the significance of recognizing an
isolated, active EBV infection in young adults with altered mental
status, especially when more common causes have been excluded.

Keywords: Epstein-Barr virus, CNS infection, aseptic meningitis, altered
mental status, CSF PCR, viral encephalitis.

\textbf{Introduction}

EBV infection is commonly characterized by fever, malaise, sore throat,
upper respiratory symptoms, headache, and lymphadenopathy. CNS
involvement is uncommon, occurring in 0.5-7.5\% of all EBV infections
{[}1{]}, and can present with a wide spectrum of symptoms, including
encephalitis, meningitis, myelitis, cranial neuropathy, mononeuritis
multiplex, brachial plexopathy, acute psychosis, Guillain Barr\selectlanguage{ngerman}é
syndrome, to acute cerebellar ataxia or seizures {[}1-3{]}. These
neurological symptoms usually manifest 1-3 weeks after the onset of
respiratory symptoms {[}1,4{]} but could also manifest much later, as in
the case of our patient. Interestingly, EBV-related CNS infection tends
to occur in younger adults, with an average age of 36, as reported in
Japan {[}4{]}. We report a case of EBV-associated CNS infection in an
immunocompetent adult.

\textbf{Case Presentation}

An 18-year-old Caucasian male with a past medical history of infectious
mononucleosis eight weeks ago presented with altered mental status. His
friends found him lying on the floor with a fever, groaning, combative,
and not able to be calmed with verbal measures. He was alert and
oriented as recently as the day prior. Emergency medical services (EMS)
brought him to an outside facility, where he was sedated and intubated
to protect his airway and transferred to our facility. Physical
examination demonstrated a fever of 39.16 \selectlanguage{english} (102.5\selectlanguage{english}), no
lymphadenopathy, mild hepatosplenomegaly, and nuchal rigidity. Initial
neurological examination under sedation was otherwise non-focal.

\textbf{Methods}

The patient had elevated leukocytosis with no left shift. Atypical
lymphocytes were detected. A mononucleosis screen (heterophile
antibodies) test was positive. The glucose level was mildly elevated.
Serum salicylate, alcohol, and acetaminophen levels were negative. His
serum creatinine, creatinine kinase, and aldolase levels were elevated
(Table \emph{1} ). The urine drug screen test was negative (Table
\emph{2} ). A computed tomography (CT) scan without contrast of the head
showed no intracranial abnormalities. He was treated empirically with
piperacillin-tazobactam and intravenous fluid resuscitation before being
transferred to the intensive care unit (ICU).

On the first day of arrival to the ICU, the patient remained sedated due
to severe agitation. Piperacillin-tazobactam was switched to Ceftriaxone
and Vancomycin, and Dexamethasone was added for suspected bacterial
meningitis. Serum HIV, HSV, and Syphilis screen were negative. The
patient tested positive for serum Epstein Barr Virus (EBV) Viral Capsid
Antigen (VCA) IgG, EBV VCA IgM, and EBV Nuclear Antigen (EBNA) IgG. His
serum creatinine kinase remained elevated (Table \emph{1} ). Urinalysis
was positive for blood and red blood cells (RBC) (Table \emph{2} ). He
received aggressive fluid hydration for rhabdomyolysis due to combative
behavior and sedation.

The magnetic resonance imaging (MRI) of the head was normal, with no
restricted diffusion in the diffusion-weighted image (DWI), and the
apparent diffusion coefficient (ADC) map. The electroencephalography
(EEG) only showed continued generalized slowed activity and absent
post-dominant rhythm consistent with encephalopathy (Figure \emph{1} ).

A lumbar puncture was performed to obtain cerebrospinal fluid (CSF) for
analysis. The opening pressure was elevated, and the CSF was clear. CSF
analysis demonstrated increased WBC with lymphocytes predominance,
increased protein, and mildly increased glucose, which was consistent
with aseptic meningitis (Table \emph{3} ).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1: Routine EEG showing generalized slowing with absent PDR

Intravenous Acyclovir was added to cover for possible herpes
meningoencephalitis. The CSF panel came back later, and EBV DNA was
detected. The central nervous system viral panel, bacterial meningitis
panel, and other micro-organism panels were all negative (Table\emph{4}
).

The acid-fast bacilli (AFB) stain and mycobacterium culture were also
negative. He was diagnosed with viral meningoencephalitis due to EBV
infection.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Table 1: Basic Bloodwork: Complete Blood Count (CBC), Serum
Chemistries, and Serology/Immunology}

Table 2: Urinalysis and Urine Drug Screen\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Table 3: Lumbar Puncture Opening Pressure and CSF Analysis\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Results

The patient's mental status started to improve over the next 24 hours;
he became more cooperative, started responding to commands, and was
successfully extubated. The neurological examination after extubating
which included cranial nerves, muscle strength and sensation, and tendon
reflexes were all unremarkable, although he still has neck stiffness and
limited hip flexion due to muscle pain. The patient remained slightly
confused and exhibited some degree of unusual behavior and language use
noticeable by his parents. He complained of some muscle aches and
headaches. The decision to discontinue antibiotics, acyclovir, and
dexamethasone was made after 4 complete days of treatment as the
etiology of his illness was likely from EBV infection.

His clinical and mental status gradually improved with supportive and
symptomatic treatment. By the fourth day of admission, his mental status
was back to normal baseline. He was able to walk around with minimal
muscle aches and a mild posterior headache. The patient continued to
exhibit no neurological deficit. Eventually, he was discharged home by
the seventh day.

Table 4: CSF Microbiology Panel\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\par\null

\subsubsection*{Discussion}

{\label{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.

\subsubsection*{Conclusions}

{\label{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.

\par\null

\textbf{AUTHOR CONTRIBUTIONS}

Gwyn Srifuengfung: writing-original draft, review, and editing

Pichatorn Suppakitjanusant: conceptualization, review and editing

Nattanicha Chaisrimaneepan:~Resources; writing -- original draft;
writing -- review and editing.

\textbf{ACKNOWLEDGEMENT}

Not applicable

\textbf{FUNDING INFORMATION}

The authors did not receive financial support for the research,
authorship, and/or publication of this article.

\textbf{CONFLICT OF INTEREST STATEMENT}

There are no conflicts of interest to declare.

\textbf{CONSENT}

Verbal and written consent was obtained from the patient to publish this
case.

\subsubsection*{References}

{\label{references}}

\begin{enumerate}
\tightlist
\item
  Portegies P, Corssmit N: Epstein-Barr virus and the nervous system.
  Current Opinion in Neurology. 2000, 13:301-304.
  10.1097/00019052-200006000-00012
\item
  Fujimoto H, Asaoka K, Imaizumi T, Ayabe M, Shoji H, Kaji M:
  Epstein-Barr virus infections of the central nervous system. Internal
  Medicine. 2003, 42:33-40. 10.2169/internalmedicine.42.33
\item
  Evans AS, Neiderman JC, Cenabre LC, West B, Richards VA: A prospective
  evaluation of heterophile and Epstein-Barr virus-specific IgM antibody
  tests in clinical and subclinical infectious mononucleosis:
  specificity and sensitivity of the tests and persistence of antibody.
  . The Journal of Infectious Diseases. 1975, 132:546-554.
  10.1093/infdis/132.5.546
\item
  Yamashita S-i, Murakami C, Izumi Y, et al.: Severe chronic active
  giftein-Barr virus infection accompanied by virus-associated
  hemophagocytic syndrome, cerebellar ataxia and encephalitis.
  Psychiatry and Clinical Neurosciences. 1998, 52:449-452.
  10.1046/j.1440-1819.1998.00406.x
\item
  Huang L, Zhang X, Fang X: Case Report: Epstein-Barr virus encephalitis
  complicated with brain stem hemorrhage in an immune-competent adult.
  Frontiers in Immunology. 2021, 12:10.3389/fimmu.2021.618830
\item
  Hofer M, Weber A, Haffner K, et al.: Acute hemorrhagic
  leukoencephalitis (Hurst's disease) linked to Epstein-Barr virus
  infection. Acta Neuropathologica. 2005, 109:226-230.
  10.1007/s00401-004-0930-3
\item
  Francisci D, Sensini A, Fratini D, et al.: Acute fatal necrotizing
  hemorrhagic encephalitis caused by Epstein-Barr virus in a young adult
  immunocompetent man. Journal of NeuroVirology. 2004, 10:414-417.
  10.1080/13550280490521050
\item
  Zhang N, Zuo Y, Jiang L, Peng Y, Huang X, Zuo L: Epstein-barr virus
  and neurological diseases. Frontiers in Molecular Biosciences. 2022,
  8:10.3389/fmolb.2021.816098
\item
  Lee GH, Kim J, Kim HW, Cho JW: Clinical significance of Epstein-Barr
  virus in the cerebrospinal fluid of immunocompetent patients. Clin
  Neurol Neurosurg. 2021, 202:106507. 10.1016/j.clineuro.2021.106507
\item
  Jha HC, Mehta D: Lu J, et al.: Gammaherpesvirus Infection of Human
  Neuronal Cells. mBio. 2015, 6:10.1128/mbio.01844-01815.
  10.1128/mbio.01844-15
\item
  Tsuruyama Y, Mori N, Yoshida S, Hayashi T: Epstein-Barr virus-related
  encephalitis in a young woman: A case report. J Infect Chemother.
  2020, 26:741-744. 10.1016/j.jiac.2020.02.005
\item
  Grose C, Henle W, Henle G, Feorino PM: Primary Epstein-Barr-virus
  infections in acute neurologic diseases. New England Journal of
  Medicine. 1975, 292:392-395. 10.1056/nejm197502202920804
\item
  Tselis A, Duman R, Storch GA, Lisak RP: Epstein-Barr virus
  encephalomyelitis diagnosed by polymerase chain reaction. Neurology.
  1997, 48:1351-1355. 10.1212/WNL.48.5.1351
\item
  Weinberg A, Li S, Palmer M, Tyler KL: Quantitative CSF PCR in
  Epstein-Barr virus infections of the central nervous system. Annals of
  Neurology. 2002, 52:543-548.
\item
  Kim JH, Joo BE, Koh SB: Serial diffusion-weighted MR imaging findings
  in a patient with Epstein-Barr virus encephalitis. Journal of
  Neurology. 2007, 254:1616-1618. 10.1007/s00415-007-0619-3
\item
  Zhang S, Feng J, Shi Y: Transient widespread cortical and splenial
  lesions in acute encephalitis/encephalopathy associated with primary
  Epstein-Barr virus infection. International Journal of Infectious
  Diseases. 2016, 42:7-10. 10.1016/j.ijid.2015.11.009
\item
  Misra UK, Kalita J, Phadke RV, et al.: Usefulness of various MRI
  sequences in the diagnosis of viral encephalitis. Acta Tropica. 2010,
  116:206-211.
\item
  Bhatti N, Larson E, Hickey M, Seal D: Encephalitis due to Epstein-Barr
  virus. Journal of Infection. 1990, 20:69-72.
  10.1016/S0163-4453(90)92412-E
\end{enumerate}

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