Zapalenie mózgu związane z infekcją wirusem Epsteina-Barr: seria ponad 40 przypadków

Pavel Dyachenko1, Olha Smiianova2, Victoria Kurhanskaya2, Alexander Oleshko2, Anatoly Dyachenko2

1 Center of Infectious Disorders of the Nervous System, Kyiv, Ukraine

2 SUMY STATE UNIVERSITY, SUMY, UKRAINE

Abstract

Introduction: Epstein-Barr virus (EBV) infection can present with neurologic manifestations including encephalitis, aseptic meningitis, Guillain-Barre syndrome, and many others. Most reported cases have been in children. Little is known about EBV encephalitis in adults.

The aim: To describe the clinical presentations, investigational findings, management and outcome of adult patients with EBV encephalitis.

Materials and methods: This report conducted a retrospective review of all cases of EBV-associated encephalitis compiled in the Kyiv’s referral hospital from January 2016 to December 2017.

Review: Out of 226 adult patients hospitalized with acute encephalitis during the study period, 48 (21.2%) were identified as having evidence of EBV-infection: convincing EBV serology and/or positive cerebrospinal fluid (CSF) polymerase chain reaction (PCR) in patients that had no bacterial cause of encephalitis. EBV monoinfection was registered in 24 (50%) patients. Mixed herpesvirus infection with one to four viruses in addition to EBV was detected in the rest. The most common symptoms were fever, confusion, headache, focal neurological deficits, vestibulo-ataxic disorders. CSF cytosis, content of protein and glucose were close to normal. Magnetic resonance imaging (MRI) showed focal (28/58.3%) and diffuse (15/31.3%) changes of the brain parenchymal. All patients got antiviral medication: ganciclovir, valganciclovir or valaciclovir, as a rule. Outcome: 26 (54%) patients recovered without any disabling sequela, 21 (44%) patients with remaining preservations were transferred to a convalescence facility. One patient, which condition worsened against the background of the therapy, were moved to an intensive care unit. No patient died.

Conclusions: CNS infection with EBV only and as a mixed infection is common in Ukraine. Presentation of EBV-infection is non-specific, both as MR imaging, sometimes reminding of HSV-1 infection. Prognosis of the disease is favorable.

Wiad Lek 2018, 71, 6, -1230

 

INTRODUCTION

Epstein-Barr virus (EBV) is a highly ubiquitous herpesvirus that asymptomatically infects close to 100% of the general population before adulthood worldwide regardless of demographics or location. Classified as a human gammaherpesvirus (Human herpesvirus 4), EBV known to infect primarily B lymphocytes through the interaction of viral glycoprotein gp350/220 with the cellular receptor CD21 [1,2]. The virus can also infect other lymphocytes and certain types of epithelial cells due to interaction viral protein BMRF-2 with β-1 integrins [3]. Subsequently, fusion of the viral envelope with the cell membrane occurs in both cases, allowing the virus to enter the host [4]. Primary infection results in transient viremia, followed by a rapid immune response. EBV replicates in the oropharynx and is transmitted through oral secretions, the virus is most commonly known as the cause of infectious mononucleosis [5].

After primary infection of B lymphocytes or epithelial cells, EBV initiates either latent (nonproductive) or lytic (productive) replication. Latently infected cells maintain EBV genomes as 184-kb episomes in cell nuclei and express a limited repertoire of viral gene products [6]. In latent infection, among the most commonly expressed viral genes are six nuclear antigens (EBNA1, -2, 3A, 3B, -3C, and -LP), three membrane-associated proteins (LMP-1, -2A, -2B), and two small noncoding RNAs (EBER1 and EBER2) [7]. There are four known EBV latency programs in which the expression patterns of these genes are altered [8]. EBNA1, which binds to the origin of latent replication on the viral genome, mediates replication of the episome during the host cell mitosis. It is expressed in all latency programs and is therefore a beneficial target to determine infection [9]. In lytic infection, viral genes selectively replicate virion genomes, which causes release of viral particles from the host cell. In B cells, lytic replication generally occurs after reactivation from the latent phase, while in epithelial cells, lytic replication occurs for a short period initially after infection, eventually returning to the latent state [10,11]. Following primary infection and establishing lifelong latency EBV can periodically reactivates, spreading into the brain and causing encephalitis both upon primary and recurrent infection.

EBV is associated with several lymphoproliferative diseases (Burkitt’s lymphoma, Hodgkin’s disease, and lymphoproliferative disease in immuno-compromised individuals [12]. The virus is clinically also linked to a wide range of neural disorders, such as primary CNS lymphoma, multiple sclerosis (MS), Alzheimer’s disease, cerebellar ataxia, subacute sensory neuropathy, meningoencephalitis, cranial nerve palsies, and Guillain-Barré syndrome [13-16].

Encephalitis refers to an acute, usually diffuse, inflammatory process with parenchymal brain involvement. As a rule, the process involves different brain compartments giving a complex clinical picture. While isolated primary infection of the meninges or brain may also occur, a combined meningoencephalitis is more common. Human herpesviruses (HVs) are the most common cause of sporadic aseptic encephalitis, which can be lethal or result in severe neurological defects in a significant fraction of survivors even with antiviral therapy. With the introduction of more accurate and sophisticated diagnostic tools, up to 50 % of cases have been found to have a viral origin [17]. In Ukrainian settings, aseptic encephalitis is thought to be common, but very little is known about the prevalence and clinical peculiarities of different human herpesviruses as causes of the disease and there have been few studies examining this question [18]. In this single center study have been shown that Epstein–Barr virus (EBV), Herpes simplex virus (HSV) types 1 and 2, and Human herpes virus type 7 are the most common cause of the CNS infections of Ukrainian adults (20%, and both of 12%, respectively).

Here we present a comprehensive clinical, radiological and virological analysis of 48 adult patients with CNS lesions linked with EBV-infection.

THE AIM

To describe the clinical presentations, investigational findings, management and outcome of adult patients with EBV encephalitis.

MATERIALS AND METHODS

STUDY DESIGN, PATIENTS AND SITE

We reviewed retrospectively the clinical and laboratory records as well as the radiology data of brain imaging of EBV-associated encephalitis cases registered in the database of The Center of Infectious Disorders of the Nervous System (CIDNS, Kyiv, Ukraine). CIDNS is an adult tertiary referral, infectious diseases hospital covering the entire territory of the country. It has 20 beds with approximately 200-250 admissions annually.

Basic demographic information was collected from all patients using case report forms. Patients were managed by hospital doctors following routine clinical practice i.e. history, physical examination, hematology, biochemistry, blood and CSF culture, and lumbar punctures (LP), and radiology. The CSF and serum samples were collected from all patients at admission and immediately sent to a lab for analysis.

CLINICAL DIAGNOSIS AND FINAL DECISION

The final conclusion for the etiology of infection and recruiting the patient into the study was mainly based on the detection of viral DNA in CSF or blood, however neuroimaging data and characteristic clinical signs also were taken into account. The diagnosis was considered to be Confirmed when the DNA of any pathogen was found by PCR in the CSF (or blood) samples; Highly probable – when intrathecal IgG-VCA against a specific virus and/or IgM-VCA and IgG-EA in blood were detected; Suspected – when only IgG-VCA were found in the blood [19]. Only patients with a confirmed or highly probable EBV-infection of CNS were enrolled into the study. Cases of meningitis without clinical manifestation of brain involvement also entered in the list of exclusions.

Written inform consent was obtained from all patients or from close relatives.

VACCINE STATUS

According to the Order of the Ministry of Health of Ukraine No. 276 of October 31, 2000, mandatory preventive vaccinations are conducted against the following infections: Hepatitis B, Tuberculosis, Diphtheria, Pertussis (Whooping cough), Tetanus, Poliomyelitis, Measles, Rubella, epidemic Parotitis. No regular antiherpetic vaccines are currently used in Ukraine.

SEROLOGY

The diagnostic algorithm included testing for antibodies of class M to herpes simplex virus1/2 (HSV1/2), cytomegalovirus (CMV), Epstein Barr virus (EBV), varicella zoster virus (VZV), and class G to human herpesvirus (HHV) 1-6, and autoantibodies to the main protein of myelin, S-100, neurospecific enolase (NSE), the general human brain antigen. As a rule, results of EBV serology including VCA-IgG and IgM were recorded to assess whether the patient had primary infection, reactivation or latency.

INTRATHECAL ANTIBODY (ITAB)

Intrathecal antibody (ITAB) synthesis to EBV, one of the inclusion criteria of this study, was determined by the standard method used at our laboratory [20,21]. Briefly, we calculated the serum/CSF sample ratio by measuring the IgG titers of the specific virus by ELISA, where after this ratio was compared with the ratio of corresponding IgG titers against a reference virus (for example, measles, or another antigen). In addition, the CSF/serum albumin ratio and IgG index, (CSF/serum IgG ratio)/ (CSF/serum albumin ratio), were calculated to estimate blood-brain barrier damage and intrathecal antibody production [22].

REAL-TIME PCR ANALYSIS

The qualitative and quantitative analysis of viral DNA was provided by the certified “DNA lab” (Kyiv) using Real-Time PCR kits (ABAnalitika). The kit sensitivity was 0.4 – 2 viral genome copies (gc) / µL DNA extract (depending on specific virus), the linear range was 2.5 to 107 gc / reaction.

STATISTICAL ANALYSIS

For statistical analysis continuous data were compared with Mann-Whitney U test. Proportions were analyzed by Fisher’s exact test. A p value of ≤0.05 was considered statistically significant.

REVIEW

DEMOGRAPHY

Overall 226 patients with herpesvirus-associated brain parenchymal lesions were retrospectively analyzed during 2016-2017. 48 of all meeting the final criteria of EBV-linked CNS disorders were enrolled between January 2016 and December 2017. The majority of patients admitted to CIDNS were transferred from another hospital. All patients have proven EBV infection and symptoms of possible encephalitis (CNS disorders). A total of 11 (22.9%) patients were males, and 37 (77.1%) – females, the male to female ratio was 1:3.3. The median age of patients was 36.9 years (range 20-60 years). The demographic characteristics of the participants are outlined in Table I. On admission of all patients, the condition of only one was considered severe.

CLINICAL MANIFESTATIONS

Preadmission illnesses lasted a median of 52 days, range 11 to 188. Clinical profiles observed among the patients are characterized by extreme diversity and a combination of several CNS symptoms and syndromes. The symptoms of the patients on admission are presented by frequency in Table 2. Overall, headache 28 (58.3%) and cochlea-vestibular impairments 32 (66.6%) were the most commonly recorded symptoms. Vegetative dysfunction 10 (20.8%), fever 4 (8.3%), sleep disorders 5 (10.4%), mental confusion 6 (12.5%), pyramidal insufficiencies 12 (25.0%), convulsions 9 (18.7%), scattered neurological symptoms 13 (27.0%), pelvic disorders 2 (4.2%), reduced hearing 2 (4.2%) were reported less frequently. A minority of patients had neurological signs e.g. nerve palsies/paresis 4 (8.3%). Profound hearing loss was not detected.

In 19 (39.5%) cases clinical/radiological diagnosis of encephalitis, arachnoencephalitis, and meningoencephalitis was made. In 14 (29.1%) patients the clinical diagnosis was arachnoiditis without encephalitis, 6 (12.5%) patients had disseminated encephalomyelitis.

CSF AND BLOOD PROFILES

All of patients had lumbar punctures (LPs) done either on admission (n-43, 89.5%) or by the next day. White cell count (WCC) in 71% of CSF samples was < 10 cells/mm3. In the remaining samples, small cytosis was observed. Lymphocyte prevailed. The protein content of CSF was normal in 39 (81.2%) patients, and slightly increased (up to 0.99 g / l) in 9 patients. Normal level of WBC, or a small leukopenia was recorded in the blood. In 42 (87.5%) of 48 patients EBV was the only pathogen found by PCR in CSF or blood. DNA concentration vary from 2000 gc/ml to more than 200000 gc/ml (median ~ 32000 gc/ml). No other DNA was detected.

SEROLOGY

G class antibodies to EBV-VCA were detected in CSF of all 48 patients and in blood, 47 (97.9%) of them. In 17 (35.4%) patients anti-EBV ITAB synthesis was revealed. In liquor of 11 patients ITAB and EBV DNA were present simultaneously. Antibodies to EBV early antigen were found in sera of 7 patients (14.5%). Besides EBV, specific IgG to another HVs were detected. The mixed infection was represented by associations of 2, 3, 4 and even 5 viruses. The most common participants in the association were HSV-1/2 (13/27%), HSV-6 (7/14.5%), and HSV-7 (9/18.7%).

IMAGING

An important diagnostic and prognostic value has also neurovascular changes in the structure of the brain (Table II). FLAIR and T2 weighted images of MRI brain were used (Fig. 1, 2). The focal changes of the limbic system around bilateral, temporal, occipital, and frontal areas are most common (28/58.3%). Encephalitis often involves the cortex, hippocampal, and extrahippocampal structures involving the amygdala, tentorial cortex, thalamus, hypothalamus and deep forebrain structures, cerebellum, and brain stem (Fig. 1, 2). Diffuse lesions were observed in 15 (31.3%) patients. MRI of five patients (10.4%) had no changes. Signs develop gradually, but are somewhat delayed as compared to the clinical symptoms. Edema, necrosis, and sclerosis are not frequently found. These typical findings are subsequently resolved and brain atrophy is observed in the convalescent period.

TREATMENT

Patients with approved neurological symptoms received Ganciclovir (10 mg/kg, per day intravenous for 3-6 weeks), Valgancilovir (for 2-3 weeks) and then Valaciclovir. Interferon α2b 3000000 IU per day for 2 weeks, or human immunoglobulin intravenous (0.2 g/kg per day for 5 day) and managed supportively with ademetionine, 400 mg, and citicoline, 1000 mg both intravenous daily.

OUTCOME

The mean duration of hospital stay was 19.7 ± 15.3 days (range: 7 – 69). As a result of treatment, 26 (54%) patients had a good outcome and after discharge they returned home. The condition of 21 (44%) patients improved significantly (decrease of some neurologic symptoms, but with preservation of some manifestations of cerebrosthenic, vestibulo-atactic syndromes, pyramidal insufficiency). These patients were transferred to a convalescence facility. One patient, which condition worsened against the background of the therapy (dysfunction of the stem and cortical structures increased), were moved to an intensive care unit for further treatment. No patient died.

DISCUSSION

The data described here highlight the main clinical characteristics of EBV-associated encephalitis in Ukrainian adult patients. Should first emphasize the unnatural gender ratio of patients with a large prevalence of women. Of course, there is a sex balance in the general population, but this really reflects the gender composition of patients on hospital treatment. For example, in our center, seven out of eight hospital wards are reserved for women. The clinical and etiological diversity of herpesvirus infections make diagnosis difficult, although it is clear that the identification of an infectious agent is critically important, not only for establishing an accurate diagnosis, but also for the timely administration of specific treatment [23]. Diagnostic procedures include serological responses to specific antibodies in the blood and liquor, the detection of pathogens by molecular methods in CSF and blood, and sometimes propagation of pathogens in cell culture [24]. In this study, in virtually all patients examined, the presence of G class antibodies to several herpesviruses (which are considered an etiological factor in the overwhelming majority of infectious lesions of the CNS), both in CSF and in blood, had been established. This fact can be explained by the persistence of the viruses in the body with regular remissions that maintain a high level of immune response. Consequently, it is not possible to establish the correct cause of CNS damage on the basis of the presence of specific IgG only even in CSF. The diagnosis should be verified through epidemiological data and clinical symptoms, among which fever, headache, altered consciousness, seizures, routine CSF analyzes and neuroimaging [24]. Despite all diagnostic achievements, the etiologic cause of much of the cases in the world remains unknown. Thus, in the California encephalitic project, in which 1570 patients took part, 63% had no encephalitis cause [25]. In a similar French study, the cause of the disease remained unknown in 80% of cases [26]. The high incidence of an unidentified diagnosis is partly due to the lack of sensitivity and specificity of the diagnostic methods currently used in the clinic [23,25]. An analysis of cerebrospinal fluid in sporadic encephalitis typically exhibits lymphocytic pleocytosis and fluctuations of glucose and protein near normal level, but often normal indicators can be observed only at the onset of the disease [27]. In CSF, a small number of erythrocytes is sometimes found, which reflects the potentially hemorrhagic nature of the disease [28]. In this study the opening pressure was sometimes elevated, and a CSF cytosis was not exceed 10 cells/mm3 in about 70% of our patients. The level of both protein and CSF/blood glucose ratio was mostly normal. Increased CSF antibody to specific herpesvirus, and a reduced serum/CSF antibody ratio, might help to make diagnose. According to the literature data, intrathecal antibody detection is an important evidence for etiology [29]. On the contrary, systemic serological responses should not be considered for diagnosis, because so far there is no conclusive evidence linking ITAB synthesis and viral replication. There is no doubt only the appearance of antibodies to the early antigen. The data we have obtained also indicate that the interpretation must be very cautious. Therefore, positive results were taken into account only in case of coincidence with PCR data.

The use of DNA analyses enhanced substantially our ability to diagnose patients. Indeed, PCR was the only diagnostic tool in our setting for viral pathogens. Timely made diagnosis allowed appropriate treatment to be given. PCR detection of pathogen DNA in CSF is sensitive and specific, and has become the diagnostic procedure of choice, although PCR results can be negative during the early stages of disease [30].

In this study EBV-monoinfection was observed in 24 (50%) patients. In addition to EBV in 24 (50%) cases another herpesviruses were found. Co-infection is a common phenomenon in relation to herpesviruses. For example, in addition to EBV DNA coinfection with another pathogen was found in 25% of encephalitis [31].

Immunosuppression sharply increases the number of mixed infections: a single virus was detected in 20 out of 45 HIV-infected persons, 19 cases were co-infected with two viruses, and six cases were positive for three viruses [32].

Most of our patients had serology consistent with past EBV immunity and reactivation. This could imply that other infections in the CNS may trigger EBV reactivation. Sometimes EBV DNA was found in CSF but no in blood. Perhaps, preferential EBV replication in the CSF is stimulated by other CNS infections [33]. Multiplex PCR tests for simultaneous detection of several herpesviruses should be used in every case. This will shed more light on the real frequency of the EBV (and other herpesviruses) presence in the CNS of patients hospitalized due to neurological symptoms.

In the correct diagnosis of CNS infections neuroimaging becomes key. The instrument of neuroimaging can be computed tomography (CT), preferably with contrast, or MRI. From our point of view, MRI is better suited for the diagnosis of encephalitis due to higher resolving capacity. The absence of changes in MRI does not exclude CNS lesions, especially in the early stages of the infection, so it should be repeated 4-7 days if suspicion remains [34]. Thus, in one study, in 25% of patients with clinically and biologically diagnosed HVE, no pathological changes in MRI were detected [35].

CONCLUSIONS

EBV infection accounted for about 20% of acute encephalitis cases. Clinical presentations, laboratory data, and MRI are non-specific, so sometimes making a diagnosis of Epstein-Barr virus encephalitis can be difficult, and, consequently, a combination of serologic and molecular techniques should be used when investigating a patient with acute encephalitis. EBV encephalitis proceed more easily than infections caused by other herpesviruses: a high fever is rare, and the content of cells and protein in the liquor remain normal more often. This report also suggests that treatment scheme we used might be beneficial for the long term outcome in adult EBV encephalitis patients.

This study had some limitations; one was the non-inclusion of other viral agents such as enterovirus, adenovirus and arbovirus that are known to be responsible for similar neurological symptoms.

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Authors’ contributions:

According to the order of the Authorship.

Conflict of interest:

The Authors declare no conflict of interest.

CORRESPONDING AUTHOR

Olha Smiianova

Sumy State University

1 Sanatorna Str., 40018, Sumy, Ukraine

tel: +380507713008

e-mail: vladlor60@ukr.net

Received: 28.05.2018

Accepted: 15.08.2018

Table I. Demographic characteristics of the study participants

Number of patients

48 (100%)

Age, Me (range)

36.9 (20–65)

≤ 20 years

2 (4.1%)

21–30 years

13 (27.0%)

31–40 years

12 (27.0%)

41–50 years

10 (20.8%)

51-60 years

11 (22.9%)

Male

11 (22.9%)

Female

37 (77.1%)

 

Fig.1. EBV-Encephalitis with lesion of brainstem, cerebellum, andtemporal structures.

 

Fig.2. Encephalitis with focal lesions in the left frontal-temporal lobe, associated with EBV+ HSV1/2 co-infection.

Table II. Summary of clinical features, laboratory, and radiology data

Clinical signs

Patients (n=48/100%)

Fever

4 / 8.3

Meningism (stiff neck)

3 / 6.2

Headache

28 / 58.3

Decreased level of consciousness

1 / 2.0

Disorientation

4 / 8.3

Confusion

6 / 12.5

Seizures

9 / 18.7

Focal neurological sings

13 / 27.0

Vestibulo-atactic syndrome

32 / 66.6

Speech disorders

1 / 2.0

Cranial nerve palsy

4 / 8.3

Cerebellous syndrome

13 / 27

Sensory disorders

6 / 12.5

Myelitis

8 / 16.6

Aggressiveness

1 / 2.0

Apathy

39 / 81.2

Agitation

7 / 14.5

Parkinsonism

1 / 2.0

Hallucination

1 / 2.0

White cell count in CSF

 

Normal (≤10/mm3)

37 / 69.3

>10 mm3

11 / 30.8

Predominance of PMNs

3 / 6.2

Predominance of lymphocytes

45 / 93.8

CSF protein

 

Normal (0.15-0.35 g/L)

40 / 83.3

Elevated (>0.35 g/L)

8 / 16.7

CSF/serum glucose ratio

 

Normal (>0.4)

46 / 95.8

Low (≤0.4)

2 / 4.2

Typical infectious pattern

 

Bacterial a

5 / 10.4

Viral b

43 / 89.6

Viral DNA in CSF and/or blood

 

EBV- monoinfection

24 / 50

Mixt infection

24 / 50

Neuroimaging (MRI data)

 

Focal lesions

28 / 58.3

Diffuse lesions

15 / 31.3

W/o changes

5 / 10.4

Outcomes

 

Complete recovery

26 / 54.2

Improvement

21 / 43.8

Deterioration

1 / 2.0

Sequelae

0

Death

0

a Typical bacterial infections pattern: WBC count >100/mm3,

predominance of PMNs, mild to marked elevation of protein, normal to marked decrease of CSF/serum glucose ratio.

b Typical viral infections pattern: WBC count ≤100/mm3,

predominance of lymphocytes, normal to elevated protein, normal CSF/serum glucose ratio.