Case Report: A Case of Epstein Barr Virus-related Glial Fibrillary Acidic Protein Astrocytopathy Refractory to Conventional Immunotherapy

doi:10.21203/rs.3.rs-4916639/v1

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Case Report

Case Report: A Case of Epstein Barr Virus-related Glial Fibrillary Acidic Protein Astrocytopathy Refractory to Conventional Immunotherapy

https://doi.org/10.21203/rs.3.rs-4916639/v1

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Background

Epstein-Barr virus (EBV) infection has been associated with the development of glial fibrillary acidic protein astrocytopathy (GFAP-A), with most cases responding favorably to steroids and/or intravenous immunoglobulin (IVIG). We report a case of EBV-related GFAP-A exhibiting a poor response to conventional immunotherapy.

Case presentation

A 62-year-old Chinese male presented with dysuria, fever, and headache, rapidly progressing to paraparesis. Initial investigations indicated pulmonary infection and viral encephalitis. Despite intensive care and antiviral treatment, his condition deteriorated, necessitating tracheostomy and intubation. Upon transfer to a tertiary neurology center, he had reduced tone, power, and areflexia in the lower limbs, and a loss of sensation below the T6 level. Cerebrospinal fluid (CSF) analysis revealed markedly elevated cell counts and protein levels. MRI showed leptomeningeal enhancement in the left frontal lobe, cervical and thoracic spines. EBV DNA and GFAP-IgG were detected in the CSF, suggesting a diagnosis of EBV-related GFAP-A. Treatment with IV acyclovir, high-dose steroids, and IVIG was administered with no clinical improvement.

Conclusions

This report presents a case of EBV-related GFAP-A refractory to treatments with steroids and IVIG. It suggests that higher levels of CSF protein and cell count may predict worse outcomes and a poorer prognosis.

Epstein-Barr virus

glial fibrillary acidic protein astrocytopathy

steroids

intravenous immunoglobulin

refractory

case report

Epstein-Barr virus (EBV), or human herpesvirus 4, is a double-stranded DNA virus affecting 90–95% of the global population (1). The pathophysiology of EBV-related neurological disorders remains unclear and has been suggested to involve direct infection, immune hyperactivity, or reactivation of latent infections (2, 3).

Glial fibrillary acidic protein astrocytopathy (GFAP-A) is an autoimmune inflammatory disorder of the central nervous system first described in 2016 (4), presenting with symptoms involving the meninges, brain parenchyma, spinal cord, optic or peripheral nerves. Radiologically, it is characterized by linear radial perivascular enhancement on brain MRI and longitudinally extensive T2- hyperintense lesion with linear enhancement in the spine (5, 6). Histologically, the presence of GFAP-IgG antibodies in cerebrospinal fluid (CSF) is a key diagnostic marker with high specificity (6). Standard acute treatment involves steroid and/or intravenous immunoglobulin (IVIG) therapy, with 80% of cases showing good responses (5). Chronic treatment involves mycophenolate mofetil (MMF), rituximab, azathioprine and cyclosporine; however, evidence is not clear on the effectiveness of these treatments and their clinical outcomes (7).

In rare cases, GFAP-A has been linked to EBV infection, with most patients responding to standard immunotherapy (8–11). We report a new case of GFAP-A associated with EBV infection which had a poor response to steroids and IVIG.

A 62-year-old Chinese male with a background of Type II diabetes was admitted to a local hospital in China with dysuria, fever, and headache. CT chest indicated a pulmonary infection, which failed to respond to antibiotics. On Day 4, he developed paraparesis and was diagnosed with viral encephalitis based on CSF analysis (exact values undisclosed). He was then transferred to the intensive care unit of another hospital for further treatment.

Following transfer, his pulmonary condition deteriorated, leading to tracheostomy and intubation. Antiviral treatment was initiated. On Day 9, a repeat CSF analysis showed an elevated cell count (339×10⁶/L) and high protein levels (> 3g/L), suggesting an intracranial infection. Despite treatment with IV methylprednisolone (0.5g×3d), there was no improvement, and he was transferred to a tertiary neurology center on Day 17.

Upon arrival, he presented with a Glasgow Coma Scale score of E4VTM6, nuchal rigidity, and reduced tone in all four limbs. Power was grade 4 in the upper limbs and grade 0 in the lower limbs. Reflexes were absent in the lower limbs and Babinski signs were negative. Deep and superficial sensation was absent below the T6 level. On Day 18, a persistently elevated cell count (160×10⁶/L) and protein levels (1g/L) were noted. Targeted next-generation sequencing (tNGS) identified EBV (8766 reads), indicating a possible EBV-related central nervous system infection.

Treatment with IV acyclovir (0.75g q8h), dexamethasone (10mg qd), and human immunoglobulin (IVIG, 0.4g/kg/d×5d) was initiated without improvement. CT scans showed no significant abnormalities in the brain and spinal regions. On Day 28, a repeat CSF analysis showed a decrease in cell count (90×10⁶/L) and protein levels (0.4g/L), and tNGS revealed a reduction in EBV sequences (2857 reads).

On Day 38, he was successfully extubated. MRI showed leptomeningeal enhancement in the left frontal lobe, cervical and thoracic spines, with discontinuous long T1- and T2-weighted signals (Fig. 1). However, lumbar spine MRI and electromyography were both normal. Despite these results, he continued to have flaccid paraparesis. Subsequently, another course of IVIG (0.4g/kg/d×5d) was administered.

On Day 45, a stable CSF cell count (92×10⁶/L) and protein level (5g/L) were observed, and tNGS demonstrated clearance of EBV (0 read). Autoimmune antibody testing detected GFAP IgG antibody (serum titer 1:10, CSF titer 1:1) and type 2 oligoclonal bands, leading to a diagnosis of GFAP astrocytopathy. Consequently, acyclovir was discontinued, and dexamethasone was converted to methylprednisolone pulse therapy (500mg/d×5d, 80mg/d×5d, and 40mg/d×5d). On Day 53, when his lung infection improved, methylprednisolone was stepped down to oral prednisone acetate 15mg, and oral MMF 1g was added as chronic treatment. Despite these interventions, the patient’s paraparesis persisted without signs of improvement.

The literature on EBV-associated GFAP-A is limited, with eight cases identified through our search (Supplementary Table 1) (8–11). This report presents a patient with high EBV sequence count in the CSF and clinical and imaging findings characteristic of GFAP-A, suggesting a potential linkage between EBV infection and the development of GFAP-A. While the underlying mechanism remains unclear, EBI2 (EBV-induced gene 2) has been suggested to play a role by influencing astrocyte migration and modulating immune cell responses via the MAPK/ERK signaling pathway (9, 12).

Another significant finding was the patient’s lack of response to extensive steroid and IVIG therapy, diverging from the positive outcomes observed in the previously reported cases (Supplementary Table 1). This discrepancy may be attributed to the severity of the cytokine storm induced by the EBV infection, as evidenced by the patient's high initial CSF protein (> 3 g/L) and cell count (339×10⁶/L) (Fig. 2). Notably, only one case, Patient 5, reported similar CSF protein (2.8 g/L) and cell count (392×10⁶/L) levels, associated with a poorer outcome at the 6-month follow-up (Supplementary Table 1) (9). These observations suggest that early elevated CSF protein levels and cell counts might be indicative of a poor response to steroid and IVIG therapy. This differential response could be linked to the GFAP-A's reliance on cytotoxic T-cell responses (5). In the case of significantly heightened immune hyperactivity, steroid and IVIG may not fully suppress T-cell activity, potentially leading to a partial response and a poorer prognosis.

Meanwhile, the relationship between treatment outcomes and EBV replication levels in the CSF remains to be elucidated. While our study utilized tNGS, most reported cases employed metagenomic Next-Generation Sequencing (mNGS) and polymerase chain reaction (PCR) to assess EBV levels. While mNGS offers a broader detection range and greater sequencing depth, tNGS selectively amplifies and sequences specific pathogens or genetic markers, enabling precise detection of low-abundance sequences (13, 14). Because cases with favorable treatment outcomes have typically reported lower EBV sequence counts using mNGS as opposed to tNGS as in our case (Supplementary Table 1), the exact relationship between EBV replication levels and prognosis requires further research to establish.

In conclusion, our case of EBV-related GFAP-A refractory to steroids and IVIG demonstrates the complexity of treatment responses in this rare condition. The presence of higher CSF cell counts and protein levels may suggest a poorer therapeutic response, indicating a need for future research to clarify the relationship between EBV-induced immune responses and treatment outcomes.

CSF Cerebrospinal fluid

CT Computed tomography

EBI2 Epstein-Barr virus-induced gene 2

EBV Epstein-Barr virus

GFAP-A Glial fibrillary acidic protein astrocytopathy

GFAP-IgG Glial fibrillary acidic protein immunoglobulin G

IV Intravenous

IVIG Intravenous immunoglobulin

MAPK/ERK Mitogen-activated protein kinases/extracellular signal-regulated kinase

MMF Mycophenolate mofetil

mNGS Metagenomic next-generation sequencing

MRI Magnetic resonance imaging

PCR Polymerase chain reaction

tNGS Targeted next-generation sequencing

Ethics approval and consent to participate

Ethics approval was exempt by the Ethics Committee of Shanghai Donglei Brain Hospital as all information is anonymized.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that there are no conflicts of interest.

Funding

The authors report no targeted funding.

Authors’ contributions

WZ designed the study. TZ, DS and DH collected the data. YL prepared the figures. WZ and SJ drafted the manuscript and the supplementary table. SJ revised the manuscript. The authors read and approved the final manuscript.

Acknowledgements

We thank the patient and his family for their permission to publish this information.

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No competing interests reported.

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You are reading this latest preprint version

Case Report: A Case of Epstein Barr Virus-related Glial Fibrillary Acidic Protein Astrocytopathy Refractory to Conventional Immunotherapy

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Version 1

Abstract

Background

Case presentation

Conclusions

Figures

Background

Case Presentation

Discussion and Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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Version 1