A case report of autoimmune glial fibrillary acidic protein astrocytopathy combined with Epstein-Barr virus infection

Abstract

Background

This report provides a comprehensive overview of the clinical manifestations, diagnostic evaluations, treatment, and prognosis of a 36-year-old male patient diagnosed with autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) in conjunction with Epstein-Barr virus (EBV) infection at our institution. Reports of GFAP-A associated with viral infections are infrequent.

Case presentation

The patient exhibited a range of symptoms, including fever, gait instability resembling ataxia, a sensation akin to stepping on cotton, diminished responsiveness, cognitive decline, urinary and bowel dysfunction, and persistent hiccups. Enhanced imaging of the thoracic spine revealed patchy meningeal enhancement, with central canal-like enhancement observed in coronal views. Additionally, radiating perivascular linear enhancement was noted in the ventricular white matter, cerebellum, and other regions, alongside the aforementioned central canal-like enhancement. Next-generation sequencing (NGS) of cerebrospinal fluid (CSF) confirmed the presence of human herpesvirus type 4 (EBV). Both cell-based assay (CBA) and tissue-based assay (TBA) tests validated the presence of GFAP antibodies in the CSF. Following treatment with acyclovir for antiviral therapy and high-dose corticosteroid therapy, the patient demonstrated significant clinical improvement.

Conclusions

It is postulated that the viral infection may have precipitated autoimmune meningoencephalitis. Providing more related cases for the diagnosis of this disease.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12883-025-04363-6.

Background

Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a corticosteroid-responsive autoimmune meningoencephalomyelitis that predominantly affects the meninges, brain parenchyma, optic nerves, and spinal cord, thereby representing a significant central nervous system disorder [1–3]. In 2016, Professor Lennon and his team first reported the clinical symptoms and imaging features of 16 patients diagnosed with GFAP-A, identifying anti-GFAP antibodies (GFAP-immunoglobulin G, GFAP-IgG) as a specific biomarker for the disease. Currently, there are no standardized guidelines or consensus regarding the treatment of GFAP-A. there are few reports on GFAP, and cases combined with Epstein-Barr virus (EBV) infection are even rarer. This report discusses a recent case of autoimmune GFAP-A complicated by EBV infection, which was admitted to our hospital. And focuses on the mechanism by which viral infections may trigger the disease, considering that EBV infection might be a potential cause of elevated GFAP levels [5, 6]. EBV primarily persists in memory B cells during latent infection. Due to its natural infection cycle and associated pathological abnormalities, EBV can also infect various other cell types [4]. By stimulating infected cells, EBV can elicit a strong cell-mediated immune response in hosts with normal immune function, which may lead to autoimmune reactions [5]. Moreover, studies have suggested that EBV infection might damage astrocytes, thereby triggering an excessive autoimmune response following antigen exposure [6]. It is recommended that GFAP-A patients undergo further evaluation of infection markers upon admission. Early antiviral treatment may help alleviate the disease, and the use of high-dose corticosteroid therapy may accelerate recovery.

Case presentation

The patient, referred to as Li, is a 36-year-old male who was admitted to our institution with the primary complaint of fever for 12 days, followed by an unsteady gait for 4 days. The febrile episode began 12 days prior to admission, with a peak temperature recorded at 39.6 °C, and was accompanied by symptoms of nausea, vomiting, and a generalized headache. The fever exhibited fluctuations throughout this period. A cranial CT scan conducted at an external facility indicated a possible left temporal pole arachnoid cyst, with no other significant findings noted on the plain scan. Following this, the patient returned home and received intravenous treatment with acyclovir and azithromycin (specific dosages unknown) at a community hospital for 6 days, during which his body temperature normalized, and the headache partially subsided. However, 8 days prior to admission, the patient began to experience progressive symptoms, including cervical rigidity and lethargy. Four days before hospitalization, he developed an unsteady gait, described as a subjective sensation of “walking on cotton.” Concurrently, he exhibited cognitive slowing, episodic memory impairment, dysuria, constipation, and persistent singultus. One day prior to admission, he experienced odynophagia, which significantly hindered his ability to consume both solids and liquids. Upon evaluation in the emergency department, a preliminary diagnosis of acute disseminated encephalomyelitis (ADEM) was proposed. The patient’s overall condition was suboptimal, characterized by excessive somnolence, reduced appetite, and urinary and gastrointestinal dysfunction; however, there was no significant weight loss observed. The patient was previously healthy with no history of hypertension, diabetes, autoimmune disorders, or malignancy. He denied any history of neurological conditions including epilepsy, stroke, encephalitis, or myelitis. There was no psychiatric history of depression, anxiety disorders, or other mental health conditions. He received routine childhood vaccinations (including varicella vaccine) with no special vaccinations in the past 3 years. No known drug or food allergies. The family history was negative for neurological or autoimmune disorders. There was no recent travel to endemic areas or exposure to radiation or toxins. He had a 10-year history of smoking, averaging 10 cigarettes per day, and occasionally consumed alcohol in small quantities. He had no history of any surgical procedures, anesthesia complications, significant trauma, or blood transfusions.

Upon admission, the patient underwent a comprehensive physical examination, which revealed a slow speech pattern, hypophonia, and mild memory deficits upon gross assessment. Notably, the patient’s orientation, arithmetic ability, comprehension, and judgment were found to be intact. Evaluation of the cranial nerves indicated no deficits; however, the patient demonstrated dysphagia while maintaining preserved bilateral pharyngeal reflexes. The motor assessment revealed a muscle strength rating of 4/5 across all extremities, accompanied by mild hypertonia in the upper limbs. Bilateral motor tremors were observed in the upper limbs. Coordination testing, which included finger-to-nose and heel-to-shin maneuvers, demonstrated precision and symmetry. Sensory evaluations for position sense, motion sense, vibration sense, and pain sensation were symmetrical across all limbs. Reflex assessments revealed hyperreflexia in the biceps, triceps, and brachioradialis bilaterally, while the patellar and Achilles reflexes were absent in the lower extremities. Plantar reflexes were symmetrical, and no pathological signs were detected. Cervical rigidity was present, with a limitation of four fingers in flexion; however, both Brudzinski’s and Kernig’s signs were negative. Additionally, urinary and fecal retention were noted. The scores on the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) were both recorded at 23.

Laboratory findings

Hematologic evaluation revealed an elevated C-reactive protein (CRP) level of 23.77 mg/L and a leukocyte count of 7.09 × 10^9/L, with a neutrophilic predominance of 77.6%. Electrolyte analysis indicated hypokalemia (3.39 mmol/L) and hyponatremia (129.00 mmol/L). A 16-channel electroencephalogram (EEG) demonstrated abnormal cerebral activity characterized by polymorphic theta waves (4–7 Hz) of varying amplitudes, peaking at 90 µV.4-hour video EEG conducted during sleep revealed sharp waves and irregular slow-wave activity predominantly in the right frontal and anterior temporal regions, with occasional contralateral involvement. CSF analysis exhibited a normal opening pressure of 170 mmHg and a clear appearance. CSF pleocytosis was noted, with an elevated leukocyte count of 53 × 10^6/L, consisting of 4% neutrophils and 96% mononuclear cells. The Pandy test returned a positive result. CSF protein concentration was significantly elevated at 1360.10 mg/L, while glucose and chloride levels remained within normal reference ranges. No acid-fast bacilli, bacterial, fungal, or Cryptococcus elements were identified upon staining. Additional serological and CSF-based investigations for viral, mycobacterial, and mycoplasma pathogens yielded negative results. An extensive autoimmune panel conducted at Jiangsu Xiansheng Medical Diagnostic Laboratory was negative for antibodies associated with classical autoimmune encephalitis and paraneoplastic syndromes.(details in Appendix 1).However, immunological assays specific to central nervous system demyelination revealed a positive result for glial fibrillary acidic protein (GFAP) IgG in the CSF (1:10+, Fig. 1A), while the serum counterpart remained negative. In the Fig. 1A, green fluorescence represents the cells containing the target antigen (HEK293T living cells), and red fluorescence represents the antibody in the specimen (anti-human IgG secondary antibody). The positive cells are those with the overlap of red fluorescence and green fluorescence in specific parts. Tissue-based assay (TBA) screening demonstrated positive fluorescence for GFAP antibodies in cerebellar, hippocampal, and cortical regions within the CSF, while serum results analyses yielded negative (Fig. 1B). Genomic sequencing conducted through next-generation sequencing (NGS) of the CSF identified the presence of EBV, characterized by 12 specific sequences and a relative abundance of 100%. Concurrent blood NGS detected Klebsiella oxytoca, which presented with 15 specific sequences and a relative abundance of 0.82%. Neuroimaging studies, including fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) of the brain, revealed multiple patchy hyperintensities in the bilateral basal ganglia, corona radiata, and thalamic regions, as well as abnormal signal intensities in the cervical spinal cord, suggestive of ADEM (Fig. 2). MRI of the cervical, thoratic, and lumbar spine disclosed focal hyperintensities at the C2–3 vertebral level, raising suspicion for concurrent myelitis, along with localized signal anomalies in the lower thoracic spinal cord (Fig. 3). Post-contrast thoratic spine MRI exhibited linear dural enhancement and central canal-like enhancement (Fig. 4). Cranial post-contrast MRI revealed enhancement in the bilateral cerebral peduncles, medulla, and pons, indicative of leptomeningeal involvement, in addition to radiating perivascular linear enhancement in the periventricular white matter and cerebellum, characterized by a central canal-like enhancement pattern (Fig. 5).

Fig. 1.

A: Autoimmune Encephalitis Autoantibodies – CSF: Positive for GFAP IgG at a dilution of 1:10+.B: Tissue-Based Assay Screening for Autoantibodies in Cerebrospinal Fluid (Neurological autoantibodies were screened by rat brain tissue section): Demonstrates positive fluorescence resembling GFAP antibodies in the cerebellum, hippocampus, and cerebral cortex. *Green fluorescence represents the cell containing the target antigen (HEK293T living cells), and red fluorescence represents the antibody in the specimen (anti-human IgG secondary antibody). The positive cells are those with the overlap of red fluorescence and green fluorescence in specific parts

Fig. 2.

Brain MRI with FLAIR demonstrates multiple patchy lesions in the bilateral basal ganglia, corona radiata, and thalamic regions

Fig. 3.

MRI of the cervical, thoratic, and lumbar spine –At the level of the C2-3 vertebrae, there is an abnormal signal observed in the spinal cord, which suggests the possibility of myelitis. Additionally, in the lower thoratic spinal cord, there is localized thickening accompanied by an abnormal signal, which may indicate the presence of a lesion

Fig. 4.

Enhanced MRI of the thoratic spine – The image demonstrates strip-like dural enhancement, with a central canal-like enhancement observable in the sagittal view

Fig. 5.

Enhanced Brain MRI. A: Enhancement in the bilateral cerebral peduncles, medulla, and pons, suggesting the presence of leptomeningeal enhancement. B: radiating perivascular linear enhancement around blood vessels in the periventricular white matter and cerebellum, accompanied by enhancement resembling a central canal

In summary, taking into account the array of clinical manifestations, laboratory parameters, and neuroimaging findings, a definitive diagnosis of GFAP-A complicated by EBV infection was established.

Treatment

The patient presented to the Ear, Nose, and Throat (ENT) department with complaints of throat pain that impaired his ability to eat and drink. A diagnosis of acute laryngitis was suspected, and the patient was subsequently treated with budesonide nebulization. Notably, his swallowing difficulties showed improvement after three days of treatment.

Despite the initial treatment, the patient continued to exhibit fever, with temperatures fluctuating between 36 °C and 38.4 °C. Ceftriaxone was administered due to a suspected infection based on blood tests results; however, the fever persisted. On the third day of hospitalization, NGS of CSF identified an EBV infection, which prompted the initiation of acyclovir antiviral therapy. After three days of treatment, the fever subsided, and there was a slight improvement in limb weakness. On the seventh day, following a positive result for GFAP antibodies in the CSF and findings from cranial MRI, corticosteroid pulse therapy was initiated. The patient received 500 mg of methylprednisolone sodium succinate daily for three days, which was subsequently reduced to 250 mg daily for the following three days, and then transitioned to oral prednisone at a dosage of 60 mg daily. Notable improvement was observed on the first day of corticosteroid therapy, characterized by a reduction in limb weakness and upper limb tremors. During the neurological examination, the patient was alert and communicative, albeit with mild memory impairment. The cranial nerve examination yielded normal results. Muscle strength was assessed at 5-/5 in all limbs, with mildly increased muscle tone noted in the upper limbs. Kinetic tremors were present in the upper limbs. Reflexes were slightly hyperactive in the biceps, triceps, and brachioradialis, while lower limb reflexes were diminished, with absent patellar and ankle reflexes. Plantar reflexes remained normal and symmetrical. No pathological signs such as Brudzinski’s or Kernig’s signs, were observed, and neck stiffness was absent. The patient continued to experience urinary and fecal retention. On the third day of corticosteroid therapy, the patient reported an urge to defecate but was unable to control bowel movements. By the sixth day, both tremors and limb weakness had significantly improved. The neurological examination revealed no abnormalities, and the patient had no additional complaints. Upon discharge, he was prescribed prednisone at a dosage of 60 mg daily, with a tapering regimen involving a reduction of one tablet every two weeks until reaching a maintenance dose of 5 mg daily for a duration of six months. A follow-up appointment was recommended in three months for repeat EEG, brain MRI, and spinal MRI, with a lumbar puncture for GFAP antibody re-evaluation if deemed necessary. One month post-discharge, the patient returned for an outpatient follow-up. He exhibited no tremors and demonstrated normal bowel and urinary function; however, due to personal financial constraints, follow up imaging and testing was not able to be performed.

Discussion

Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is classified as a corticosteroid-responsive autoimmune meningoencephalomyelitis [1, 2, 7–9]. The median age of onset is 42 years, and there is no established correlation with gender [1, 2]. This condition primarily affects the meninges, brain parenchyma, optic nerves, and spinal cord. The clinical presentation is heterogeneous and may manifest as meningitis, encephalitis, or myelitis, either individually or in combination [9].

Although the precise pathogenesis of GFAP-A remains ambiguous, it is frequently linked to infections, tumors, and immune deficiencies, which encompass rheumatic and endocrine disorders [2, 9]. Research suggests that preceding infections may contribute to the condition, as 27% of 102 patients diagnosed with GFAP-A reported a history of prior infections [2, 9].

Currently, there are limited reports linking GFAP being associated to viral infections, but it is plausible that such infections may precipitate autoimmune encephalomyelitis. The relationship between EBV infection and GFAP-A pertains to the virus’s impact on the nervous system.

According to various studies examining the relationship between EBV and GFAP-A, there is a growing consensus that EBV infection may serve as a potential trigger for GFAP elevation. A study conducted in 2017 reported that in the initial patient, a lumbar puncture performed 10 days post-symptom onset showed a positive EBV infection alongside the presence of oligoclonal bands, but GFAP levels were negative at that time. Notably, one month later, GFAP was subsequently found to be positive [10]. The same study indicated that in certain cases, GFAP may initially present as negative at the onset of the disease but can later become positive, typically within a timeframe of approximately 15 days [11]. In the case presented herein, the patient experienced fever 12 days prior to admission, and treatment with acyclovir resulted in partial symptom relief and a reduction in temperature.

The latent infection of EBV predominantly resides in memory B cells. However, due to its natural infection cycle and the associated pathological abnormalities, EBV is capable of infecting various other cell types, including gastric epithelial cells, B lymphocytes, T lymphocytes, natural killer (NK) lymphocytes, astrocytes, and neurons [4]. Rickson posited that EBV elicits a robust cell-mediated immune response in immunocompetent hosts by stimulating infected cells, which may potentially lead to autoimmune reactions [5]. Furthermore, it has been suggested that EBV infection contributes to the destruction of astrocytes, which may result in an exaggerated autoimmune response following antigen exposure [6]. Additionally, Rutkowska found that EBV-induced gene factor 2 (EBI2) plays a crucial role in T-cell-dependent antibody responses, as well as in B cell migration and differentiation. Notably, EBI2 is expressed in astrocytes and signals through the pERK 1/2 pathway, inducing ERK phosphorylation and calcium signaling. This mechanism promotes astrocyte migration [12], which may play a crucial role in neuroinflammatory responses and nerve injury repair. In the context of EBV infection, studies have demonstrated that the virus can directly infect glial cells, particularly astrocytes, leading to a significant upregulation of GFAP expression. This upregulation is thought to be a response to neuroinflammation, as glial cell activation and the release of inflammatory factors have been correlated with increased GFAP expression. Such processes may contribute to neuronal damage and the development of associated neurological disorders [5, 6]. Despite these findings, the precise mechanisms underlying the relationship between EBV infection and GFAP-A remain to be fully elucidated.

GFAP is recognized as the fourth neuroglial autoantigen of clinical significance, alongside aquaporin-4 (AQP4), myelin oligodendrocyte glycoprotein (MOG), and SRY-box transcription factor 1 (SOX1), exhibiting high expression levels in astrocytes [2, 6]. GFAP is predominantly expressed in the central nervous system and is almost exclusively localized to astrocytes, where it functions as the primary intermediate filament in mature astrocytes. This protein plays a critical role in regulating astrocyte morphology and motility, thereby contributing to cellular stability, maintaining the structural integrity of white matter, and ensuring the proper functioning of the blood-brain barrier [13]. GFAP-IgG is an antibody that targets intracellular antigens and is not inherently pathogenic. However, the neuroinflammatory response mediated by cytotoxic T cells within an autoimmune context is considered a potential mechanism underlying GFAP-A [9, 14]. Current literature indicates that brain biopsies from GFAP-IgG-positive rats show a necrotizing inflammatory process characterized by the infiltration of CD8 + T lymphocytes and macrophages [1, 9].

Additionally, approximately 40% of patients diagnosed with GFAP-A also exhibit the presence of other neurological autoantibodies, with the most common being anti-N-methyl-D-aspartate receptor (NMDAR) antibodies (22%), followed by anti-aquaporin-4 (AQP4) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. The presence of both GFAP-IgG and other autoimmune antibodies holds clinical significance, particularly in predicting the likelihood of an associated ovarian teratoma [2, 9, 14, 15]. Flanagan et al. conducted a study involving 102 cases, identifying ovarian teratomas in 5 out of 7 patients (71%) who presented with coexisting autoantibodies [2]. Some research suggests that patients with anti-NMDAR-positive GFAP-A may experience transient headaches and mild neurological deficits without the classic presentation of NMDAR encephalitis, a condition referred to as Hypertensive Angiopathy with NF-κB Dysregulation and autoantibody-associated Leukoencephalopathy (HANDL) syndrome [16]. A study conducted at the Mayo Clinic found that 6 out of 16 patients (38%) developed neurological symptoms within three years prior to the diagnosis of a tumor, with ovarian teratomas being the most frequently identified malignancy [1]. Consequently, tumor screening is recommended for patients with GFAP-A, particularly those who also possess additional autoimmune antibodies [1, 15]. Approximately one-fourth of affected individuals have one or more autoimmune-related conditions, most notably rheumatic diseases such as rheumatoid arthritis, as well as endocrine disorders, including type 1 diabetes and hypothyroidism [1, 2, 9]. This underscores the necessity for comprehensive screening for autoimmune disorders and malignancies [9]. In this particular case, the patient underwent a CT scan of the entire abdomen at a foreign hospital prior to admission, followed by a chest CT after admission; neither of these scans revealed any significant abnormalities.

MRI findings in GFAP-A patients can range from normal to nonspecific abnormalities [2], with high-intensity signals on T2-weighted imaging being the most prevalent observation. A distinctive imaging feature is the presence of periventricular radial linear enhancement on gadolinium-enhanced MRI, which is observed in 56% of cases [9, 15]. Similar enhancement patterns may also be noted in the cerebellum [2, 16, 17]. These imaging characteristics exhibit overlap with findings seen in other conditions, such as lymphomatoid granulomatosis, ganglioneuromatosis, and CNS vasculitis [2, 18]. Therefore, the identification of GFAP-IgG antibodies in cerebrospinal fluid is essential for distinguishing GFAP-A from these alternative disorders. Additionally, in certain instances, meningeal enhancement—affecting the membranes surrounding the brain and spinal cord —and linear enhancement along the central canal may also be observed [2, 9, 13–15]. In the case under discussion, the patient’s MRI exhibited these specific patterns. Diffusion-weighted imaging (DWI) and magnetic resonance angiography (MRA) were largely unremarkable [2]. Radiologically, spinal lesions are frequently characterized as longitudinally extensive transverse myelitis, occurring in 75% of cases and typically involving three or more vertebral segments, however, some cases may also present with punctate or patchy enhancement patterns [2].

CSF analysis predominantly reveals elevated lymphocyte counts and leukocytosis in 88% of patients, with a median leukocyte count of 78 cells/µL [2]. Additionally, protein levels are elevated in 83% of cases, with a median concentration of 80 mg/dL, and oligoclonal bands are detected in 54% of patients. These CSF abnormalities are also indicative of infectious or neoplastic meningoencephalitis, which may increase the likelihood of misdiagnosis. Nevertheless, the presence of GFAP-IgG antibodies is a critical distinguishing factor that aids clinicians in identifying immune-mediated, corticosteroid-responsive disorders [2]. The existing literature and retrospective case analyses consistently indicate that the detection of GFAP-IgG antibodies in CSF or serum exhibits high specificity for this condition. Furthermore, studies indicate that the sensitivity of CSF antibody detection is significantly more sensitive than that of serum testing [1, 2].

Research conducted by Flanagan et al. identified subtypes of GFAP-IgG,, with GFAP-IgG α demonstrating the highest sensitivity and being predominantly present in mature astrocytes. In contrast, GFAP-IgG δ and ε appear in immature astrocytes. While the expression of GFAP-IgG δ has been linked to spinal astrocytomas, subtype-specific testing for GFAP-IgG is not presently mandated for the diagnosis of GFAP-A [2].

Therapeutically, 87.5% of patients show clinical improvement following corticosteroid treatment. Plasma exchange and intravenous immunoglobulin (IVIG) may also be beneficial; however, their use is less prevalent during the acute phase. GFAP astrocytopathy has a high risk of relapse, particularly during the tapering of corticosteroids, which is often associated with the emergence of new MRI lesions and increased CSF leukocyte counts. Consequently, the implementation of long-term immunosuppressive therapy is strongly recommended to mitigate the risk of relapse [8, 9, 14].

Abbreviations

ADEM

Acute disseminated encephalomyelitis

AQP4

Aquaporin-4

CSF

Cerebrospinal fluid

CBA

Cell-based assay

CRP

C-reactive protein

EBV

Epstein-Barr virus/human herpesvirus type 4

EBV

Electroencephalogram

ENT

Ear, Nose, and Throat

EBI2

EBV-induced gene factor 2

FLAIR

Fluid-attenuated inversion recovery

GFAP

Glial fibrillary acidic protein

GFAP-A

Autoimmune glial fibrillary acidic protein astrocytopathy

GFAP-IgG

Anti-GFAP antibodies (GFAP-immunoglobulin G)

MRI

Magnetic resonance imaging

MRA

Magnetic resonance angiography

TBA

Tissue-based assay

Authors’ contributions

Qi An: Manuscript writing, literature review; Limei Liu : Research guidance, manuscript review.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

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

Declarations

Ethics approval and consent to participate

Written informed consent was obtained from the patient for the publication of this case report series and any accompanying images.And this case report was approved by the ethics committee of the Second Hospital of Dalian Medical University.

Competing interests

The authors declare no competing interests.

Consent for publication

Written informed consent was obtained from the patient and their legal guardian/family member for publication of this case series and any potentially identifiable clinical information or images.