Bilateral immune-mediated optic neuritis following HPV vaccination in an adolescent: diagnostic challenges and a rare clinical presentation

Abstract

Background

Optic neuritis (ON) is an inflammatory condition of the optic nerve that causes damage to the myelin sheath and nerve fibers, leading to acute visual impairment. While often idiopathic, ON is increasingly recognized in association with immune-mediated triggers, including post-vaccination phenomena. The proposed pathophysiology involves molecular mimicry, where vaccine-induced antigens trigger a cross-reactive immune response against myelin basic protein. Distinguishing vaccine-associated ON from primary demyelinating diseases, such as Multiple Sclerosis (MS) or Neuromyelitis Optica Spectrum Disorder (NMOSD), poses as significant diagnostic challenge, particularly in adolescents. Prompt differentiation is essential to guide clinical management and therapeutic interventions.

Case presentation

We report a case of a previously healthy 15-year-old female who presented with a two week history of painful visual loss in the right eye, occurring seven days after quadrivalent HPV vaccination. Examination revealed marked asymmetry in visual acuity and a right-sided relative afferent pupillary defect (RAPD). Other cranial nerves (III–XII), motor, sensory, and cerebellar examinations were unremarkable; no papilledema was noted. Laboratory investigations and cerebrospinal fluid (CSF) analysis were normal, except for mild microcytic anemia. MRI of the brain, orbits, and spine demonstrated bilateral optic nerve and perineural enhancement without evidence of demyelinating plaques, confirming bilateral optic neuritis. Autoimmune serology and metabolic panels (ANA, B12, folate, zinc) were within normal limits; serum AQP4-IgG and MOG-IgG were not available at the time of writing the report. The patient received five days of intravenous methylprednisolone, resulting in substantial visual recovery at follow-up.

Conclusion

This case demonstrates the diagnostic complexity of optic neuritis in adolescents and highlights the necessity of maintaining a high index of clinical suspicion for vaccine-associated immune-mediated events. Although bilateral optic neuritis temporally associated with vaccination is rare and the precise pathophysiological link remains a subject of ongoing debate, a thorough assessment of the clinical chronology and temporal relationship to immunization can facilitate a prompt diagnosis. Timely intervention with corticosteroids is essential to mitigate progression and prevent permanent visual sequelae. However, long-term longitudinal surveillance is mandatory to distinguish such monophasic episodes from the initial manifestation of a chronic demyelinating disease.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12883-026-05052-8.

Introduction

Optic neuritis (ON) is an inflammatory condition of the optic nerve characterized by myelin sheath damage and secondary axonal injury. Retinal ganglion cells (RGCs) undergo apoptosis as a result of this process, which may cause long-term visual impairment or irreversible vision loss. The exact cause of ON is frequently still unknown despite a great deal of research. However, several causes have been identified and linked, such as environmental triggers, infectious agents, autoimmune disorders, demyelinating diseases, and systemic inflammatory illnesses [1].

Optic neuritis is a leading cause of acute unilateral vision loss, orbital pain, and impaired color vision. Notably, ON is the initial clinical manifestation in approximately 20% of patients diagnosed with Multiple Sclerosis (MS) [2]. The annual incidence of optic neuritis varies geographically, with a reported rate of approximately five cases per 100,000 people in Central Europe and similar regions [3]. This figure often serves as a baseline for assessing trends in demyelinating diseases, although a higher incidence has been reported in subgroups with Neuromyelitis Optica Spectrum Disorder (NMOSD) or other autoimmune conditions [4].

In order to minimize long-term axonal damage and maximize vision recovery, early detection and management are crucial. Early identification and therapy, usually with high-dose corticosteroids, can lessen the inflammatory insult to the optic nerve and speed up visual recovery [5]. We describe a 15-year-old girl who had unilateral visual complaints and eventually developed bilateral optic neuritis following vaccination. Ophthalmological tests and MRI revealed bilateral optic nerve damage despite the unilateral clinical complaint.

Case presentation

A previously healthy 15-year-old female presented to the emergency department with a two-week history of painful eye movement and progressive vision loss in the right eye. The systemic neurological review was negative for associated symptoms. On initial assessment, the patient was alert and hemodynamically stable (Temperature: 37 °C, Heart Rate: 88 Bpm, Blood Pressure: 126/78 mmHg, and SpO2 of 99%). The patient had received the quadrivalent human papillomavirus vaccine (Gardasil) seven days prior to the onset in the Kingdom of Saudi Arabia, where the vaccine is recommended but not mandatory. Family and social histories were unremarkable. Physical examination revealed diminished visual acuity in the right eye, measured at 6/12, while the left eye demonstrated a baseline acuity of 6/6. Color vision testing using Ishihara plates revealed impairment in the right eye (10/14) compared to intact color vision in the left eye (14/14). A right-sided relative afferent pupillary defect (RAPD) was noted, Slit-lamp examination confirmed clear corneas and lenses bilaterally with pupils that were round and reactive to light. Fundoscopy showed no evidence of papilledema, and the remainder of the cranial nerve examination was unremarkable.

Initial laboratory investigations demonstrated a normal C-reactive protein (CRP) level and an erythrocyte sedimentation rate (ESR) of 2 mm/hr. A comprehensive metabolic panel (CMP) confirmed stable renal function, normal blood glucose levels, and unremarkable hepatic enzymes. Serum electrolytes revealed mild, clinically insignificant hyponatremia and hypokalemia. A complete blood count showed mild microcytic anemia but was otherwise unremarkable (Table 1).

Table 1.

Baseline hematological, inflammatory, and metabolic parameters upon admission, including reference ranges

Parameter	Patient value	Reference value
WBC	7.12	(4.5–11.4) (10*9/L)
Hemoglobin	11.5	(12–15.6 g/dL)
MCV	78. 7	(78–93)(fL)
CRP	2.5 mg/l	(0–10) (mg/L)
ESR	2 mm/h	0–20 mm/hr
Serum Creatinine	60.1 µmol/L	44–88 µmol/L
BUN (Blood Urea Nitrogen)	3.3 mmol/L	3.2–6.4 mmol/L
ALT (Alanine Aminotransferase)	13.54 U/L	8–27 U/L
AST (Aspartate Aminotransferase)	13.35 U/L	16–28 U/L
Alkaline Phosphatase (ALP)	68 U/L	76–419 U/L
Serum Sodium	133 mmol/L	139–146 mmol/L
Serum Potassium	3.5 mmol/L	3.82–5.49 mmol/L
Total Bilirubin	4.4 µmol/L	3.4–12.0 µmol/L

CSF study was unremarkable with normal values and parameters as shown in the following table (Table 2).

Table 2.

Results of cerebrospinal fluid (CSF) biochemical and cytological analysis

Parameter	Patient value	Reference value
Protein	0.3	0.15–0.45 g/L
WBC - BF	0	0–5 cells/µL
RBC	53	0 cells/µL
Glucose	3.6 mmol/L	2.2–3.9 mmol/L (or 40–70 mg/dL)
Appearance	clear - colorless	Clear and colorless

Subsequent MRI of the brain, orbits, and spine with contrast specifically the coronal section (Fig. 1) and axial section (Fig. 2) and (Fig. 3) of the brain and orbits—provided the definitive diagnosis. The imaging demonstrated bilateral optic nerve enhancement extending into the perineural area, suggestive of bilateral optic neuritis, with no evidence of demyelinating plaques in the cerebral white matter.

Fig. 1.

Coronal T2-weighted, fat-suppressed magnetic resonance imaging (MRI) of the orbits. The image demonstrates bilateral, symmetrical signal abnormalities within the intraorbital segments of the optic nerves. There is marked, diffuse T2-hyperintensity and moderate expansion of the optic nerve diameters, consistent with significant inflammatory edema. (Arrows indicate the areas of maximal nerve thickening and hyperintensity)

Fig. 2.

Axial T2-weighted, fat-suppressed MRI sequence at the level of the mid-orbits. The image reveals bilateral, longitudinal signal hyperintensity involving optic nerves. These findings are characteristic of acute optic neuritis. No associated lesions are visualized within the visualized portions of the brain parenchyma at this level. (Red circles highlight the diffuse high-signal intensity along the course of the optic nerves)

Fig. 3.

Axial post-contrast T1-weighted, MRI of the orbits. The image demonstrates active contrast enhancement within the intraorbital segments of the optic nerves. The hyperintensity highlights acute inflammatory process, tracking longitudinally along the nerve parenchyma

Serum ANA, zinc, folate, vitamin B12, and other laboratory tests were all within the anticipated normal range. Neuromyelitis Optica Spectrum Disorder and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease were the main differential diagnosis due to the severity and bilateral nature of the presentation. AQP4-IgG and MOG-IgG testing were not accessible at the facility at the time of admission and report writing, despite the fact that this required additional immunological correlation. The patient was admitted to the general neurology ward and received a five-day course of intravenous methylprednisolone, which resulted in significant improvement in visual acuity.

The patient clinical progression was monitored closely, and a short-term assessment was performed that showed early signs of recovery the patient was vitally stable and reported subjective clinical improvement. Objective visual acuity reassessment confirmed this trajectory of clinical improvement, with improvement noted in both eyes 6/7.5 in the right eye, 6/6 in the left eye. Follow-up neuro-ophthalmological exam showed a completely resolved RAPD and no signs of acute disc swelling in either optic nerve.

A comprehensive reassessment follow up evaluation was subsequently conducted one month later included a follow up MRI of the brain and orbits to monitor the resolution of the inflammatory process, Comparison with the initial study from the previous month The optic nerves demonstrated normal caliber and a lack of the previously noted diffuse T2-hyperintensity. The post-contrast images showed only mild residual enhancement in the retro-orbital fat around the optic nerves, slightly more pronounced on the right, consistent with resolving optic neuritis. There were no signs of new acute inflammatory lesions or demyelinating plaques.

The potential causal relationship between the quadrivalent HPV vaccination and the onset of bilateral optic neuritis was evaluated using the World Health Organization (WHO) Causality Assessment for Adverse Events Following Immunization (AEFI). Given the clear temporal sequence (onset seven days post-vaccination), the recognized literature regarding post-vaccination demyelination, and the absence of alternative etiologies on neuroimaging and CSF analysis, the event was categorized as a Consistent Causal Association (A1 Probable) The case therefore represented an acute, severe episode of bilateral optic neuritis in an adolescent female, potentially triggered by a recent vaccination, requiring urgent investigation to distinguish between monophasic isolated optic neuritis and an early presentation of a chronic demyelinating disease.

Discussion

Pathophysiology of optic neuritis and immune-mediated mechanisms

The inflammatory, immune-mediated demyelination of the optic nerve is the hallmark of optic neuritis (ON). Both innate and adaptive immune responses are known individuals in the underlying pathophysiology, which is usually brought on by cellular immunological attacks on the myelin sheath, the generation of autoantibodies, and molecular mimicry [6]. The distinguishing characteristic is demyelination, which causes acute visual symptoms by severely impairing nerve signal transmission due to the loss of the protective myelin layer [7]. Additionally, when T cells and macrophages enter the optic nerve, they release chemokines and cytokines that harm oligodendrocytes that produce myelin, causing an inflammatory cascade [6].

Comparison of unilateral vs. bilateral optic neuritis

Optic neuritis may manifest either as unilateral or bilateral involvement, which is often further categorized into typical or atypical forms based not only on the designated etiology but also on the basis of clinical patterns [8]. While unilateral presentation is a common presentation in adults and frequently associated with Multiple Sclerosis (MS) [9, 10], bilateral involvement is categorized as simultaneous, sequential, or recurrent often suggests idiopathic, parainfectious, or autoimmune etiologies like NMOSD or MOGAD [7, 11, 12] One noteworthy aspect of this case was that, despite bilateral optic nerve enhancement on MRI were appreciated, there was unilateral vision impairment on clinical presentation. This clinical-radiographic dissociation is consistent with subclinical inflammation, a phenomenon where imaging evidence of disease precedes or exceeds functional deficit. Literature suggests that in acute optic neuritis, the degree of inflammatory demyelination or axonal dysfunction in the contralateral nerve may remain below the appreciated threshold required to trigger symptomatic vision loss or a measurable pupillary defect. Similar subclinical events are well known in other neurological disorders, such as silent lacunar infarcts and radiologically isolated syndrome (RIS), exhibited similar phenomena where imaging shows structural damage without accompanying clinical symptoms [13, 14].

Distinguish features of MS, NMOSD, and MOG-AD

While MS, NMOSD, and MOGAD all involve CNS inflammation, they differ not only in clinical presentation but also in pathophysiology and prognosis. NMOSD primarily affects middle-aged females of Afro-Caribbean or Asian descent and is characterized by AQP4-IgG antibodies and severe, often bilateral, attacks with poor recovery [15, 16]. MOGAD exhibits a biphasic incidence pattern and is distinguished by MOG-IgG antibodies, frequently presenting as bilateral optic neuritis or transverse myelitis with a generally favorable recovery compared to NMOSD [17, 18]. In contrast, MS-related optic neuritis is typically unilateral and associated with characteristic MRI findings such as periventricular plaques or Dawson’s fingers [16]. In this case, vaccine-associated optic neuritis was suspected over these syndromes due to the absence of MS-typical brain lesions, and the distinct temporal latency following HPV vaccination. These differences are summarized in Table 3.

Table 3.

Differential Features of NMOSD, MOGAD, and Vaccine-Induced Optic Neuritis

Feature	NMOSD (AQP4+)	MOGAD	Vaccine-Induced ON
Typical Trigger	Idiopathic/Autoimmune	Idiopathic/Autoimmune	1–4 weeks post-vaccination
Antibody Status	AQP4-IgG Positive [15]	MOG-IgG Positive [16]	Negative (as in this case)
MRI Findings	Long-segment (> 1/2 nerve) [15]	Puffy, anterior enhancement [16]	Localized or bilateral; resolves
Spine Involvement	Longitudinally Extensive Transverse Myelitis common [15]	Short or long segments [16]	Typically absent
Prognosis	Often poor; high relapse [15]	Good recovery; moderate relapse [16]	Excellent recovery; low relapse

Imaging patterns and diagnostic significance (perineural enhancement, absence of plaques)

Neuroimaging is crucial for the diagnosis, prognosis, and differentiation of various forms of optic neuritis. Contrast enhancement of the optic nerve, usually seen in fat-suppressed, post-contrast T1-weighted sequences, is the most frequent MRI finding linked to optic neuritis. This enhancement frequently coincides with clinical severity and can be either localized or extended along large segments of the nerve [19]. Optic perineuritis, which is distinct from multiple sclerosis (MS) or conventional optic neuritis, is strongly suggested by perineural enhancement, in which the contrast surrounds the nerve sheath rather than the nerve itself. This characteristic pattern is strongly diagnostic for optic perineuritis and differentiates it from other inflammatory conditions; in contrast, MS-related optic neuritis typically exhibits notable enhancement within the nerve parenchyma, particularly in the intraorbital segment [20]. One important diagnostic finding is the absence of brain plaques on imaging. The characteristic periventricular plaques, often referred to as “Dawson’s fingers,” are characteristic signs of MS. When these are absent and the clinical picture includes atypical features such as bilateral involvement, chiasmal extension, or long-segment optic inflammation an alternative etiology such as NMOSD or MOGAD must be investigated thoroughly. Extensive and bilateral optic nerve enhancement, frequently involving the anterior and canalicular segments or the optic chiasm, is more common and in favor of the diagnosis of NMOSD and MOGAD. Further differentiation is clinically important NMOSD lesions are frequently longer and may be associated with spinal cord involvement (such as LETM), while MOGAD imaging may demonstrate large, “fluffy” lesions that typically resolve completely [21].

Review of literature on post-vaccination optic neuritis (frequency, proposed mechanisms)

With a mean start of 10.8 days (typically ranging from 1 day to 1 month) after injection, a noteworthy finding is that post-vaccination optic neuritis (ON) has been found to be the most common neurological adverse event across nine different vaccines [22].

However, large-scale epidemiological data, including robust case-control and retrospective cohort studies, confirm that the absolute incidence of ON following immunizations (including HPV and COVID-19) is exceptionally low, estimated between 0.2 and 18.6 cases per 10 million doses.This rate is typically within or below the baseline incidence of optic neuritis observed in the general population [23]. Most patients experience positive clinical outcomes. While ongoing evidence and data suggest a marginal increase in reporting rates for COVID-19 vaccines when compared to influenza vaccines, the absolute risk remains exceptionally small [23]. Immune-mediated processes are the primary mechanisms proposed behind the post-vaccination ON. Other leading theories include systemic immune hyperactivation (potentially triggered by vaccine adjuvants), molecular mimicry where the immune response to vaccine antigens cross-reacts with myelin proteins in the optic nerve and the induction of demyelinating processes in genetically predisposed individuals. Furthermore, rare reports of post-vaccination ON associated with MOG-IgG and AQP4-IgG suggest that immunization may, in infrequent instances, unmask an underlying sensitivity to MOGAD or NMOSD [24].

From an immunodiagnostic perspective, there are currently no validated, vaccine-specific serum or cerebrospinal fluid (CSF) biomarkers capable of establishing an absolute, definitive cause-and-effect relationship between Human Papillomavirus (HPV) immunization and optic nerve demyelination. While diagnostic workups routinely utilize established biomarkers such as (AQP4-IgG) and (MOG-IgG) to rule out primary demyelinating diseases like NMOSD and MOGAD, a specific marker for vaccine-induced autoreactivity does not yet exist. Consequently, establishing a plausible association relies heavily on a careful assessment of clinical chronology, the documentation of an appropriate post-vaccination latency period, the exclusion of alternate infectious or metabolic etiologies, and the application of standardized causality assessment frameworks such as those provided by the World Health Organization (WHO). Post-HPV vaccination optic neuritis is an exceedingly rare occurrence, documented only in sporadic case reports and small series. Both unilateral and bilateral presentations have been reported, occasionally in association with other central nervous system demyelinating disorders. In previously healthy children and adolescents, and the majority of these events occurred within days to a few weeks following HPV vaccine administration [25, 26].

Conclusion

This case underlines the rarity of bilateral involvement following immunizations and the diagnostic difficulties of the many illnesses presenting with optic neuritis. Although unilateral or bilateral post-vaccination optic neuritis is rare, the exact pathophysiological processes are still up for debate. The literature has linked theories like molecular mimicry and other immunological phenomena, but conclusive causal relationships frequently require substantial clinical correlation. In this particular case, a prior immunization was temporally linked to the development of bilateral ocular neuritis. A more focused differential diagnosis was made possible by a methodical approach to the clinical history and the chronological order of occurrences. This emphasizes the need for comprehensive research and prompt action to slow the progression of the disease and avoid long-term visual consequences.

Author contributions

All authors contributed to the conception and design of the study. MSG and HIA wrote the first draft of the manuscript. FA and MA critically revised the manuscript for intellectual con-tent. All authors critically revised the manuscript and approved the final version.”

Funding

The study was self-funded by the authors.

Data availability

All data supporting the findings of this case report are contained within the article. Additional anonymized clinical information is available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Verbal and written informed consent for publication of clinical details and/or clinical images was obtained from the parents of the patient.

Competing interests

The authors declare no competing interests.