A Case Report of Rare MOG Antibody-Associated Optic Neuritis Related to Hepatitis E Virus Infection

Introduction

Hepatitis E virus (HEV) is an unenveloped, positive-sense single-stranded RNA virus belonging to the Hepeviridae family. It can cause acute hepatitis, which is usually self-limiting and asymptomatic or mild, requiring no specific treatment, and the virus can be spontaneously cleared within 4–6 weeks.^1,2 Individuals with compromised immune systems are often unable to clear HEV through their immune responses in a short time, potentially progressing to chronic hepatitis.³ Most HEV infections are asymptomatic, with less than 5% of patients developing typical acute hepatitis symptoms such as fever, stomach pain, nausea, vomiting, and jaundice.^4,5 HEV infection can present with multisystem and multi-organ extrahepatic manifestations, including the nervous system, kidneys, hematologic system, and pancreas.⁶ Neurological damage is the most common extrahepatic manifestation of HEV infection,⁷ with neuralgic amyotrophy (primarily bilateral muscle atrophy) and Guillain-Barré syndrome (GBS) being the most common, followed by myalgia and encephalitis/myelitis.^8,9 To date, only one case report has associated HEV infection with optic neuropathy. The patient initially experienced blurred vision and later developed complete vision loss, ultimately diagnosed as acute HEV infection leading to central nervous system multifocal disseminated inflammatory lesions.¹⁰ Cases of HEV infection presenting with optic neuropathy symptoms remain scarce. Here, we present a rare case of Myelin oligodendrocyte glycoprotein (MOG) antibody-associated optic neuritis related to HEV infection in an immunocompetent patient.

Case Presentation

The patient is a 49-year-old male with a healthy lifestyle and regular physical activity. On April 17, 2024, he experienced fatigue, poor appetite, slightly yellowish urine, and a low-grade fever of 37.7°C without any apparent cause. Blood tests showed elevated liver function indices: alanine aminotransferase (ALT) at 3337 U/L (Ref: 9–50), aspartate aminotransferase (AST) at 2769 U/L (Ref: 15–40), and total bilirubin (TBIL) at 46 μmol/L (Ref: ≤ 23) (Figure 1). Urinalysis was abnormal with positive results for urine bilirubin (1+) and urobilinogen (1+). On April 19, serological testing for hepatitis A, C, D, and E antibodies revealed positive IgM antibodies for hepatitis E virus (HEV), leading to a diagnosis of acute hepatitis E. The patient was admitted for the first time on April 20 for treatment.

Figure 1 Changes of liver function indexes in patients during hospitalization. ALT: alanine aminotransferase (Ref: 9–50 U/L); AST: aspartate aminotransferase (Ref: 15–40 U/L); ALP: alkaline phosphatase (Ref: 45–125 U/L); GGT: γ-glutamyl transferase (Ref: 10–60 U/L); TBIL: total bilirubin (Ref: ≤23.0 μmol/L); DBIL: direct bilirubin (Ref: ≤8.0 μmol/L); IBIL: indirect bilirubin (Ref: 3.4–13.7 μmol/L); Scr: serum creatinine (Ref: 59–104 μmol/L).

The patient, with no significant past medical history, exhibited clear consciousness, low energy, poor appetite and sleep, normal bowel movements, yellowish urine, and unspecified weight changes since the onset of symptoms. During hospitalization, coagulation function was normal. Treatment included magnesium isoglycyrrhizinate, ademetionine, bicyclol tablets, and ursodeoxycholic acid tablets. ALT, AST, and TBIL levels gradually decreased to normal (Figure 1). By April 30, the patient’s clinical symptoms improved, and he was discharged in good condition.

On May 3, the patient was readmitted due to gradually worsening blurred vision, accompanied by posterior ocular pain for four days. One day before admission, the ophthalmologic examination revealed visual acuity vision of the right eye (VOD) 0.6, vision of the left eye (VOS) 0.6, intraocular pressure Tod: 18 mmHg, Tos: 20 mmHg. Both eyes showed no conjunctival congestion, vitreous opacity, optic disc edema with blurred margins, dilated veins, and flat retinas. Fundus photography showed bilateral optic disc edema. Optic disc optical coherence tomography (OCT) showed thickened nerve fiber layer, suggesting optic disc edema. Relative afferent pupillary defect (RAPD) was negative. Upon admission, his pulse was 62 beats/min (Ref: 60–100), respiratory rate 17 breaths/min (Ref: 12–20), blood pressure 128/74 mmHg, and body temperature 36.7°C. The patient was conscious, with no significant conjunctival congestion or eyelid edema, a soft and non-tender abdomen, and no palpable liver or spleen below the ribs. There was no edema in the lower extremities. Neurological examination showed equal, round pupils with sensitive light reflexes, and restricted bilateral eye abduction. Other neurological examinations, including cranial nerves, sensory nerves, and motor nerves, were normal. Blood tests, urinalysis, coagulation function, D-dimer, and erythrocyte sedimentation rate (ESR) were normal. Tests for homocysteine, C-reactive protein (CRP), glucose, cardiac enzymes, amylase, calcium, magnesium, and phosphorus were also normal. Liver and kidney function [ALT: 91 U/L (Ref: 9–50 U/L), GGT: 192 U/L (Ref: 10–60 U/L), direct bilirubin: 8.4 μmol/L (Ref: ≤8.0 μmol/L), creatinine: 47 μmol/L (Ref: 59–104 μmol/L), uric acid: 178 μmol/L (Ref: 208–428 μmol/L)], lipid analysis (total cholesterol: 6.02 mmol/L, LDL cholesterol: 3.86 mmol/L, apolipoprotein B: 1.11 g/L), and immunological tests (immunoglobulin M: 3.17 g/L) showed some abnormalities. Tests for TP-TRUST, Treponema pallidum antibodies, HIV antibodies, glycated hemoglobin, rheumatoid factor, antistreptolysin O, brain natriuretic peptide (BNP), thyroid function, fecal analysis, and fungal examination were normal. Hepatitis B tests showed positive results for surface antibody, e antibody, and core antibody. Tumor markers were negative. Cervical spine magnetic resonance imaging (MRI) was normal. Lumbar puncture and cerebrospinal fluid (CSF) analysis showed clear, colorless fluid with positive Pandy’s test (2+), red blood cells: 102/μL, white blood cells: 10/μL, neutrophils: 32%, lymphocytes: 63%, monocytes: 5%. CSF biochemistry showed protein: 971.0 mg/L, glucose: 4.25 mmol/L, chloride: 123.3 mmol/L; lactate dehydrogenase (LDH): 26 U/L, Adenosine deaminase (ADA): 0 U/L. Cryptococcal, bacterial cultures, and acid-fast staining were negative. Sarcoid optic neuropathy may present with manifestations such as hilar lymphadenopathy or skin nodules, potentially elevated serum Angiotensin Converting Enzyme (ACE) levels, granulomas around the optic nerve on imaging. This patient showed no hilar lymphadenopathy or skin nodules. Furthermore, MRI revealed no perineural granulomas, leading to the exclusion of sarcoid optic neuropathy. Additionally, the absence of necrotic lesions on MRI ruled out toxoplasmic optic neuropathy as a primary consideration. Nevertheless, CSF demyelinating antibody testing revealed positive MOG IgG antibody (Live Cell-Based Assay, normal Ref: negative) at 1:10 titer, and oligoclonal bands were negative. HEV IgM antibody [Hepatitis E Virus IgM Antibody Detection Kit (Enzyme-Linked Immunosorbent Assay) of Wantai Biopharm, and Shanghai Kehua Bio-Engineering] was positive. Cranial MRI showed bilateral optic nerve swelling with abnormal signals and slight fluid accumulation in the optic nerve sheath, consistent with optic neuritis (Figure 2A). MOG antibody-associated optic neuritis, likely related to HEV infection, was considered.

Figure 2 The patient’s imaging results. (A) The result of cranial MRI on May 2. (B) The result of orbital MRI on May 13.

The patient received methylprednisolone 500 mg daily (with gradual tapering after symptom relief), human immunoglobulin 25 g daily for five days, neurotrophic treatment (mecobalamin injection 1 mL daily, thiamine tablets 25 mg three times daily), gastric protection (rabeprazole tablets 20 mg daily), calcium supplementation (calcium carbonate D3 tablets 600 mg daily), and comprehensive liver protection and electrolyte balance treatment.

After treatment, the patient’s visual acuity improved to VOD: 0.8, VOS: 0.8 on May 9, OCT showed normal result. His optic disc edema had reduced, and visual field defects showed significant improvement compared to previous findings, and the symptoms of eye pain have improved. A lumbar puncture on May 10 showed decreased CSF protein levels. By May 12, liver and kidney function indices were normal. An orbital MRI on May 13 compared to the May 3 cranial MRI showed improved bilateral optic nerve swelling and reduced fluid in the optic nerve sheath (Figure 2B). The patient’s symptoms improved, and he was discharged on May 14 with advice to follow up in the neurology outpatient clinic. As of this writing, the patient has no discomfort and is fully recovered. The clinical course of the patient were showed in Figure 3.

Figure 3 The clinical course of the patient. ALT: alanine aminotransferase (Ref: 9–50 U/L); AST: aspartate aminotransferase (Ref: 15–40 U/L); GGT: γ-glutamyl transferase (Ref: 10–60 U/L); TBIL: total bilirubin (Ref: ≤23.0 μmol/L); DBIL: direct bilirubin (Ref: ≤8.0 μmol/L); Scr: serum creatinine (Ref: 59–104 μmol/L). Abbreviations: HEV, hepatitis E virus; VOD, vision of the right eye; VOS, vision of the left eye; OCT, optical coherence tomography; RAPD, relative afferent pupillary defect; CSF, cerebrospinal fluid; MOG, Myelin oligodendrocyte glycoprotein; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imaging.

Discussion

Neurological involvement in HEV infection is not uncommon, but many aspects remain unclear. Known neurological conditions associated with HEV infection include radiculopathies and plexopathies (Guillain-Barré syndrome, neuralgic amyotrophy, and meningoradiculitis), central nervous system disorders (meningoencephalitis, cerebral ischemia, seizures or epilepsy, transverse myelitis), neuropathies (polyneuritis, peripheral neuropathies, idiopathic facial nerve palsy, oculomotor nerve palsy, vestibular neuritis), and neuromuscular junction and muscle diseases (myositis, myasthenia gravis).^11,12 This study reports a rare case of MOG antibody-associated optic neuritis related to HEV infection, providing additional reference for neurological complications in HEV infection.

MOG is a minor component of the outermost layer of the myelin sheath in the central nervous system (CNS), expressed on the surface of oligodendrocytes, contributing to myelin adhesion and integrity.^13,14 MOG antibody-associated disease (MOGAD) is a CNS autoimmune disorder diagnosed by positive serum MOG-IgG antibodies and characteristic pathological features.¹⁵ The exact pathogenesis remains unclear, with some suggesting infections as initial triggers inducing autoimmunity.¹⁶ However, no specific pathogens have been identified, and many MOGAD patients do not report infection-related antecedent symptoms.¹⁶ In the pathogenesis of MOGAD, MOG-specific B cells, plasma cells, and their produced antibodies (anti-MOG antibodies) play a central role. Research indicates that these MOG-specific B cells and antibodies can activate effector T cells via antigen-presenting cells within the central nervous system.^17,18 Subsequently, they cross the blood-brain barrier, bind to MOG antigens expressed on target structures, and initiate a series of pathogenic processes.^19–22 Specifically, anti-MOG antibodies (IgG1) bind to MOG expressed on the surface of myelin and oligodendrocytes, leading to myelin damage and demyelination through mechanisms such as antibody-dependent cellular cytotoxicity or complement activation.^19,20 Concurrently, activated MOG-specific B cells and plasma cells further activate CD4+ T cells and macrophages, promoting the release of pro-inflammatory cytokines such as IL-6, IL-17, and TNF-α, which exacerbates inflammatory responses and myelin injury.^21,22 The characteristic pathological hallmarks of MOGAD include perivenous and confluent white matter demyelination, MOG-dominant myelin loss, intracortical demyelination, inflammatory infiltrates predominantly composed of CD4+ T cells and granulocytes, complement deposition within active lesions, partial axonal preservation, and reactive gliosis. These pathological features are further supported by the presence of MOG-specific CD4+ T cells within patient lesions, confirming their critical role in disease pathogenesis.^21,22

MOGAD can present as various clinical syndromes, including acute disseminated encephalomyelitis (ADEM), autoimmune encephalitis, optic neuritis, and transverse myelitis (TM). Optic neuritis is the most common initial manifestation in adults (50% of cases), and about 80% of MOGAD patients develop optic neuritis at some point, characterized by varying degrees of vision loss and almost always accompanied by eye pain, often exacerbated by eye movement.^23,24 Studies suggest that MOG antibody-associated optic neuritis may be related to vascular damage, with MOG antibodies potentially causing retinal destruction and degeneration through perivascular inflammation rather than direct damage to retinal ganglion cells and their axons.²⁵

In this case, the patient was diagnosed with acute hepatitis E based on positive serological HEV antibodies, with normalized liver and kidney function indices after symptomatic treatment. However, the patient subsequently developed blurred vision, with no significant eyelid congestion or edema, but restricted bilateral eye abduction. Serological and CSF tests were positive for HEV, and CSF MOG antibody testing was also positive. Cranial MRI showed bilateral optic nerve swelling with abnormal signals and slight fluid accumulation in the optic nerve sheath (Figure 2A), consistent with MOG antibody-associated optic neuritis, likely related to acute HEV infection. Due to limited testing capabilities at our hospital, HEV RNA detection was not available, which constitutes a limitation of this study as it resulted in insufficient evidence. However, during the period when the patient exhibited symptoms of HEV infection and optic neuritis, no other potential causative factors for optic neuritis were identified. Moreover, the patient’s optic neuritis symptoms significantly improved with symptomatic therapy, providing supportive evidence for the association between HEV infection and optic neuritis.

Studies have shown that hepatitis-related viral infections can stimulate immune responses, leading to abnormal autoantibodies and various autoimmune diseases.^26,27 HEV is typically an acute infection, and the relationship between HEV and autoimmunity remains controversial. However, HEV infection has been associated with peripheral nervous system autoimmune diseases, such as Guillain-Barré syndrome.^28,29 Additionally, HEV infection is linked to central nervous system inflammatory diseases, with some patients developing vision loss following HEV infection.¹⁰ These findings suggest that HEV infection may be associated with autoimmune diseases and optic neuritis. This case provides valuable evidence for exploring the relationship between HEV and autoimmunity.

Existing studies have extensively explored the association between infections and MOGAD, indicating that various pathogenic infections-including viral, bacterial, mycoplasma, and chlamydial infections-may be linked to the onset of the disease. Common clinical manifestations include optic neuritis, myelitis, and acute disseminated encephalomyelitis.³⁰ Viruses implicated in MOGAD comprise SARS-CoV-2, human immunodeficiency virus (HIV), varicella-zoster virus, human herpesvirus type 6, Zika virus, mumps virus, herpes simplex virus (genital), adenovirus, rubella virus, and dengue virus.³⁰ Pathogen-induced autoimmunity is thought to arise through mechanisms such as molecular mimicry, bystander activation, superantigen activity, and epitope spreading.^31,32 Among these, molecular mimicry is one of the most widely cited theories. It occurs when pathogen-derived peptides share structural homology with human peptides, leading to the production of cross-reactive antibodies and effector immune cells that can target host tissues via autoimmune mechanisms.³³ In the context of MOGAD, pathogens including SARS-CoV-2, Mycoplasma, influenza A virus, varicella-zoster virus, and Chlamydia have been suggested to trigger the production of anti-MOG antibodies through molecular mimicry.^33–36 In the present case, CSF demyelinating antibody testing revealed a positive result for MOG-IgG, suggesting that HEV infection may also have induced MOGAD via a molecular mimicry pathway.

Acute HEV infection is generally self-limiting, with most patients fully recovering. During the acute phase, patients should rest, maintain a light diet, and receive hepatoprotective, transaminase-lowering, and jaundice-reducing medications, typically without antiviral treatment. For this case, after diagnosing acute hepatitis E, the patient was treated with magnesium isoglycyrrhizinate, ademetionine, bicyclol tablets, and ursodeoxycholic acid tablets. Following the diagnosis of MOG antibody-associated optic neuritis, immunotherapy, including steroids and neurotrophic drugs, was administered, resulting in improvement and discharge.

Conclusion

This report describes a rare case of MOG antibody-associated optic neuritis related to HEV infection in an immunocompetent patient. Unlike previous reports of HEV-related neurological infections, this patient initially presented with elevated liver enzymes, followed by blurred vision. MRI and CSF tests confirmed HEV-related MOG antibody-associated optic neuritis. This case, along with previous studies, suggests considering HEV infection in patients with acute neurological impairment and significantly elevated liver enzymes. Following a diagnosis of acute hepatitis E, clinicians should be vigilant for potential neurological complications.