Herpes simplex viral encephalitis with acute memory impairment and low cellular cerebrospinal fluid: A case report with systematic review literature

Herpes simplex encephalitis (HSVE) is a potentially fatal infectious central nervous system (CNS) disorder. Thus, early detection is critical in determining the case's fate. Clinical history and examination, brain computed tomography, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and lumbar puncture have been used to establish a diagnosis. This report describes a case of HSVE with hypocellular cerebrospinal fluid (CSF) and an uncommon form of memory impairment. However, MRI results were consistent with HSVE, and CSF PCR tested positive for HSV-1 DNA that responded to treatment. We routinely advise patients to begin antiviral therapy as soon as possible to avoid complications.


Introduction
Viral encephalitis is a severe neurological condition marked by inflammation of the brain parenchyma.The extent of brain involvement and prognosis is primarily determined by the causative pathogen and the host's immunological state [1].Herpes simplex virus encephalitis (HSVE) is the most common viral encephalitis, with mortality rates up to 70 % in the lack of proper treatment, and only a minority retrieve their normal function [2].Clinical findings, MRI scans, and the findings of CSF analysis are all crucial in diagnosing HSVE [3].
One or both temporal lobes are typically abnormal in herpes simplex encephalitis with occasional involvement of the orbitofrontal cortex, insula, or cingulate gyrus [3].Temporal lobe systems are also responsible for remote memory and semantic memory (our facts and understanding of the world).This clarifies that memory loss is the most common and frequently disabling complication of viral encephalitis [4].
Damage to the temporal lobe in the dominant hemisphere is associated with semantic memory deficit and anomia.Simultaneously, lesions in the prefrontal cortex and subcortical areas that disrupt these areas' interconnections may produce executive dysfunction [5].Moreover, it is well-known that involvement of the temporal lobe's cortex or hemorrhage, and the role of HSV as a differential diagnosis in rapid progressive dementia, are significant aspects to consider [6].McGrath et al. reported that 69 % of patients with HSVE were presented with short-and long-term memory impairment, and 45 % were associated with personality and behavioral abnormalities [7].Due to the variety and extent of cognitive sequelae, the knowledge of the impact of HSVE on acute cognitive dysfunction is based on detailed single case reports.Therefore, this report aimed to describe a case after HSVE where acute cognitive dysfunction were observed with MRI findings and hypocellular CSF.By presenting this particular case, we aim to contribute to the existing literature on viral encephalitis and deepen our comprehension of the various clinical and laboratory findings that can accompany this condition.

Case report
A 46-year-old Egyptian male (working in Saudi Arabia) with no significant history of chronic medical disease presented with flu-like symptoms, including headache, malaise, and a low-grade fever (37.8 • C).Three days before he arrived at our hospital.One day later, the patient became distracted, and his wife noticed some memory concerns (primarily with random and recent memory).The patient was oriented on the day of arrival, with no signs of meningeal irritation and no fever (due to analgesic use).Furthermore, we discovered a decrease in attention span, which has been associated with memory affection.However, there was no irritability, agitation, fits, motor, or sensory deficit.
We ordered a computerized tomography (CT) of the brain, which revealed a normal brain with no mass, lesions, or vascular event.A lumbar puncture was also performed for CSF sampling, which revealed clear CSF with normal CSF opening pressure.Unexpectedly, we found hypocellular CSF (less than five cells) [3,4] with predominant lymphocytes and occasional neutrophils with no red blood cells (RBCs).The CSF glucose level was 3.1 mmol/L (normal range: 2.2-3.9 mmol/L), and the CSF protein level was 56.5 mg/dl (normal range: 15-45 mg/dl).The white blood cell (WBC) count was 10.88 × 10 3 on the complete blood count (CBC).After the patient's admission, CSF cultures were taken for bacteria and tuberculosis, and the results were negative.After that, we ordered a CSF polymerase chain reaction (PCR), through using Multiplex PCR techniques.The results were positive for herpes simplex virus (HSV) type 1 (HSV-1).Also, PCR panel for other viruses (including enteroviruses, CMV, and EBV) in the CSF samples were negative.
Once the patient was admitted, we started empirical treatment immediately, including ceftriaxone 2 g IV BID (stopped after PCR results), acyclovir 1000 mg IV TID for 21 days, with good hydration and follow-up of renal function daily.Moreover, dexamethasone 8 mg IV QID was administered as an empirical treatment; however, it was decreased after a few days in a tapering manner.The dynamic contrastenhanced magnetic resonance imaging (DCE-MRI) of his brain showed left mesial temporal, insular areas of abnormal signal with mass effect in the form of obliteration of the temporal horn and effacement of the cortical sulci with corresponding restricted diffusion (Fig. 1).However, no abnormal contrast enhancement was observed.After one month of follow-up, the patient showed a significant improvement after medical treatment, according to the patient's examination and family notes.Written informed consent was obtained from the patient for using the clinical images and the case details.

Methods
We systematically reviewed case reports that reported herpes simplex encephalitis presenting or complicating with the acute onset of memory dysfunction.We searched PubMed, Scopus, and Web of Science from inception up to February 23, 2024, using the following search terms: ("herpes simplex" OR "HSV" OR "TORCH") AND ("encephalitis" OR "brain infection") AND ("memory" OR "amnesia").We excluded study designs other than case reports.

Results
Our search resulted in 951 citations.After screening the titles and abstracts of these articles, we identified 45 articles for full-text screening.Of these, nine articles were not in English, and 15 did not meet the inclusion criteria of reporting an acute onset of memory dysfunction.Finally, we included 21 articles  reporting 22 cases in this review.The age of the patients ranged from 13 to 78, and 7 cases [9,10,14,18,19,22,28] were females as shown in the PRISMA figure (Fig. 2).All cases presented with or rapidly developed memory dysfunction, such as short-term memory impairment, retrograde or anterograde amnesia.All cases had favorable outcomes except two cases [8,21] with fatal outcomes and four cases [11,18,21,22] without reported outcomes.Table 1 displays the included cases' demographic characteristics, clinical features, and neuroimaging.

Discussion
Viral encephalitis is a serious condition characterized by brain inflammation that can lead to neurological symptoms, including memory impairment.HSV-1 encephalitis is considered the commonest cause of sporadic fatal encephalitis globally, even with available antiviral treatment [29].HSVE patients are classically present with fever, headache, and seizures.Over 90 % of adults exhibit classic signs and symptoms [30].
Viral encephalitis is commonly accompanied by changes in CSF composition, such as increased cellularity due to infiltration of immune cells and elevated protein levels [3].Changes in CSF composition, such as increased cellularity brought on by immune cell infiltration and elevated protein levels, are frequently linked to viral encephalitis.However, our case report involves an unusual presentation where the CSF analysis revealed a hypocellular profile, considered a rare finding.This unusual finding could have some proposed explanations.First, it is possible that the CSF sample was taken at a time that was not the best for identifying inflammation.When CSF is collected in some viral encephalitis cases, the immune system might not have been fully activated.As a result, performing another lumbar puncture at a different time may produce a different set of results.However, the CSF sample was done three days after the beginning of symptoms, which is a sufficient period to cause the elevation of mononuclear cells, as mentioned in Ekmekci et al. [31].
Another explanation of this finding is that HSV has developed mechanisms to evade or suppress the immune system, resulting in atypical CSF findings [32,33].The inconsistency between our case's MRI findings and the CSF analysis raises several crucial concerns.Firstly, it points out the limitations of depending entirely on MRI results for diagnosis.MRI is useful for identifying structural abnormalities, but it may not always be consistent with CSF findings or clinical symptoms.As a result, clinicians interpret MRI results considering other diagnostic modalities.Secondly, our case emphasizes the importance of conducting thorough laboratory investigations in cases with contradictory findings.On the other hand, It is widely recognized from past studies that normal cerebrospinal fluid (CSF) cell counts can occur in HSV encephalitis, and it is recommended to perform repeated lumbar punctures in cases of suspicion.Also, normocellular CSF in HSE is not rare, and can be seen in normal as well as immunocompromised hosts as discussed in the study of Saraya et al. [34].
In the context of HSE, several case reports have highlighted different aspects of memory loss [10,28].As presented in our case, anterograde amnesia involving both verbal and visuospatial memory has previously been indicated in patients with HSE who have temporal lesions [15,28,35].Eslinger et al. [28] described a 17-year-old girl with initial flu-like symptoms that progressed to agitation and photophobia followed by seizures and right hemiparesis.CT scan and T1-weighted MR images showed a well-defined abnormal signal area in the right hemisphere.
The entire right temporal lobe was damaged except the posterior sector, the superior temporal gyrus.The patient exhibited marked retrograde and antrograde amnesia with significant dissociation between verbal and non-verbal learning.Previous studies [36] demonstrated non-verbal learning impairment in right medial temporal lobe surgery for epilepsy.Eslinger et al. [28] case affection of this area was severe and seemed to be associated with the destruction of the right medial temporal lobe.
Similarly, Sellner et al. [10] presented a 25-year-old pregnant woman who initially developed nonspecific symptoms such as fever, headache, nausea, and vomiting.However, as the disease progressed, the patient developed prominent memory deficits characterized by anterograde and retrograde amnesia.During a brain MRI scan, temporopolar and mesial hyperintensity was discovered in the right hemisphere using coronal fluid-attenuated inversion recovery (FLAIR) sequences.According to previous studies [37], damage to the dominant mesial temporal lobe (MTL) (usually the left) impairs verbal memory, while damage to the nondominant MTL (usually the right) impairs visuospatial memory [37].However, memory affection is not a common presentation of acute HSV-1 encephalitis.It has mostly occurred post-infection as sequelae of the disease or secondary to immune-mediated mechanisms due to reduced white matter integrity [38].

Conclusion
In contrast to typical MRI findings, this case report highlights a rare presentation of acute memory affection due to viral encephalitis with hypocellular CSF.The disparity between clinical symptoms, imaging results, and CSF analysis complicates diagnosis.Given the fatality of HSVE, it is critical to begin specific antiviral treatment as soon as a case is suspected to avoid complications and improve outcomes.

Table 1
Demographic characteristics, clinical features, and neuroimaging of the included cases.